Q2. 2021/06/21 Nanotein拿到Biotech Top 10時,有揭露已經給幾家做CAR-T的公司,送去做Beta-testing(驗收測試)了!當時Polaris北加廠生產研究用的nanoparticles!2021年底打算生產GMP的reagent! 2022/04/15 Nanotein的官網有聘請到一位LNP的專家Zach Imam,同時也看到了test kit的產品兩瓶STEM-T and APEX-T reagent! 並同時呈現優於競爭對手 CD8+ Tscm cells 55X、CD4+ Tscm cells 13X、Total T cells 6X!
我們知道世界上做CAR-T medium reagent,最大最好的有Thermo Fisher, Bio-Techne R&D Systems, Agilent technologies…….. 請問 a. test kit已經做出來了,距離接單量產之間還有技術上的困難嗎? b. 所謂的競爭對手是這幾家嗎? c. 對方有沒有對Nanotein的產品產生過興趣? d. 有談過合作、代理、授權、併購之類的嗎?
Q3. 成都廠建築物及佔地面積是北加廠的十倍之大,從2022/04/11上市前公開說明書看到,目前是在做ADI的凍乾製程為主。員工數從去年的27人→增加到33人! 剛向母公司借貸的2千萬美金,請問 a. 是要增加做E. coli的生產線嗎?是300L產線嗎? b. 有沒有拿到中國的cGMP? c. 是不是要做Nanotein的medium需要的抗體? d. 有提到也要做哺乳動物細胞,這是紅海市場,考量點是?
高雄現埸 琛哥+CFO回答 a. 是的,是做E. coli的生產線。 老揚:是300L產線嗎? 答:是的。 老揚:是disposable嗎? 答:是的,是一次性的。
Q5. 2022/04/26法說有說,北加廠產線接近滿載!但是目前只有簽約三家代工,Helix BioMedix and Primmune 兩家,自2019年開始的營收貢獻看,不可能讓300L產線的北加廠產線接近滿載!請問 a. 是因為第三家代工→Nanotein有大單量產才滿載的嗎? b. 從2022/04/11上市前公開說明書看到,2023年現金收支預測,2023/07月開始,營收十級跳為每月7325萬,這是預估Nanotein的代工收入?還是MPM的ADI代工收入? 美女CFO回信: (a) 北加工廠同時也要生產ADI 啊,所以產能是有限的。 (b)2023年營收的估計部分是來自Nanotein ,另一部分是MPM拿到藥證後的估計銷貨收入。
Q6. 北加廠300L產線就可以做很多事了,請問 a. 與UCI Dr. Felgner的合作,進度如何?是否已掌握關鍵LNP及RNA修飾技術? b. 會等到宜蘭廠成立後才有mRNA代工嗎?
高雄現埸 老揚:跟UCI的簽約已經半年了,剩半年,關鍵技術轉移順利嗎? 琛哥:跟UCI做的是universal vaccine(所有冠狀病毒株和變種病毒株)!現在是second quarter,每個禮拜都會開會,進度很順利!蔡博士是Felgner的得意門生,Felgner的老婆也是台灣人,他們關係非常好!Felgner跟美國政府申請到一個project,他同時也把Polaris納入成這個project的技術公司! 美女CFO:北加廠主要還是做ADI為主! 「鬼叔」:從以上的對話推估,北加廠ADI、成都廠Nanotein、宜蘭廠mRNA的主軸是成型了!當然只是小量生產臨床實驗用的ADI、mRNA universal vaccine、Nanotein medium test kit,都將是北加廠的工作無誤! 最重要的是→關鍵技術轉移順利!Polaris也間接變成拿美國政府計劃資金的公司!
Q7. 感謝公司一直在創造公司的價值,關於投資人最關心的ADI-PEG 20授權/賣斷,請問 a. 有意願合作的藥商們,有來接觸過嗎? b. 從2022/04/26法說看到公司傾向採分區授權/賣斷?(如大中華地區、非大中華地區!),目前公司的想法是 會一次賣斷?還是會以第二張藥證、第三張藥證為milestone?還是會以銷售額達標為milestone? c. 目前,那一個區域談的比較順?
2. 2021/06/21 Nanotein拿到Biotech Top 10時,有揭露已經給幾家做CAR-T的公司,送去做Beta-testing(驗收測試)了!當時Polaris北加廠生產研究用的nanoparticles!2021年底打算生產GMP的reagent! 2022/04/15 Nanotein的官網有聘請到一位LNP的專家Zach Imam,同時也看到了test kit的產品兩瓶STEM-T and APEX-T reagent! 並同時呈現優於競爭對手 CD8+ Tscm cells 55X、CD4+ Tscm cells 13X、Total T cells 6X! 我們知道世界上做CAR-T medium reagent,最大最好的有Thermo Fisher, Bio-Techne R&D Systems, Agilent technologies…….. 請問 a. test kit已經做出來了,距離接單量產之間還有技術上的困難嗎? b. 所謂的競爭對手是這幾家嗎? c. 對方有沒有對Nanotein的產品產生過興趣? d. 有談過合作、代理、授權、併購之類的嗎?
3. 成都廠建築物及佔地面積是北加廠的十倍之大,從2022/04/11上市前公開說明書看到,目前是在做ADI的凍乾製程為主。員工數從去年的27人→增加到33人! 剛向母公司借貸的2千萬美金,請問 a. 是要增加做E. coli的生產線嗎?是300L產線嗎? b. 有沒有拿到中國的cGMP? c. 是不是要做Nanotein的medium需要的抗體? d. 有提到也要做哺乳動物細胞,這是紅海市場,考量點是?
4. mRNA代工,楊育民董事有介紹公司與Moderna交流過嗎?
5. 2022/04/26法說有說,北加廠產線接近滿載!但是目前只有簽約三家代工,Helix BioMedix and Primmune 兩家,自2019年開始的營收貢獻看,不可能讓300L產線的北加廠產線接近滿載!請問 a. 是因為第三家代工→Nanotein有大單量產才滿載的嗎? b. 從2022/04/11上市前公開說明書看到,2023年現金收支預測,2023/07月開始,營收十級跳為每月7325萬,這是預估Nanotein的代工收入?還是MPM的ADI代工收入?
6. 北加廠300L產線就可以做很多事了,請問 a. 與UCI Dr. Felgner的合作,進度如何?是否已掌握關鍵LNP及RNA修飾技術? b. 會等到宜蘭廠成立後才有mRNA代工嗎?
1. 2022/02/06重訊公告,MPM有拿到FDA fast track and EAP,我們知道fast track是rolling review,而滾動式審查並不需要等2022/08底的解盲數據,解盲之前就可以先提供部分資料審查,請問有進入section 1了嗎? Ans. 為免送了section1,在準備section2時又一直要回覆FDA關於section1的問題,琛哥的策略是→等臨床數據出來再送!因為FDA是臨床醫師在主導的,只要臨床數據漂亮,其他的都會審的比較寬鬆! 琛哥額外透露的專業知識 - Rolling submission可以分clinical data, preclinical data,製藥作業流程等…. - 你先送section1,FDA也未必會先審!
2. STS軟組織肉瘤phase 2數據,從去年的ASCO資料可看到,可以降低化療40%的劑量,請問 a. Phase 3會按照化療降低40%的劑量來設計嗎? b. Phase 3預計啟動的時間迫在眉睫,應該會delay,請問進度上與Dr. Brian Van Tine開過PI會議了嗎? c. Breakthrough therapy有著落嗎? Ans. a. 會按照化療降低40%的劑量來設計 b. 2022/01/25已召開過一次committee會議 c. 沒有預計申請Breakthrough therapy了!
3. 肝癌單藥三期基因(SNP-WWOX-GG type)篩選已開始收案,收案人數150人,只有在台灣收案,沒有白人 請問 a. 沒有白人的三期數據,做完有可能拿FDA藥證嗎? b. 有沒有先與FDA開過Type B meeting之類的會議,有白紙黑字的協議或承諾嗎? c. 大陸CFDA藥證,是否也需要在大陸地區重做一次肝癌單藥三期基因(SNP-WWOX-GG type)篩選實驗? Ans. a. 美國相關收案困難度高,因為WWOX這個基因篩選,美國的process很複雜,台灣相對簡單,所以先在台灣收案,美國目前也有在進行中,越南有一家醫院也在談收案了 b. FDA有review過,FDA有comment公司有回覆,沒有什麼問題 c. 大陸預計用凍乾製劑做臨床(所以是需要另外收案的!大陸真麻煩!)
4. GBM腦癌,最近國外新聞一直報導的風風火火,05/27 05:00有ASCO poster abstract release phase IB data. 請問 a. phase 2/3什麼時候啟動?從2022/04/11上市前公開說明書「表八」中看到,p-117(內文頁面) p-170(pdf頁面) 2021年03月腦癌開始收錄第二期,建議劑量組受試者! 是真的嗎?還是時間點有寫錯了?也未見公告! b. 依然是林口長庚主導嗎?倫敦帝國大學會參與嗎? Ans. a. 應該是寫錯,不是「2021年03月腦癌開始收錄第二期」,是前6個病人的其中3個病人cohort 2→36mg/dl! phase 1 data四個月後會整理出來,之後就會啟動phase 2 至於是phase 2/3 or phase 2 alone→尚未決定! b. 沒有回答到!
5. Clinical trial gov上看到Opdivo+ADI 肝癌聯藥phase 2,ADI+venetoclax+Azacitindine血癌phase 1 其中都有看到BMS施貴寶的藥,請問 a. 這兩項實驗單純就是MD anderson的PI有興趣嗎? b. 北極星藥業有沒有與BMS,就「實驗合作方面」在交流? Ans. a+b. MD anderson是一個平台,公司沒有與BMS,就「實驗合作方面」在交流,就是MD anderson的PI有興趣而已!
1. 2022/02/06重訊公告,MPM有拿到FDA fast track and EAP,我們知道fast track是rolling review,而滾動式審查並不需要等2022/08底的解盲數據,解盲之前就可以先提供部分資料審查,請問有進入section 1了嗎?
2. STS軟組織肉瘤phase 2數據,從去年的ASCO資料可看到,可以降低化療40%的劑量,請問 a. Phase 3會按照化療降低40%的劑量來設計嗎? b. Phase 3預計啟動的時間迫在眉睫,應該會delay,請問進度上與Dr. Brian Van Tine開過PI會議了嗎? c. Breakthrough therapy有著落嗎?
3. 肝癌單藥三期基因(SNP-WWOX-GG type)篩選已開始收案,收案人數150人,只有在台灣收案,沒有白人 請問 a. 沒有白人的三期數據,做完有可能拿FDA藥證嗎? b. 有沒有先與FDA開過Type B meeting之類的會議,有白紙黑字的協議或承諾嗎? c. 大陸CFDA藥證,是否也需要在大陸地區重做一次肝癌單藥三期基因(SNP-WWOX-GG type)篩選實驗?
4. GBM腦癌,最近國外新聞一直報導的風風火火,05/27 05:00有ASCO poster abstract release phase IB data. 請問 a. phase 2/3什麼時候啟動?從2022/04/11上市前公開說明書「表八」中看到,p-117(內文頁面) p-170(pdf頁面) 2021年03月腦癌開始收錄第二期,建議劑量組受試者! 是真的嗎?還是時間點有寫錯了?也未見公告己開始收案! b. 依然是林口長庚主導嗎?倫敦帝國大學會參與嗎?
5. Clinical trial gov上看到Opdivo+ADI 肝癌聯藥phase 2,ADI+venetoclax+Azacitindine血癌phase 1 其中都有看到BMS施貴寶的藥,請問 a. 這兩項實驗單純就是MD anderson的PI有興趣嗎? b. 北極星藥業有沒有與BMS,就「實驗合作方面」在交流?
6. 感謝公司一直在創造公司的價值,關於投資人最關心的ADI-PEG 20授權/賣斷,請問 a. 有意願合作的藥商們,有來接觸過嗎? b. 從2022/04/26法說看到公司傾向採分區授權/賣斷?(如大中華地區、非大中華地區!),目前公司的想法是 會一次賣斷?還是會以第二張藥證、第三張藥證為milestone?還是會以銷售額達標為milestone? c. 目前,那一個區域談的比較順?
1. 2007/11/30 FDA approval Nexavar for first line tx. of unresectable HCC (藥商:德國Bayer;口服藥;2020專利已過!)
2. 2018/08/16 FDA approval Lenvima for first line tx. of unresectable HCC (藥商:日本Eisai;口服藥;對照組:Nexavar) (Lenvima 478 pk Nexavar 476的mOS是non-inferior to Nexavar→13.6月:12.3月)
3. 2020/05/29 FDA 因IMbrave150 mPFS數據優異(6.8:4.3)(mOS=尚未能判讀:13.2),approve TECENTRIQ and AVASTIN for first line tx. of unresectable HCC (藥商:Roche;IV給藥;對照組:Nexavar)
1. 2017/04/27 FDA approval Stivarga for second line tx. of unresectable HCC (藥商:德國Bayer;口服藥;對照組:Placebo)
2. 2019/01/14 FDA approval CABOMETYX®(cabozantinib) for second line tx. of unresectable HCC (藥商:Exelixis;口服藥;對照組:Placebo) 研究主持人:Ghassan K. Abou-Alfa,星友們對Ghassan不陌生吧?
3. 2019/05/10 FDA approval CYRAMZA®(ramucircumab) for second line tx. of unresectable HCC (AFP>=400 ng/ml) (藥商:Eli Lily;IV給藥;對照組:Placebo)
4. 2017/04/27 FDA 因Phase 1/2 (CheckMate-040)ORR數據優異,加速審批 Opdivo for second line tx. of unresectable HCC 2020/03/11 FDA 因Phase 1/2 (CheckMate-040)ORR數據優異,加速審批 Opdivo+Yervoy for second line tx. of unresectable HCC 2021/04/29 FDA 因phase 3 (CheckMate-459 first line Opdivo pk Nexavar)clinical benefit數據與Nexavar拉不開(mOS=16.4:14.7),撤銷(5:4票) Opdivo for second line tx. of unresectable HCC的加速審批 2021/07/26 BMS向FDA申請撤銷Opdivo for second line tx. of unresectable HCC 的加速審批 (藥商:BMS;IV給藥;對照組:Placebo)
5. 2018/11/09 FDA 因KeyNote-224 ORR數據優異,加速審批 Keytruda for second line tx. of unresectable HCC 2021/04/30 即使因phase 3 (KeyNote-240與placebo相較(經Nexavar治療後復發的2線治療),mOS,mPFS都未達標,但是subgroup針對亞洲人mOS,mPFS,ORR全數都達標,FDA ODAC一致通過(8:0)維持Keytruda for second line tx. of unresectable HCC的加速審批 2021/09/27 Merck公告針對亞洲人的phase 3 (KeyNote-394)與placebo相較(經Nexavar 或oxaliplatin化療後復發的2線治療),Keytruda的mOS,mPFS,ORR全數達標! (藥商:Merck;IV給藥;對照組:Placebo)
ADI + cytarabine(傳統化療藥,Pfizer)用在 AML的phase 2數據非常好!
老揚覺得好奇怪,最近怎麼都看到BMS的影子呀? 1. ADI + Opdivo用在肝癌的Phase 2 2. ADI + Venetoclax + Azacitidine用在AML的Phase 1 BMS在solid tumor, liquid tumor差不多都佈局完了!再加上一塊代謝療法,那就真的是如虎添翼!
ADI + Opdivo用在肝癌是MD主導、MD贊助錢、北極星出藥 ADI + Venetoclax + Azacitidine用在AML是MD主導、北極星贊助錢+藥 Opdivo、Azacitidine都是BMS的藥 Venetoclax是AbbVie的藥,這可是得用白花花的鈔票買來做實驗的! Venetoclax 100mg US$120/顆,用在AML的標準用法是 Day 1: 100 mg orally= $120 Day 2: 200 mg orally= $240 Day 3: 400 mg orally= $480 Day 4 and beyond: 400 mg orally once a day of each 28-day cycle= $480*25= US$12,000 24個cycles= US$308,160 60個病人= US$18,489,600= NT$5.18億台幣! 還不含Azacitidine、其他的臨床花費……等等的費用!
ABSTRACT 11508 Phase II trial of pegylated arginine deiminase in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma. Brian Andrew Van Tine, 餘略 Background:Soft tissue sarcoma (STS) is dependent on extracellular arginine as it often lacks expression of argininosuccinate synthase 1 (ASS1), the urea cycle enzyme needed to produce intracellular arginine. PEGylated arginine deiminase (ADI-PEG 20) is an extracellular arginine-degrading enzyme that causes ASS1 deficient tumors to enter the starvation state. Preclinical data demonstrated that addition of docetaxel (D) with ADI-PEG20 upregulates expression of the transporter for gemcitabine (G), overcoming transporter level resistance, and causing increased cell death. In vivo modeling demonstrated that the combination of ADI-PEG20 with G+D was superior to G+D alone. Therefore, we performed a phase 2 trial testing the addition of ADI-PEG20 to G+D. 重點:加了ADI之後,A+D可以誘導c-Myc-driven hENT1 surface expression 進而讓GEM的抗藥性下降且吸收變多(抑制癌細胞生長、讓癌細胞死亡的能力也大大地提升了)
Methods:We performed an investigator-initiated, phase 2, multicenter, multi-arm clinical trial of ADI-PEG20 with G (90minute infusion)+D in STS, Ewing’s, osteosarcoma and small cell lung cancer. We are reporting Arm A, the STS arm. Eligible patients had STS that would be standardly treated with G+D that had progressed on at least one prior line of therapy with measurable disease by RECIST1.1 and had adequate organ function Based on a historic median PFS of 6.2 months for G+D, we targeted to enroll N = 75 patients in cohort A to detect a 2.8 month improvement with 80% power at a 5% alpha level. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), clinical benefit rate (CBR), safety, tolerability, cancer related mortality, and correlation with ASS1 expression by IHC. We evaluated PFS by Kaplan-Meier method and estimated overall response rate (ORR). 重點:clinical benefit rate (CBR)=disease control rate (DCR)
Results:75 patients were treated and deemed evaluable. The trial underwent two dose reductions by the data safety monitoring board due to prolonged neutropenia and thrombocytopenia preventing the use of day 8 G+D, consistent with preclinical mechanism of action data showing that ADI-PEG 20+D enhanced G uptake. Originally, the G dose was 900mg/m2 reduced first to 750mg/m2 then to 600mg/m2. D was dose reduced at the time of the second dose reduction from 75mg/m2 to 60mg/m2. ADI-PEG20 was given at a fixed intramuscular dose (36 mg/m2) weekly. The need for two dose reductions affected the PFS. The PFS/OS (months) were for the 600mg/m2 group (n = 31) was 6.0/N.D., leiomyosarcoma (LMS) (N = 33) 7.2/22.5, liposarcoma 5.1/17.4, and other (N = 36) 2.8/15.0. Responses were 8% complete (6/75) (3 LMS, 1 synovial and 2 angiosarcoma), 17% partial (13/75), and 43% stable disease (32/75), for an ORR of 25% (19/75) and CBR of 68% (51/75). There was a trend for ASS1 negative tumors to benefit more than ASS1 positive tumors. 重點:主要的目的是減少化療的劑量! 1. Gem第一劑就從900mg/m2減少至→750 mg/m2,第二劑再減少至→600mg/m2 2. Doc則從第二劑開始,自75mg/m2 減少至→60mg/m2 3. ADI則不變,36 mg/m2 weekly 4. 在Gem減少30%+Doc減少20%的用藥情形下(n=31) PFS=6.0 months, OS=N.D. (尚無法分析) 5. Leiomyosarcoma (n=33)的PFS=7.2 months, OS=22.5 months (漂亮的好球) 6. Liposarcoma (n=不知)的PFS=5.1 months, OS=17.4 months (這是比較惡性也比較罕見的,應該不會超過10例) 7. 其他分類 (n=36) 的PFS=2.8 months, OS=15.0 months (剩下的都是最惡性的,佔了收案數的一半,居然還活了15個月) 8. CR= 8% (6/75) (3 LMS, 1 synovial and 2 angiosarcoma), PR= 17% (13/75), SD= 43% (32/75) 9. ORR= 25% (19/75), CBR= 68% (51/75) 10. 缺乏ASS1的療效比ASS1 positive的好
Conclusions:The combination of ADI-PEG20 with G+D can be safely and effectively given at a dose of 600mg/m2 G and 60mg/m2 D. Future randomized trials of ADI-PEG20 with G+D are planned. Clinical trial information: NCT03449901 重點:ADI+Gem+Doc在Gem減少30%+Doc減少20%的用藥情形下,安全又有效!
複習 Korea這篇是回溯性研究,參考價值主要是樣本數夠大 II. Gemcitabine and Docetaxel Combination for Advanced Soft Tissue Sarcoma: A Nationwide Retrospective Study n= 218 ORR=15.1%(34/218)----CR=1, PR=33, SD=79 DCR=51.8%(113/218) Leiomyosarcoma佔比57/218的ORR=26.3% (15/57) mPFS= 3.3 months (95% CI, 2.8 to 4.7) mOS= 10.3months (95% CI, 8.4 to 12.2) 組織型態leiomyosarcoma的 hazard ratio= 其他型態的0.693 (95% CI, 0.493 to 0.975; p < 0.05)---Leiomyosarcoma的存活機率最高!
●●● III. Gem+Doc (最普遍被認可也是目前最具實證的二線用藥研究) Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Maki et al. JCO 2007 n= 73人(Gem+Doc) vs. 49人(Gem alone) ORR= 16%( CR=2, PR=10) vs. 8%(CR=0, PR=4) mPFS= 6.2 months vs. 3.0 months------------------p<0.05 mOS= 17.9 months vs. 11.5 months------------------p<0.05 Leiomyosarcoma= 40% (29/73) vs. 18% (9/49) 其中Leiomyosarcoma 的ORR= 17.2% (5/29,都是PR) vs. 11.11% (1/9,都是PR)
2019 AACR ASCO Dr. Brian Van Tine的期望是 希望ADI+Gem+Doc的mPFS可以提升到→9months! (power=80%, alpha=0.05). Gem+Doc的mPFS最好的是6.2months (Maki et. al., 2007, JCO, RCT phase 2 study) 讓整體的存活率比Maki et. al.,提高45.2% (2.8 months or 12 weeks)
I. 肺間皮癌MPM→藥效太好,提前中止實驗,待與FDA商討藥證事宜! 市場分析參考資料來源 Global Market for Malignant Mesothelioma Pegged to be Valued at US$ 600 Mn by 2025-end Published On : Jul 12, 2017 目前用藥市場分析(Mn=百萬美元;CAGR=年複合成長率) ●2020年420Mn→2025年603Mn→2030年865Mn (CAGR=7.5%)
II. 軟組織肉瘤STS→藥效太好,獲ASCO邀請口頭報告,欲與FDA商討突破性療法!或 如果mPFS大於等於9months,非常有機會Real Time Oncology Review (RTOR) →2週到24週直取藥證!(再補Phase 3) 市場分析參考資料來源 Sarcoma Drugs Market Size, Share & Trends Analysis Report By Treatment Type (Chemotherapy, Targeted Therapy), By Major Markets (U.S., U.K., Germany, Spain, Italy, France, Japan), And Segment Forecasts, 2018 - 2023 目前用藥市場分析(Mn=百萬美元;CAGR=年複合成長率) ●2020年898Mn→2025年1350Mn→2030年2030Mn (CAGR=8.50%)
FDA在2021的1月到5月總共批准了23個腫瘤聯合用藥的藥證,老揚從眾多以mPFS拿藥證的實驗中,簡單選一個為投資人介紹 2021/04/16 FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma 實驗=CHECKMATE-649 (NCT02872116) 癌別=轉移性胃食道腺癌(一線治療) 病人數=789 vs. 792(有先檢測過PD-L1 CPS ≥5的病人→就是對Opdivo這個免疫療法比較有效的) 藥物 Opdivo 240 mg + mFOLFOX6 vs. mFOLFOX6每2週 Opdivo 360 mg + CapeOX (capecitabine and oxaliplatin) vs. CapeOX每3週
非常值得一提的是 This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 5 weeks ahead of the FDA goal date. This application was granted priority review and orphan drug designation.. 這項審查使用了RTOR試點計劃→該程序簡化了在提交整個臨床申請之前的數據提交過程,並使用了評估援助書(申請人自願提供的評估援助書,以促進FDA的評估)。 FDA比批准目標日期還早了5週→批准了該申請。 該申請被授予優先權審查和孤兒藥指定。
什麼是Real-Time Oncology Review (RTOR)? 為了加快批准腫瘤藥物,FDA的腫瘤學卓越中心Oncology Center of Excellence (OCE) 於2018年6月啟動了“腫瘤學卓越中心實時腫瘤學審查(OCE-RTOR)試點計劃→就是以相對簡單、終點直接的研究設計(如ORR, mPFS),快速批准腫瘤藥物! 從RTOR時間表中可以清楚地看到,NDA / BLA的批准可以在2到24週內完成(相比之下,即使是優先審核priority review都還需要6個月)
I. 肺間皮癌MPM 以下摘錄自兩篇市場分析研究(所謂的全球僅含美、英、法、德、義、西、日) Global Malignant Pleural Mesothelioma Industry 2020-2030: Key Marketed and Emerging Drugs in the Pipeline NEWS PROVIDED BY Research and Markets Aug 20, 2020, 09:15 ET
Global Market for Malignant Mesothelioma Pegged to be Valued at US$ 600 Mn by 2025-end Published On : Jul 12, 2017
這篇Pemetrexed的聯合用藥市場分析研究提到 Pemetrexed and combination segment anticipated to grab half the market share of the global malignant mesothelioma market Pem和聯合用藥細分市場是全球MPM市場中,按藥物類型劃分的最大細分市場,估計將接近160Mn,佔2017年總市場收入的45%以上, 到2017-2025年期末預測超過300Mn,複合年增長率為8.4%。由於單獨或與其他藥物聯合使用時,Pem和聯合用藥細分市場的市佔率在30%-40%左右,預計到2025年將比2017年獲得300 BPS(3%)的市場份額。
WHO的資料 Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008 全球MPM的負荷有多大多重尚不清楚。學者Driscol估計,每年全世界有43 000人死於MPM。據估計→澳大利亞、日本、北美和西歐每年總共約有1萬例MPM病例。此外,學者Park提示每記錄四到五例MPM可能就有一例會被忽略。許多國家已經發布了MPM發病率增加的報告。然而,迄今為止,尚無既定的全球基準線可以用來評估疾病的發生趨勢。
●老揚:為什麼期中分析(2021/02/26)後三個月,才會有這個重訊?難道是第二次期中分析? Ans. 當然不是!2021/02/26的重訊是 北極星肺間皮癌三期期中分析,整體生存期達最高等級的統計顯著效果機率80%以上 那時的mOS,mPFS還不足以100%確定尚未收案的154人中會不會讓結果翻盤!
Arginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Argininedeprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.
1664 - Inhibition of arginase in combination with radiation therapy shows increased immune-activation and anti-tumor activity in syngeneic tumor models Abstract The tumor microenvironment (TME) has multiple mechanisms of immune-suppression including recruitment of arginase (ARG) expressing myeloid cells. ARG is an enzyme that catalyzes hydrolysis of L-arginine into urea and L-ornithine. Given L-arginine is essential for optimal function of both T cells and natural killer (NK) cells, inhibition of ARG has been recognized as a potential therapeutic approach to reverse immune-suppression and optimize anti-tumor immunity. We recently presented development of a novel ARG inhibitor, AZD0011, and demonstrated immune activation and anti-tumor activity as single agent and in combination with a-PD-L1 in various tumor models. We now expand these findings demonstrating combination benefit with radiation therapy. Radiation therapy (5 gray on day 6 and 9 after tumor cell implant) demonstrated an increase of both the number of arginase expressing myeloid cells, and NK cells in the TME of Lewis Lung (LL) tumors. Immuno-histochemistry also demonstrated a redistribution of the location of ARG positive myeloid cells with a marked increase at the edge of the tumor. LL tumor bearing mice receiving either AZD0011 (30 mg/kg twice daily), or radiation therapy as monotherapy did not show a significant anti-tumor response reaching 0.3% and 28% tumor growth inhibition (TGI) respectively (p>0.05 versus vehicle). In contrast, combination treatment showed a marked increased efficacy averaging 60% TGI (p<0.05 versus either monotherapy). Combination treatment also further increased several markers of immune activation including a doubling of the number of IL2+ or IFNg+ CD4+ and CD8+ T-cells in tumor draining lymph nodes. In summary, our pre-clinical data demonstrates that radiation therapy increases the number and location of intra-tumoral ARG expression myeloid cells and increased anti-tumor activity when combining the ARG inhibitor AZD0011 with radiation therapy.
297 - Innovation in delivering synthetically challenging bicyclic arginase inhibitors to enhance immunotherapy Abstract Arginase overexpression has been associated with poor survival rates in advanced cancer patients treated with Keytruda. High levels of Arginase may lead to a depletion of arginine within the tumor microenvironment, inhibiting the immune response. Thus, arginase inhibition has the potential to greatly enhance immunotherapy treatment. Discovering novel arginase inhibitors was met with several challenges including analyzing/purifying extremely polar chemical matter without chromophores, synthetically challenging space, and poor bioavailability of compounds with ClogP less than minus two. Cross-functional collaborations and innovations rapidly overcame these challenges. Structural chemistry and modeling guided the design of novel arginase inhibitors. Analytical and purification groups developed innovative analytical/purification methods. Novel technologies including ReatIR and Vapourtec flow system, provided key intermediates to enable chartering into synthetically challenging space. Through creative cyclization strategies and active transport strategy to improve bioavailability, the team ultimately delivered a diverse set of potent and extremely synthetically challenging arginase inhibitors to study the potential of arginase inhibition. Preliminary in vivo evaluation showed single agent efficacy in an EMT6 model. These arginase inhibitors have the potential to enhance immunotherapy.
2336 - Eradicating melanoma cells using combination of nutritional stress and checkpoint inhibitors
Presenter/Authors Lynn G. Feun, Chunjing Wu, Ying-Ying Li, Min You, Medhi Wangpaichitr, Miguel Suarez, Niramol G. Savaraj. University of Miami, Miami, FL, Miami VA Healthcare System, Miami, FL
Abstract Arginine (Arg) deprivation can inhibit tumors which do not express argininosuccinate synthetase (ASS), a key enzyme for synthesis of Arg. Arg deiminase (ADIPEG20) has shown antitumor activity in such tumors, including melanoma and mesothelioma. Resistance to this treatment occurs due to re-expression of ASS. We have shown that this is mediated via cMyc (positive regulator) and HIF1α ( negative regulator ). Arg starvation rapidly induces chromatin remodeling complex P300-HDAC2-Sin3A which epigenetically deacetylates H3K14ac and H3K27ac at the ASS promoter. Following the PHD2-derived HIF1α-degrading system, the promoter-bound HIF1α is degraded (Sci Rep 7:10814). This allows cMyc (an E-Box binder), to turn on ASS. Arg starvation rapidly triggers externalization of Gas6 to interact with its receptor tyrosine kinase (RTK) Axl. This activates the downstream Ras-PI3K/AKT/GSK3β pathway, resulting in stabilization of cMyc. However, this activation also turns on PDL1 gene expression. This is not surprising since cMyc has been shown to bind to PDL1 promoter and increase its expression. Thus, re-expression of ASS also leads to PDL1 expression. We studied these findings in two other cell lines, Mel114 and Skmel2, and obtained similar results, Interestingly, in three cell lines with high levels of antiapoptotic protein Bcl-2, Arg starvation only leads to growth inhibition, with only less than 2 fold increase in ASS and no PDL1 expression. These results suggest that increased Bcl-2 expression negates the necessity to increase PDL1 and ASS to prevent cell death from nutritional stress. In contrast, transfection of ASS in A2058, A375, Mel1220 and SkMel2 will only confer resistance to Arg starvation, and does not affect PDL1, Bcl2 expression or other alterations in PI3K/AKT pathway. Furthermore, in samples from patients who failed ADIPEG20 due to increased ASS expression, the primary cultures or re-biopsy tumor also exhibited high levels of PDL1 expression, which most likely will make them susceptible to anti PDL1 treatment. On the other hand, six primary cultures derived from patients who failed BRAF/MEK inhibitor (BMR) also showed low levels of ASS and increase in PDL1 expression (1.5-4 fold increase both in mRNA and proteins level compared to their parental cells). These results also applied to 5 pairs of BMR cell lines (A375/BMR, A2058/BMR, Skmel2/BMR, UACC62/BMR, MelRR/BMR). These cells also are very susceptible to combination of ADIPEG20 and PD-L1 treatment. Overall, our data suggest that combination of Arg deprivation and check point inhibitors is effective in patients whose tumors do not express ASS and as salvage therapy for BRAF/MEK inhibitor resistant patients. Supported by the VA Merit Review Award(1BX003328)
老揚點評 ●這是細胞株(cell line)的實驗,測試聯合用藥(ADI + anti PD-L1),結論發現ADI + anti PD-L1非常適合聯合使用! ●另外在BRAF/MEK inhibitor (BMR)治療失敗的病人組織切片中還發現→→→ low levels of ASS and increase in PDL1 expression!所以,理論上這些人也適用ADI + anti PD-L1聯藥治療!BRAF/MEK inhibitor是治療melanoma的標靶藥物,老揚就不多著墨了,有興趣的可以查是那幾家大藥廠、有多大的市佔率! BRAF inhibitors • Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor • Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor • Braftovi (encorafenib) BRAF V600E kinase inhibitor MEK inhibitors • Mekinist®(trametinib) MEK V600 kinase inhibitor • Cotellic® (cobimetinib) MEK V600 kinase inhibitor • Mektovi (binimteinib) MEK V600 kinase inhibitor ●anti PD-L1的免疫療法有→Tecentriq(Roche), avelumab(Pfizer), Imfinzi(AstraZeneca)→→→將來搶親(ADI)的對象! 商機很簡白 針對PD-L1表達率低而免疫療法效果差時,由於ASS的表達率低,此時ADI-PEG 20發揮療效; 相對的,針對ASS的表達率高而ADI-PEG 20效果差時,則因為PD-L1的表達率高,此時免疫療法發揮療效。 ●星友如果不健忘的話,ADI+ Tecentriq+ pem+cis的Clinical trial,台灣唯一有資格獲得國際大藥商免費提供免疫療法藥物的聯合實驗 Study in Patients With Tumours Requiring Arginine to Assess ADI-PEG 20 With Atezolizumab, Pemetrexed and Carboplatin (iTRAP)----NCT03498222 Roche(羅氏)免費提供北極星Tecentriq的聯合療法,目前停止中,公司如果有人繼續接洽Roche的話,應該並不會因前CEO吳博的離去,而停止合作….
幾個重點 1. 試驗計畫主持人華盛頓大學Dr. Brian Van Tine受邀ASCO以最具份量的 「口頭發表」方式現場簡報二期臨床試驗之成果。 ●重點:通常是Abstract寄出之後,ASCO評審建議「口頭發表」,必然是有足夠重大的成果!什麼重大成果?八九不離十就是mPFS達到或超過預期的9個月(P<0.05,Power 80%),歷史對照數據Gem+ Doc為6.2月!
30/03/2021發表ADI+低劑量化療Cytarabine→聯藥治療血癌AML的phase 1 study Phase I study of ADI-PEG20 plus low-dose cytarabine for the treatment of acute myeloid leukemia
回顧一下ADI單一用藥治療血癌AML的phase 2 study重量級的文章! A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients ●Nature-----------Nature, Science這種期刊,很多諾貝爾獎得主的研究都曾刊在這裡!
北極星指出,這項奈米蛋白產品,是源自美國柏克萊大學的國家實驗室(Lawrence Berkeley National Laboratory)發明人Curtis D. Hodge博士所帶領團隊,從國家實驗室技轉成立Nanotein公司。北極星將為其發展量產技術,並負責將未來量生產奈米蛋白產品供應全球之需,北極星除了擁有部分技術股之外,也享有將來的優先投資權。
倫敦帝國學院 腦瘤研究中心 納入北極星ADI-PEG20 治療腦瘤研究 Brain Tumour Research Centre | Faculty of Medicine | Imperial College London 倫敦帝國學院是世界排名前十的大學 其腦瘤研究中心的產學合作中 • The Clinical Research is led by Mr Kevin O’Neill and the Laboratory Translational research is led by Dr Nelofer Syed 臨床研究由神經外科專家Kevin O’Neill醫師領導,實驗室轉譯研究由Nelofer Syed博士領導 We currently have four main areas of investigation in the laboratory: 1. Arginine deprivation (ADI-PEG20) 2. Nicotinamide metabolism (FK866) 3. Angiotensin signalling (PD123319 and EMA405) 4. Ketogenic Diet 目前他們的四項主要研究中, ADI-PEG20是其中一項
Clinical trial in development • Arginine Deprivation - submission to CRUK for Phase 1 clinical trial in recurrent glioblastoma • Developing a randomised nutritional interventional multicentre phase 2/3 clinical trial 開發中的臨床研究 ADI-PEG20已向CRUK(帝國癌症研究基金會Cancer Research UK)提交進行膠質母細胞瘤復發的1期臨床試驗
研究室首頁的序言 We are particularly interested in interrogating the altered metabolism of brain tumours with a particular focus on adult glioblastoma multiforme (GBM), a highly aggressive grade IV primary CNS tumour for which there are currently no successful therapeutic interventions. The addiction of cancer cells to alternative metabolic pathways becomes their Achilles heel and provides an opportunity to develop unique therapeutic strategies. We employ a variety of omics and novel intra-operative technologies in real time to identify these disrupted metabolic pathways and test them for their therapeutic utility both in vitro and in vivo model systems. Data generated through our analysis together with publically available data is subjected to a systems biology approach using computational and mathematical methods to elucidate the pathways most crucially involved in tumour formation and progression. We believe this approach would reveal more successful treatment strategies for GBM and overcome the problems encountered by inter and intra tumoural heterogeneity, a feature thought to account for the failure of current targeted therapies. 我們對深入探討腦腫瘤的代謝變化特別感興趣,尤其關注在成年人膠質母細胞瘤(GBM),這是一種具有高度侵襲性的第IV級原發性中樞神經(CNS)腫瘤,目前尚無成功的治療方法。 癌細胞對新陳代謝途徑的依賴,成為他們的致命弱點,並為發展獨特的治療策略提供了機會。 我們在實時模式下,採用多種組學和新穎的術中技術,以鑑定這些破壞的代謝途徑,並測試它們在體外和體內模型系統中的治療作用。 通過我們的分析產生的數據以及可公開獲得的數據,將採用計算和數學方法進行系統生物學分析,以闡釋與腫瘤形成和進展最相關的途徑。 我們相信這種方法將揭示更成功的GBM治療策略,並克服腫瘤內和腫瘤內差異性所遇到的問題,該特徵被認為是當前標靶治療失敗的原因。
Current research topics • Arginine Deprivation • Angiotensin signalling in GBM (Renin Angiotensin System): • Nicotinamide metabolism (NAD) and chemosensitivity: • Ketogenic Diet -developing a multicentre phase 2/3 clinical trial • Primary vs recurrent GBM • Repurposing drugs • Bioinformatics • Analysis of exosomal DNA • Incorporation of tumour resection preclinical model
從公司未公告數據且說公司也不知道數據---------代表這次interim analysis of end of phase 2是閉門式會議(closed session)! ●北極星這次是closed seesion期中分析!closed seesion期中分析!closed seesion期中分析!
在做完評估之後,FDA DMC會做出以下建議: 一、 試驗繼續進行,不必修改試驗步驟 (continue without protocol modification)。 二、 試驗繼續進行,但是必須修改試驗步驟 (continue with protocol modification)。 三、 試驗中止(明顯有效,明顯有害,或是futility=無用) ●以公司的公告看,可以明確知道是 一、 試驗繼續進行,不必修改試驗步驟 (continue without protocol modification)。 ●這也是坐2望1的達標!不必修改試驗步驟!不必修改試驗步驟!不必修改試驗步驟! ●原本phase 2的176人是納入phase 3的!納入phase 3的!納入phase 3的!
為何認為肺間皮癌MPM interim analysis of end of phase 2 ORR坐2(phase 3後以mPFS,mOS拿藥證)望1(phase 2加速審批),且1的機率極高? 追蹤ADI這麼多年,在interim analysis of end of phase 2前,身為開版者,老揚再分析一下個人的想法。
2020/06/22 AACR線上會議 554 / 9 - Histone deacetylase inhibition is synthetically lethal with arginine deprivation in pancreatic cancers with low argininosuccinate synthetase 1 expression HDAC抑製劑+ADI-PEG 20可使胰臟導管腺癌細胞株加速致死 內文有興趣的自己看,老揚懶得翻譯了! 直接說重點 胰臟癌中最常見的是胰臟導管腺癌(pancreatic ductal adenocarcinoma, PDAC),佔所有胰臟癌的 85-90%,其死亡率非常高,根據美國癌症學會(American Cancer Society)的估計,只有 5% 的病患能夠存活超過五年,而會這麼高是因為初期很難檢測到,等到發現的時候通常都已經是末期了。 胰臟導管腺癌病人中,有15%的病人ASS1表達很低,嚴重影響復發率+存活率! 近年來醫界一直在找好的治療方式。
HDAC抑製劑panobinostat(商品名Farydak; 諾華藥商Novartis Pharmaceuticals)的核准使用癌別及核准時間 On February 23, 2015, the US Food and Drug Administration (FDA) approved panobinostat (Farydak; Novartis Pharmaceuticals), an orally administered inhibitor of histone deacetylase (HDAC), for the treatment of patients with multiple myeloma 2015年2月23日,美國食品藥品監督管理局(FDA)批准了口服組織蛋白脫乙醯基酶(HDAC)抑製劑panobinostat(商品名Farydak; 諾華藥商Novartis Pharmaceuticals)用於第三線(3-L)治療多發性骨髓瘤患者。
HDAC抑製劑panobinostat(商品名Farydak; 諾華藥商Novartis Pharmaceuticals)的作用機轉 Panobinostat blocks the enzymatic activity of HDACs at nanomolar concentrations. HDACs are responsible for removing acetyl groups from the lysine residues of histones and some nonhistone proteins. HDAC inhibition increases the acetylation of histone proteins, which causes the relaxation of chromatin and leads to transcriptional activation. In vitro, panobinostat-mediated accumulation of acetylated histones and other proteins results in cell-cycle arrest and/or apoptosis of some transformed cells. Overall, panobinostat is more cytotoxic in tumor cells than in normal cells Panobinostat可以在奈米級濃度下阻斷HDAC的酶活性。 HDAC負責從組織蛋白和一些非組織蛋白的離氨酸殘留物上除去乙醯基。 HDAC抑製作用會增加組織蛋白的乙醯化作用,從而導致染色質鬆弛並激活轉錄作用。在試管上,由panobinostat引導的乙醯化組蛋織白和其他蛋白質的積累,導致細胞週期停滯和/或某些轉化細胞的凋亡。總體而言,panobinostat在腫瘤細胞中的細胞毒性比在正常細胞中更高。
Abstract Background: Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluate the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase II clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.
MPM phase 2 ORR推估正解 1+1=2大,真是太感恩您啦,老揚昨天看了一整晚的資料、論文,一直糾結在35.5%是31人的,還是20人的!就是忘了回頭看舊資料! 幸好有您一言驚醒夢中人,現在最需要的就是您這樣的人,對公司數據了然於胸的元老星友!老揚代替所有會看必富的北極星投資人感恩您! 經老揚查證之後,您所說的 Peter於IMIG2016年會發表9/17PR、response rate 53%(4 epithelioid, 6 biphasic and 7 sarcomatoid) ●確實公司曾發英文新聞稿 查SAN DIEGO, May 5, 2016可知! 對照吳博士2016.07.05法說會投影片第26張 In the ongoing TRAP study, 20 of the 31 enrolled mesothelioma patients had sarcomatoid or biphasic subtypes; which are significantly more aggressive than the most common epithelioid subtype. Disease control rate in these non‐epithelioid patients is a perfect 100%(20/20), and the response rate is 35% (7/20). ●20161019公司公開說明書第20頁也有提到(吳博偷懶,資料沒有更新還是2016/05/05的資料) 聯合用藥之I期臨床試驗已於2014 年在英國癌症中心開始,在 17名肺間皮癌病人中,9 人有腫瘤反應(Tumor Response),其腫瘤體積縮小達50%以上(Partial Response),腫瘤反應率達53%,而另外的8 名病患病情也達到穩定控制,合併起來疾病控制率(DiseaseControl Rate (DCR))為100%。
第一個大問題 ●對照組中sarcomatoid的歷史數據為13.9% ●要搞清楚 30篇研究用的藥都不大一樣,所以13.9%中有非常大的bias誤差偏見! 如果勉強要算的話 Cis+pem, carbo+pem, carbo+pem+avastin,cis+gem又都是first line treatment的總共有34例,只有4例PR---------ORR=4/34=11.76%-------人數雖不算太少,但是不同實驗、藥也不盡相同,不大準! ●目前最屌2019/05以single arm phase 2拿MPM一線聯藥藥證的STELLAR trial→Cis/Carbo+Pem+TTfields電極療法的數據,ORR=29/72=40%(其中只有18個人26%是sarcomatoid+biphasic type) 如果勉強要算的話 non-epithelioid的真實Cis+Pem ORR可能小於(18/72)*40%→10%-------人數太少(未達30人),又加了TTfields電極療法的效果,還是不大準!
●non-epithelioid ADI+CIS+PEM的歷史ORR=7/20----35%
第二個大問題(己向有參與和FDA討論的貴人確認) ●MPM ADI+Cis+Pem主要療效指標ORR大於對照組的1倍{15% vs. 35%}則直取藥證? - 這一句話只有大於對照組的1倍是固定的,{15% vs. 35%}是浮動的!浮動的!浮動的! - 公司是以ADI+Cis+Pem實驗組的歷史數據35%(7/20)來粗估假設對照組為15%,和FDA談要療效指標ORR大於對照組的1倍(alpha,power都要夠就可以),FDA同意! - 並不是CIS+PEM的歷史數據ORR真的是15%,因為2004發表的CIS+PEM MPM藥證的研究raw data,只有原作者和藥商Eli Lilly有,除非他們願意給你,不然沒有人有這個數據! - MAPS study中的對照組43位non-epithelioid的ORR也是一樣,除非原作者和藥商Roche願意給你,不然沒有人有這個數據! - 如果是15%:35%,power=0.8,alpha=0.05,88:88,type 2 error(偽陰性)為type 1 error(偽陽性)的 8倍-----------這句話因{15% vs. 35%}是浮動的!而修正為合理的4倍!(老揚就奇怪全世界有用1,2,4倍的,從沒聽過用8倍的)
●FDA允諾accelerated approve→主要療效指標ORR大於對照組的1倍以上{例如:對照組為15%的話則實驗組必須為35%--P=0.8}則直取藥證!Phase I 31人中20人為non-epithelioid(10位sarcomatoid+10位biphasic)的ORR為35.5%)------從這裡可以暫時推出non-epithelioid的真實ORR可能小於(20/31)*35.5%→22.9%!
●另外一個影響就是標準差(SD,就是同一組內有人死的很早,有人死的很晚,差距太大),四種情況-> A. 兩組本身的標準差(SD)都很大 B. 兩組本身的標準差(SD)都很小 C. 對照組本身的標準差(SD)很大、實驗組本身的標準差(SD)很小 D. 對照組本身的標準差(SD)很小、實驗組本身的標準差(SD)很大 A.B.C.三種情況,對實驗組解盲優於對照組都是好的,只有D.不好!
老揚用今年ASCO的資料→洗臉一下大名鼎鼎的琛哥,希望您可以多用一點心思,在北極星藥業執行長這個位置! 2019/12/16是北極星藥業非常重要的日子(連董也說了),您擔任執行長至少也要做一點功課,一個地方嚴重誤導投資人 (您說沒有預定在Protocol的事情,不能隨便拿資料分析和FDA談的),以下的資料提醒您,Protocol裡有預設三個時間點必須分析資料,另外,您更不應該叫投資人自己去查資料! ascopubs.org/doi/abs/10.1200/JCO.2019.37.4_suppl.TPS477 A phase II study of ADI-PEG 20 and FOLFOX6 in patients (pts) with advanced hepatocellular carcinoma (HCC). Cross-sectional imaging will be completed every 8 weeks until progression of disease. ●每八週切一次CT/MRI分析腫瘤大小,一直到疾病惡化!
Futility will be assessed three times during the study based on having ORR data available for 56, 110, and 166 patients. This Phase 2 will be stopped for futility if the conditional power drops below 20% at any of these time points. ●大家如果還記得,吳博最後一次法說2019/01/18,也有提到,ADI+Folfox是有期中分析的,三個時間點,當收案可判讀數據為56人,110人,及166人時,任一個時間點如果ORR小於20%就會停止實驗! ●所以,22019/12/16說的,2019/12/03收案124人,可判讀數據94人,就代表 1. 56人的第一個時間點早已安全過關! 2. 最慢2020/01/28(2019/12/03後八週),就有124人的數據,第2個時間點是110人,原則上應該2019/12/31就要有數據,雖然公司(新團隊)很賤,跟賣菜郎學蓋牌,投資人還是可以注意,2020/02/25臨時股東會如果ADI+Folfox還有繼續收案,也就代表第2個時間點110人時ORR依然大於20%!通過第2次考驗!
●●●再幫新團隊和投資人解析一下,110人和166人所需多少ORR,95% CI lower bound and Power才夠! ●ADI+Folfox 95%CI lower bound 19.36% ORR=31/110=28.18%------------Power=0.82 第2個時間點,110人時如果有31個人PR or CR,Power 82%,可以考慮跟FDA談!
RECIST 1.1版本的建立,是根據超過6500名患者的big data分析。參考資料如下: Bogaerts J, Ford R, Sargent D, et al. Individual patient data analysis to assess modifications to the RECIST criteria. Eur J Cancer 2009;45(2):248–260.
3. mRECIST CR=Disappearance of any intratumoral arterial enhancement in all target lesions ●所有腫瘤內的動脈強化消失●
PR=At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions 動脈期有強化的標靶腫瘤SLD有>=30%的減小
SD=Any case that do not qualify as either PR or PD--沒有PR也沒有PD
PD=An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable target lesions recorded since treatment started--動脈期有強化的標靶腫瘤SLD有>20%的增加
什麼是viable (enhancement in the arterial phase) target lesions? 簡單一點說就是在照CT或MRI時,會打顯影劑,而腫瘤能夠吸收的顯影劑對比的部分, 在這種定義基礎上,所有腫瘤內的動脈強化消失被認為是完全緩解,也就是在用藥後追蹤的CT or MRI 上,雖然還有看到腫瘤,但是只要腫瘤不能再吸收顯影劑(影像上是黑的),就代表腫瘤已經沒有血管,沒有活化能力了!
Advanced soft tissue sarcoma 相當罕見的癌別,僅佔癌症比例的不到1%,且組織型態超過100種, 一半以上是因為p53 突變 一線用藥為doxorubicin+ifosfamide or pazopanib alone 二線用藥為gemcitabine + docetaxel 在korea, 二線用藥gemcitabine + docetaxel為off-label use 複習 korea Gemcitabine and Docetaxel Combination for Advanced Soft Tissue Sarcoma: A Nationwide Retrospective Study RECIST 1.1評估 整體的ORR=15.1%(34/218)----CR=1, PR=33, SD=79, DCR=51.8%(113/218) Leiomyosarcoma佔比57/218的ORR=26.3% (15/57) mOS= 10.3months (95% CI, 8.4 to 12.2) mPFS= 3.3 months (95% CI, 2.8 to 4.7) AE-releated discontinued= 7.8% (沒有因用藥死亡事件發生) Grade 3/4最多的為Neutropenia (35.7%) and anemia(15.1%)
預後因子的預測有兩項發現 1. 小於等於50歲的病人, hazard ratio= 大於50歲病人的1.388 (95% CI, 1.027 to 1.875; p < 0.05)---年紀大的比較好倒是挺特別的!不過作者沒有討論原因! 2. 組織型態leiomyosarcoma的 hazard ratio= 其他型態的0.693 (95% CI, 0.493 to 0.975; p < 0.05)---Leiomyosarcoma的效果最好!
●●● 2019 AACR ASCO Dr. Brian Van Tine用來對比的文獻 Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Maki et al. JCO 2007 73人(Gem+Doc) vs. 49人(Gem alone) ORR= 16%( CR=2, PR=10) vs. 8%(CR=0, PR=4) mPFS= 6.2 months vs. 3.0 months------------------p<0.05 mOS= 17.9 months vs. 11.5 months------------------p<0.05 Leiomyosarcoma= 40% (29/73) vs. 18% (9/49) 其中Leiomyosarcoma 的ORR= 17.2% (5/29,都是PR) vs. 11.11% (1/9,都是PR)
2019 AACR ASCO Dr. Brian Van Tine的期望是 Gem+Doc的mPFS最好的是6.2months (Maki et. al., 2007, JCO, RCT phase 2 study) 希望ADI+Gem+Doc的mPFS可以提升到→9months! (power=80%, alpha=0.05). 讓整體的存活率提高45.2% (2.8 months or 12 weeks)
●●● 2019/06股東會,琛哥說soft tissue sarcoma的進度 收案數30幾人,ORR 30%左右 病友個案網誌分享有No.34號 總共要收案75人! Actual Study Start Date May 9, 2018 Estimated Primary Completion Date May 9, 2020
Sponsors and Collaborators Washington University School of Medicine National Institutes of Health (NIH) National Cancer Institute (NCI)
A phase II study of ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma. Citation: J Clin Oncol 37, 2019 (suppl; abstr TPS11079) Author(s): Brian Andrew Van Tine,恕略.
Abstract: Background: The combination of gemcitabine (G) and docetaxel (D) is a standard second line therapy for soft tissue sarcoma (STS) with a modest response rate. Recent studies have looked to add agents to enhance response. We have shown that argininosuccinate synthase 1 (ASS1) expression is silenced in 88% of all sarcomas (n = 708) (Bean et al., 2016, Cell Death and Disease), and that this loss is associated with a reliance on extracellular sources of the amino acid arginine. The arginine depleting enzyme PEGylated arginine deiminase (ADI-PEG 20) depletes extracellular arginine. Preclinical studies have demonstrated that arginine starvation and D administration induce c-Myc-driven hENT1 surface expression overcoming intrinsic cell surface G transporter related resistance. To test this hypothesis, we opened this multi-institutional randomized phase II trial examining the safety and efficacy of ADI-PEG 20 with G + D in STS (NCT03449901) in July of 2018. Methods: Eligible patients are adults with metastatic or unresectable histologically or cytologically confirmed FNCLCC grade 2 or 3 STS that would be standardly treated with G and/or D. Patients are treated with ADI-PEG 20 at a dose of 36 mg/m2 via intramuscular injection on Day -7 of Cycle 1 and then on Days 1, 8, and 15 of each subsequent cycle. G will be given intravenously at a dose of 750 mg/m2 over 90 minutes on Days 1 and 8 and D will be given intravenously at a dose of 75 mg/m2 over 60 minutes on Day 8 of each cycle. The median PFS of metastatic sarcoma patients receiving the standard G + D treatment was estimated to be 6.2 months in a randomized phase II study (Maki et. al., 2007, JCO). With the addition of ADI-PEG 20, we target to improve the median PFS to 9 months, a 45.2% (2.8 months or 12 weeks) improvement in patients treated on G + D + ADI-PEG 20 against the null hypothesis median PFS of 6.2 months to achieve 80% power to detect the improvement in PFS at a 5% alpha level. Tumor specimens (pre- and post-ADI-PEG 20 during week -1) and blood are collected for correlative studies including metabolomics, pharmacodynamics, immunogenicity and ASS1 biomarkers. Quality of life will be measured using FACT-G7. Clinical trial information: NCT03449901
整個的亮點很多,揭露了好多訊息! 1. Preclinical studies have demonstrated that arginine starvation and D administration induce c-Myc-driven hENT1 surface expression overcoming intrinsic cell surface G transporter related resistance Ans.再次強調AACR的亮點→加了ADI之後,A+D可以誘導c-Myc-driven hENT1 surface expression 進而讓GEM的抗藥性下降且吸收變多(抑制腫瘤細胞生長的能力也大大地提升了)
AACR的soft tissue sarcoma,有空看看吧 Presenter/Authors Bethany C. Prudner, Richa Rathore, Abigail Godec, Samuel F. Chang, Angela Hirbe, Brian A. Van Tine. Washington Univ., St. Louis, MO Disclosures B.C. Prudner: None. R. Rathore: None. A. Godec: None. S.F. Chang: ; Relative is an employee with stock interest; Polaris, Inc. A. Hirbe: None. B.A. Van Tine: ; grant on head and neck cancer; Pfizer. ; grand on head and neck cancer; Merck. ; grant to understand angiosarcoma point mutations; Tracon. ; Epizyme. ; CytRX. ; Janssen. ; Lilly. ; Caris. ; Immune Design. ; Adaptimmune, Plexxicon; Daiichi Sankyo. Abstract The response to acute and long-term arginine starvation results in an adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. In examining modulations within the pyrimidine pathway, we identified that the addition of docetaxel (DTX) to cells treated with arginine deiminase (ADI-PEG20) results in a stabilized and translocation c-Myc to the nucleus. This effect drives increased hENT1 cell surface, allowing for the uptake of gemcitabine (GEM) and related analogues. This can be attenuated via a c-Myc/Max heterodimerization inhibitor. Combination experiments showed that the addition of ADI-PEG20 to the combination of GEM and DTX was synergistic. In addition, this combination can be used to overcome intrinsic hENT related GEM resistance to increase GEM uptake. In vivo studies indicate that the triple combination was optimal for tumor growth inhibition providing the preclinical mechanisms and justification for the ongoing clinical trial NCT03449901 ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma. ●結論就一個→加了ADI之後,GEM的抗藥性下降且吸收變多(抑制腫瘤細胞生長的能力也大大地提升了)!
A Phase I study of pegylated arginine deiminase (pegargiminase), cisplatin and pemetrexed in argininosuccinate synthetase 1-deficient recurrent high-grade glioma------(腦膠質瘤)
2019 Feb 12
Clinical cancer research--------- Impact factor 10.199 (腫瘤系期刊排名-12/222)
Prostate Cancer-specific Hallmarks of Amino Acids Metabolism: Towards a Paradigm of Precision Medicine 有人回顧了胺基酸代謝治療在攝護腺癌的地位
DOI: doi.org/10.1016/j.bbcan.2019.01.001
BBA - Reviews on Cancer--------------不是很好,但還算可以的一家期刊
Received date: 5 November 2018 Revised date: 9 January 2019 Accepted date: 9 January 2019
6.2 Arg Deprivation Arg deprivation has been studied as a potential anticancer therapy, however with a limited success. Despite that, recent development of PEGylated arginine deiminase (ADI-PEG 20) enlarged possibilities of Arg deprivation in tumours [30]. PCa tissues have been shown to frequently lack expression of argininosuccinate synthetase (ASS), a ubiquitous enzyme involved in the two-step synthesis of Arg from citrulline [92]. Unable to synthesize their own Arg, ASSdeficient cells depend on relatively inefficient amino acid transporters [93]. Arg deaminase (ADI) isolated from Mycoplasma degrades Arg into citrulline. In native form, ADI is unstable and highly antigenic. PEGylation (in ADI-PEG 20 formulation) increases ADI stability and decreases its immunogenicity allowing to be used for decreasing of plasmatic Arg to undetectable levels. Due to the lack of ASS, ADI-PEG 20 induces a late caspase-independent cell death in CWR22Rv1, but not LNCaP in vitro [94]. Noteworthy, in 2018, ADI-PEG 20 completed Phase III clinical trial for hepatocellular carcinoma, exhibiting a significant prolongation of overall survival in patients with successful depletion of Arg [30]. Hopefully, further tests of Arg deprivation for PCa management will be conducted to extend the therapeutic possibilities.
●目前看起來進度都不快,看MD平台的效率~~~ Tremelimumab + Durvalumab Chemotherapy Naive CRPC ClinicalTrials.gov Identifier: NCT03204812 Sponsor: M.D. Anderson Cancer Center Collaborator: MedImmune LLC Information provided by (Responsible Party): M.D. Anderson Cancer Center Brief Summary: The goal of this clinical research study is to study the safety and tolerability of durvalumab and tremelimumab when given to patients with metastatic (has spread) castration-resistant prostate cancer. This is an investigational study. Tremelimumab and durvalumab are not FDA approved or commercially available. They are currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work in more detail. Up to 27 participants will be enrolled in this study. All will take part at MD Anderson.
Study design Study Type : Interventional (Clinical Trial) Estimated Enrollment : 27 participants Intervention Model: Single Group Assignment Intervention Model Description: This is an open-label, single center, pilot study. Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Pilot Trial to Explore the Link Between Immunological Changes, Efficacy, Safety and Tolerability of Durvalumab (MEDI4736) Plus Tremelimumab in Chemotherapy-naïve Men With Metastatic Castration-resistant Prostate Cancer (CRPC) Actual Study Start Date : July 14, 2017 Estimated Primary Completion Date : July 2019 Estimated Study Completion Date : July 2020
1. ADI+Folfox肝癌,從8/30=26.7%到 8/33=24.2% or 8/34=23.5% or 9/34=26.5%,另外還有3例目前是SD,接下來的評估會不會變PR.... 剔除的這一位,是因為二線用藥時參加了另一個clinical trial,且是在對照組的!現在的雙盲實驗,對照組通常會打一個化療藥,所以就 等和FDA談的情況如何再說,韓國2019/01/18已核准收案、大陸也要收案了,速度只會越來越快!
無聊瀏覽了一下MD Anderson平台有什麼更新沒有,沒想到竟發現北極星肺間皮癌的研究,已經交給MD Anderson平台主持,難怪之前有星友寫信問公司,說肺間皮癌明年中就會結束,原來換平台主持當然收案就加速了! Study #2016-0740 Randomized, Double-Blind Phase 2/3 Study in Subjects with Malignant Pleural Mesothelioma with Low Argininosuccinate Synthetase 1 Expression to Assess ADI-PEG 20 with Pemetrexed and Cisplatin (ATOMIC-Meso Phase 2/3 Study)
Information and next steps Disease: Lung diseases due to external agents Study phase: Phase II/Phase III Physician name: Anne S. Tsao--------------------------●而且主持人也大有來頭! Department: Thoracic and Head and Neck Med For general questions about clinical trials: 1-855-900-3751
Anne S. Tsao, MD Cancer.Net Specialty Editor: Lung Cancer MD Anderson Cancer Center, Houston, TX Dr. Anne Tsao is Professor of Medical Oncology at the University of Texas MD Anderson Cancer Center (MDACC) specializing in thoracic medical oncology. She is a leader in her field for the study of malignant mesothelioma and thoracic oncology. Dr. Tsao earned her medical degree from the University of Chicago Pritzker School of Medicine. She completed her internship and residency at Indiana University in Indianapolis and her medical oncology fellowship at the University of Texas MDACC, where she joined the faculty after completing her training. Board certified in both internal medicine and medical oncology, Dr. Tsao currently serves as Director of the Mesothelioma Program and Director of the Thoracic Chemo-radiation Program at MDACC. Her research focuses on individualizing cancer therapy through understanding the molecular mechanisms of disease. Dr. Tsao is the principal investigator of several active clinical trials at MDACC and has led numerous trials as the international and national principal investigator. She currently serves as Co-Chair of the MDACC Clinical Research Committee. Dr. Tsao has been involved in more than 100 publications in several high-impact journals and has several first and last-author publications in Journal of Clinical Oncology, CA Cancer, Cancer Epidemiology, Biomarkers & Prevention (CEBP), Journal of Thoracic Oncology, Cancer Cell, Nature Medicine Clinical Oncology, and Molecular Cancer Therapeutics. She has also received numerous awards, including an ASCO Merit Award, MD Anderson Achievement in Research Award, ASCO Young Investigator Award, ASCO Career Development Award, NIH Clinician Scientist K12 Award, and Head and Neck SPORE Career Development Award. She has served as Program Project Leader on several large grants, including the Department of Defense PROSPECT grant. Dr. Tsao is highly active in oncology societies both nationally and internationally. This includes serving on the Scientific Advisory Committee and chairing sessions for the American Radium Society, Chair of the Communications Committee for International Association for the Study of Lung Cancer (IASLC), and Mesothelioma Applied Research Foundation (MARF). She also serves on the SWOG Executive Lung Committee, SWOG Mesothelioma Steering Committee, DSMB for NRG Thoracic Oncology, and NRG Lung Executive Committee. For ASCO, she was selected to be in the ASCO Leadership Development Program, and she has subsequently been the track leader for the Cancer Education – Professional Development, track leader for the Cancer Education – Lung, served on the Professional Development Committee, ASCO Lifelong Learning Committee – MOC Lung Committee, and Government Relations Committee. She also assists ASCO/AACR in lobbying congressional leaders for improved research funding for cancer research. Disclosure: In the past two years, Dr. Tsao has served as a consultant and/or advisor for Astellas Pharma, Boehringer Ingelheim, Genentech/Roche, Imedex, Lilly, MedImmune, Bristol-Meyers Squibb, Ariad, EMD Serono, Astra-Zeneca, Takeda, Epizyme, and Novartis and has received research funding from Genentech/Roche (Inst), MedImmune (Inst), Merck (Inst), Millennium, Eli Lilly, Polaris, Boehringer-Ingelheim, Bristol-Meyers Squibb, Ariad, Takeda, Epizyme, and Seattle Genetics. Last updated: September 2018
Rewiring urea cycle metabolism in cancer to support anabolism 在癌症中重新連接尿素循環代謝以支持合成代謝 Rom Keshet, Peter Szlosarek, Arkaitz Carracedo and Ayelet Erez DOI: 10.1038/s41568-018-0054-z
Abstract摘要 Cancer cells reprogramme metabolism to maximize the use of nitrogen and carbon for the anabolic synthesis of macromolecules that are required during tumour proliferation and growth. 在腫瘤增殖和生長期間需要大分子的代謝合成,為了這樣的需求,癌細胞會重新編程代謝,以最大限度地利用氮和碳。 To achieve this aim, one strategy is to reduce catabolism and nitrogen disposal. 為實現這一目標,一種策略是減少分解代謝和氮處理。 The urea cycle (UC) in the liver is the main metabolic pathway to convert excess nitrogen into disposable urea. 肝臟中的尿素循環(UC)是將過量的氮轉化為尿素的主要代謝途徑。 Outside the liver, UC enzymes are differentially expressed, enabling the use of nitrogen for the synthesis of UC intermediates that are required to accommodate cellular needs. 在肝臟外,尿素循環酶的獨特表達,使得合成尿素循環的介質能夠使用氮,此尿素循環的介質是滿足細胞需求之必須。 Interestingly, the expression of UC enzymes is altered in cancer, revealing a revolutionary mechanism to maximize nitrogen incorporation into biomass. 有趣的是,尿素循環酶的表達在癌症中發生了改變,揭示了一種革命性的機制--最大化地把氮併入生物體。 In this Review , we discuss the metabolic benefits underlying UC deregulation in cancer and the relevance of these alterations for cancer diagnosis and therapy. 在本評論,我們討論了癌症中解除管制尿素循環的代謝效益,以及這些改變癌症診斷和治療的相關性。 ●●●想看機轉的請自己看圖,想了解單一療法的請自行看原文(因單一療法已成歷史)!老揚就只從聯藥開始講了..........
Arginine-deprivation combination therapy. 剝奪精胺酸的聯合藥物療法 In view of the modest benefits of arginine-deprivation monotherapy and potential limitations of current therapeutics, such as drug neutralizing antibodies in the case of ADI-PEG20 or the generation of polyamines by ARGs (ARG converts arginine into ornithine and urea), next-generation studies have focused instead on implementing drug combinations for arginine-dependent cancers. 鑑於精氨酸剝奪單一療法的適度益處和現有療法的潛在局限性,例如ADI-PEG20的藥物中和抗體或ARG(ARG將精氨酸轉化為鳥氨酸和尿素)產生的多胺,下一代研究的重點是實施精氨酸依賴性癌症的聯合藥物療法。
One such strategy is based on the increased pyrimidine synthesis described for ASS1-deficient tumours. 這樣的策略是基於增加ASS1缺陷腫瘤的嘧啶合成。
Indeed, ADI-PEG20 was shown to suppress de novo pyrimidine synthesis and salvage pathways, increasing the efficacy of antifolate therapy, a concept that was tested in the phase I study called TRAP (tumours requiring arginine to assess ADI-PEG20 with pemetrexed and cisplatin). 實際上,ADI-PEG20顯示抑制嘧啶重新合成和補救途徑,增加了抗葉酸治療的功效,這一概念在phase I研究中(稱為TRAP---ADI+pem+cis評估腫瘤對精氨酸的需求)已被測試過了。
Patients with ASS1-deficient thoracic cancers, mesothelioma and non-squamous NSCLC exhibited a 100% disease control rate and a partial response rate of 78% in response to ADI-PEG20, pemetrexed and cisplatin or twice that expected in these malignancies in response to pemetrexed and cisplatin alone. ADI+pem+cis在ASS1缺陷性胸腺癌,間皮癌和non-squamous NSCLC患者的DCR=100%、PR=78%,或者是pem+cis的兩倍。
In contrast to ADI-PEG20 monotherapy, triplet drug therapy led to a sustained reduction of plasma arginine and a reciprocal increase in citrulline to at least 18 weeks. 與ADI-PEG20單一療法相比,ADI+pem+cis導致血漿中精氨酸持續減少並且citrulline對等地增加至少18週。
These TRAP data support an ongoing phase II/III trial of ADI-PEG20 or placebo combined with pemetrexed and platinum in patients with chemorefractory mesotheliomas. 這些TRAP的數據,支持正在進行的,對化療有頑固抗性的間皮瘤II期/ III期ADI+pem+cis或placebo+pem+cis。
Similarly, ADI-PEG20 has been combined with folinic acid, 5-fluorouracil and oxaliplatin in HCC and related gastrointestinal cancers with good tolerability, and a phase II study is underway. 同樣地,ADI-PEG20+Folfox在HCC與相關胃腸道癌中的耐受性良好,並且正在進行II期研究(樞紐實驗)。
Additionally, small molecule inhibitors of ASS1 and related UC enzymes may broaden the scope of ADT in the clinic. 另外,ASS1的小分子抑製劑和相關的UC酶可以擴大臨床中ADT(Arginine-deprivative therapy精氨酸剝奪療法=ADI)的範圍。
Thus, while MDLA suppressed colorectal tumorigenesis partly via impaired glycolysis and lipid metabolism, more potent ASS1 antagonists under development may have a future application in combination with ADT. 因此,儘管MDLA(N-methyl-dl-aspartic acid, N-甲基-dl-天冬氨酸)部分地通過損壞糖酵解和脂質代謝來抑制結腸直腸腫瘤發生,但正在開發的更有效的ASS1拮抗劑在未來可能與ADT組合使用。 ●老揚:意思就是ADI+ASS1拮抗劑聯合用藥。
These studies emphasize further the importance of defining the role of UC dysregulation in a given tumour type, as this will directly influence drug selection and clinical trial design. 這些研究進一步強調了,在特定腫瘤類型中定義UC失調作用的重要性,因為這將直接影響藥物選擇和臨床試驗設計。
Resistance to arginine deprivation精氨酸剝奪療法的抗藥性 Various resistance mechanisms have been reported upon arginine depletion in cancer. In clinical trials, relapse was attributed partly to neutralizing anti-drug antibodies, with recovery of plasma arginine and citrulline levels to pretreatment levels by 8 weeks. 已經報導了癌症中精氨酸耗盡的各種抗性機制。在臨床試驗中,復發部分歸因於抗體產生,中和了藥效,血漿中精氨酸和瓜氨酸的量在第8週恢復到治療前的水平。
Cell intrinsic mechanisms associated with resistance to arginine depletion include overexpression of ASS1 to increase endogenous arginine production and activation of transcriptional programmes such as MYC and STAT5, although the molecular means for bypassing arginine auxotrophy in the latter are not completely understood. 與精氨酸耗竭相關的細胞內在機制,包括ASS1的過度表達,以增加內源性精氨酸產生,和轉錄程序如MYC和STAT5的活化,儘管在後者中繞過精氨酸營養缺陷型的分子方法尚不完全清楚。 ●老揚:這個就要問全世界研究MYC的大師→Dr. Chi Van Dang了!好家在他已是北極星的科學顧問!
In AML, relapse occurred despite low arginine levels and no evidence for ASS1 re-expression, emphasizing additional mechanisms of resistance. Collectively, these results suggest that additional resistance mechanisms are yet to be defined. 在AML中,儘管精氨酸水平低且沒有ASS1重新表達的證據,但仍發生復發,強調了其他抗性機制。總的來說,這些結果表明尚未確定其他抗性機制。 ●老揚:就是因為可能還有其他的抗性機制存在,所以AML的ADI單藥效果已經非常好,還要再進行ADI + low dose cytarabine的聯藥實驗的原因!北極星可貴之處就在這裡,一定要破解所有問題!
Undoubtedly, a logical approach to limiting resistance is by exploiting rational drug combinations, as described above. In addition to modifying intrinsic resistance via improved drug enzyme formulations, bypassing several tumour-derived resistance pathways may substantially improve efficacy in the clinic. 毫無疑問,解決藥物抗性的合理方法是利用合理的藥物組合,如上所述。除了通過改良的藥物製劑方式改變內在抗性之外,通過了解幾種不同腫瘤衍生的抗性途徑,可以顯著提高臨床的功效。
Autophagy, or the autophagosomal turnover of organelles and cellular proteins to provide a source of arginine, is emerging as a key pathway of resistance in multiple preclinical studies of arginine deprivation. 自噬,或細胞器和細胞蛋白的自噬體轉換提供精氨酸來源,正在成為精氨酸剝奪的多個臨床前研究中的抗性的關鍵途徑。
Therefore, clinical trials are warranted to assess whether autophagy inhibition will reverse resistance to arginine-depleting agents. In addition, because arginine deprivation also inhibits mTOR while activating autophagy, preclinical modelling supports advancing combinations of arginine depletion and mTOR blockade into the clinic. 因此,有必要進行臨床試驗以評估自噬抑制,是否會逆轉對精氨酸消耗劑的抗性。此外,由於精氨酸剝奪在激活自噬的同時也抑制了mTOR,因此臨床前模型實驗也支持將精氨酸耗竭和mTOR阻斷的組合推進到臨床中。
Another key consideration is the upregulation of tumour-specific metabolic pathways bypassing the effects of arginine deprivation. In particular, arginine deprivation upregulated ASS1 via MYC, which also upregulated glycolysis and glutaminolysis in ADI-PEG20-resistant melanoma cell lines with collateral sensitivity to PI3K–AKT and glutaminase inhibition, respectively. 另一個關鍵考慮因素是,通過精氨酸剝奪的影響,上調腫瘤特異性代謝途徑。特別是,精氨酸剝奪通過MYC上調ASS1,MYC也分別在ADI-PEG20抗性黑素瘤細胞系中,上調糖酵解和谷氨酸分解,對PI3K-AKT和谷氨酸酶抑制劑具有並行的敏感性。
More fundamentally, ornithine derived from ARG therapy generates pro-tumorigenic polyamines via upregulation of ODC. Indeed, a human PEGylated ARG promoted NSCLC xenograft growth, while tumour control required concomitant use of the ODC inhibitor eflornithine. 更基本的是,源自ARG療法(ARG將精氨酸轉化為鳥氨酸和尿素)的鳥氨酸通過ODC(Ornithine decarboxylase)的上調,產生促腫瘤發生的多胺。實際上,人類PEG化的ARG會促進NSCLC異種移植物生長,而腫瘤控制需要同時使用ODC抑製劑eflornithine。
Notably, polyamine inhibition with eflornithine was effective against ASS1-deficient but not ASS1-proficient mesothelioma cell lines, and in the ADAM trial, tumour control correlated with reduced plasma putrescine levels. Thus, primary resistance to ADI-PEG20 in mesothelioma and other arginine-auxotrophic cancers may be modulated with additional blockade of polyamine synthesis. 值得注意的是,用eflornithine抑制多胺對ASS1缺陷的間皮瘤細胞株是有效的,但是對ASS1-豐富的間皮瘤細胞株則無效,並且在ADAM試驗中,腫瘤控制與降低的血漿中putrescine水平相關。因此,可以通過額外阻斷多胺合成來調節間皮瘤和其他精氨酸 - 營養缺陷型癌症中對ADI-PEG20的初級抗性。 ●老揚:就是可以考慮ADI+多胺合成阻斷劑的聯藥組合,也許可以降低ADI的抗性,這應該就是第2代ADI、第3代ADI的內容。
Potential relevance for immunotherapy We have recently shown that most cancers exhibit changes in the expression of two or more UC enzymes, which maximize nitrogen rewiring towards anabolic routes, thus supporting tumour growth and aggressiveness. 我們最近表明,大多數癌症表現出兩種或更多種UC酶的表達變化,這使得氮重新排列到合成代謝的途徑,從而支持了腫瘤的生長和侵襲性。
The immediate metabolic consequence of UC rewiring is the increased availability of UC substrates for pyrimidine synthesis by CAD. The increase in pyrimidine synthesis alters the ratio between purine and pyrimidine levels, favouring pyrimidines. UC重新佈線的直接代謝結果是,CAD對嘧啶合成的UC基質的可用性增加。嘧啶合成的增加改變了嘌呤和嘧啶水平之間的比例,有利於嘧啶。
The resultant nucleotide pool imbalance promotes a specific identifiable mutagenic signature, manifesting as an increase in transversion mutations from purine to pyrimidines at the DNA and RNA levels. 由此產生的核苷酸庫不平衡,促進了特異性可識別的誘變特徵,表現為在DNA和RNA水平上從嘌呤到嘧啶的顛換突變的增加。
Because the increased abundance of pyrimidines affects DNA replication and transcription, the mutated DNA and RNA both contribute to a detectable increase in transversion mutations at the protein level. Interestingly, this genomic change augments the synthesis of hydrophobic neopeptides and enhances the response to anti-programmed cell death 1 (PD1) immunotherapy. 由於嘧啶的豐度增加會影響DNA的複制和轉錄,因此突變的DNA和RNA都會在蛋白質水平上促成轉換突變的可檢測性增加。有趣的是,這種基因組改變增強了疏水性新肽的合成,並增強了對anti-PD1免疫療法的反應。
In line with the results of this study, another promising therapeutic approach explores the benefit of combinational therapy of ADI-PEG20 with immunotherapy. ADI-PEG20 has been shown to upregulate expression of PD1 ligand 1 (PDL1) in ASS1-deficient tumour cell lines and increase T cell infiltration, leading to potentiation of PD1 and/or PDL1 antagonists in vivo, which supports the exploration of checkpoint blockade therapy in ASS1-deficient cancers. 符合這項研究的結果,另一種有希望的治療方法,探討了ADI-PEG20與免疫療法聯合治療的益處。已顯示ADI-PEG20可上調ASS1缺陷型腫瘤細胞中PD-L1的表達,並增加T細胞浸潤,導致體內PD1和/或PDL1拮抗劑的增強,這支持了checkpoint blockade therapy的探索。 ●老揚:從這句可知ADI+Keytruda→可上升ASS1缺陷癌症的PD-L1 expression!就等著起東風吧!
Moreover, a potential immunosuppressive state owing to reduced access to arginine by the immune compartment is circumvented with ADI-PEG20, as its degradation product citrulline is recirculated by T cells for arginine biosynthesis. 此外,由於免疫區隔對精氨酸的使用減少,而導致的潛在免疫抑制狀態被ADI-PEG20規避,因為精氨酸的降解產物瓜氨酸,被T細胞再循環用於精氨酸生物合成。
Thus, the PD1 antagonist pembrolizumab is being combined with ADI-PEG20 in solid tumours, and a quadruplet drug combination of ADI-PEG20 with the PDL1 inhibitor atezolizumab, pemetrexed and carboplatin is being tested in thoracic cancers.因此,ADI+Keytruda在solid tumor,ADI+Tecentriq+pem+car的四聯藥物組合,正在thoracic cancers(NSCLC)進行測試。 ●老揚:所以和Roche的ADI+Tecentriq+pem+car早已開始,只是clinical trial網站尚未更新而已!
A study of co-hARG1-PEG in combination with pembrolizumab has also opened, focusing on patients with relapsed small-cell lung cancer. 聯合hARG1-PEG聯合Keytruda的研究也已開始,重點關注在復發性SCLC肺癌患者。
Further mechanistic insights via repeat biopsies and serum biomarkers for immunological parameters and the use of 89Zr-positron emission tomography for imaging PDL1 induction may enable effective translation of this novel immunometabolic approach in patients. 通過重複切片和血清生物標記物的免疫學參數的進一步機制見解,以及89Zr-正電子發射斷層掃描,用於成像PDL1誘導的使用,可以使得能夠在患者中有效地翻譯這種新的免疫代謝途徑。
Conclusions and future perspectives結論以及未來展望 Understanding the metabolic reprogramming in cancer may provide a foundation for innovative metabolic therapies. To fully capture the prospect of metabolic rewiring in cancer, we need to comprehend the balance between catabolism and anabolism. 了解癌症中的代謝重編程可以為創新的代謝療法提供基礎。為了充分捕捉癌症代謝重新佈線的前景,我們需要理解分解代謝和合成代謝之間的平衡。
The pronounced appetite of tumours for nitrogen promotes UC rewiring in multiple cancers. As of yet, the major metabolic route affected by UC rewiring in cancer is nucleic acid synthesis, specifically pyrimidine synthesis. Not surprisingly, CAD enzyme as well as other enzymes involved in purine metabolism share high homology with UC enzymes, enabling efficient metabolic substrate exchange. 腫瘤對氮的顯著胃口促進了UC在多種癌症中的重新佈線。到目前為止,受UC重新佈線影響的主要代謝途徑是核酸合成,特別是嘧啶合成。毫不奇怪,CAD酶以及參與嘌呤代謝的其他酶與UC酶具有高度同源性,從而實現有效的代謝基質交換。
Tracking changes in UC enzyme expression to decipher the exchange of nitrogenous substrates between the UC and CAD in cancer provides promising therapeutic opportunities. Treating cancers that exhibit a rewired UC with pyrimidine synthesis inhibitors (such as 5-fluorouracil) or with drugs that further disturb the physiological purine to pyrimidine ratio (for example, methotrexate) might prove beneficial in clinical trials. 追踪UC酶表達的變化,以破譯癌症中UC和CAD之間的含氮基質的交換,提供了有希望的治療機會。用嘧啶合成抑製劑(如5-氟尿嘧啶)或用進一步擾亂生理嘌呤與嘧啶比例的藥物(例如methotrexate)治療,顯示重新連接的UC的癌症可能在臨床試驗中證明是有益的。
In addition, the increased synthesis of immunogenic neopeptides suggests that inducing UC dysregulation in cancer stimulates the response to immune therapy. Lastly, UC intermediates provide substrates essential for cancer growth, proliferation and survival. In turn, cancer cells will face shortages of these metabolites, which could increase their dependence on external nitrogen sources, thus leading to therapeutically exploitable cancer vulnerabilities. 此外,免疫原性新肽的合成增加,表明誘導癌症中的UC失調刺激了對免疫療法的反應。最後,UC中間體提供癌症生長,增殖和存活所必需的基質。反過來,癌細胞將面臨這些代謝物的短缺,這可能增加它們對外部氮源的依賴性,從而導致治療上可利用的癌細胞脆弱性。
It is intriguing to hypothesize that cancer cell autonomous alterations in nitrogen usage could influence systemic nitrogen metabolism. Indeed, concentrations of nitrogenous metabolites in the plasma and urine of mice and individuals with cancer are altered compared with healthy controls, which is in line with the potential use of UC enzyme levels as biomarkers for cancer diagnosis and therapy. 有趣的是,假設氮的使用中,癌細胞自主改變可能影響全身氮代謝。實際上,與健康對照相比,小鼠和患有癌症的個體的血漿和尿液中的含氮代謝物濃度發生改變,這與UC酶水平作為癌症診斷和治療的生物標誌物的潛在用途一致。
These studies require further exploration with larger animal and patient cohorts and yet might indicate that cancer dependence on nitrogen can be monitored through non-invasive liquid biopsy. 這些研究需要對更大的動物和患者世代進行進一步探索,但可能表明可以通過非侵入性液體切片來監測癌症對氮的依賴性。
Cancer leads to systemic alterations in the form of cachexia, a major cause of cancer deaths and of deteriorating quality of life. Thus, identifying early systemic signs of tumour nitrogen dependence might not only advance diagnosis and therapeutic approaches against cancer but also serve as a warning sign of later-evolving detrimental systemic alterations. 癌症會導致嚴重營養缺乏的系統性改變,嚴重營養缺乏是癌症死亡和生活質量惡化的主要原因。因此,確定腫瘤氮依賴的早期系統性體徵,可能不僅可以推進針對癌症的診斷和治療方法,還可以作為後來發生有害的系統性改變的警告標誌。
Rewiring UC enzymes and intermediates in the tumour and potentially in the host exemplifies a new and exciting era for cancer metabolism. As we build a more profound understanding of this pathway and its alterations, we will be capable of identifying more effective personalized therapeutic strategies against cancer. The smart complementation of these metabolic strategies with chemotherapy or other targeted treatments will be instrumental in the search for the ultimate Achilles’heel of cancer. 在腫瘤中和可能在宿主中重新連接UC酶和中間體是癌症新陳代謝的新時代。隨著我們對該途徑及其改變的更深刻理解,我們將能夠識別更有效的、針對癌症的個性化治療策略。這些代謝策略與化學療法或其他標靶治療的巧妙互補,將有助於尋找最終的癌症的致命點。
Rewiring urea cycle metabolism in cancer to support anabolism Rom Keshet, Peter Szlosarek, Arkaitz Carracedo and Ayelet Erez DOI: 10.1038/s41568-018-0054-z
生技007大,承你看得起,可惜老揚只是一個nobody而已,能做的不多,只能盡力做. 大家來欣賞一下這篇研究吧~~ Rewiring of cisplatin-resistant bladder cancer cells through epigenetic regulation of genes involved in amino acid metabolism 透過調節涉及氨基酸代謝的表觀遺傳基因,重新探測(佈線)對cisplatin有抗藥性的膀胱癌細胞 Abstract Alterations in DNA methylation are important epigenetic markers in bladder cancer (BC). These epigenome modifications may drive the mechanisms of aggressive chemo-resistant BC. Clinicopathological biomarkers that indicate chemotherapeutic resistance are critical for better assessing treatment strategies for individual patients. Thus, in this study, we aimed to determine whether DNA methylation of certain metabolic enzymes is significantly altered in cisplatin-resistant BC cells. DNA甲基化的改變是膀胱癌(BC)中重要的表觀遺傳標記。這些表觀基因的修飾可以驅動,對化療藥有抗性的侵略性膀胱癌細胞(BC)的機制。臨床病理學生物標誌說明了,化療抗藥性對於更好地評估,個體的治療策略是至關重要的。因此,在本研究中,我們的目的是確定,某些代謝酶的DNA甲基化,在對cisplatin有抗藥性的膀胱癌細胞,是否有顯著改變。
Methods: To characterize CpG methylation and nucleosome accessibility in cisplatin-resistant BC cells, the Illumina Infinium HM450 DNA methylation assay was performed. Perturbed gene expression was found to be associated with cisplatin resistance, and the biological roles of spermidine/spermine N1-acetyltransferase (SAT1) and argininosuccinate synthase 1 (ASS1) were further studied using qRT-PCR analysis and various cell biology assays, including western blot. 方法:描述對cisplatin有抗藥性的膀胱癌細胞中,CpG甲基化和核小體可及性, 以Illumina Infinium HM450 DNA甲基化進行測定。使用qRT-PCR、各種細胞的生物學檢測,包括western blot的分析發現,擾亂基因的表達與→對cisplatin的抗藥性、SAT1和 ASS1的生物學作用角色相關。 ●DNA甲基化是指在DNA序列上某些特定區域-胞嘧啶 (Cytosine, 簡稱C) 5’端的碳原子結構上,加上化學基團-甲基(-CH3),此作用影響且調控基因表現。甲基化常發生在C及鳥嘌呤 (Guanine, 簡稱G) 密集的區域,此區域稱為CpG島 (CpG island) 且常坐落在基因的啟動子位置上,操控著基因是否進行轉錄作用。
Results: ASS1 and SAT1, genes for amino acid and polyamine metabolism catalysts, respectively, were found to be vastly hypermethylated, resulting in greatly downregulated expression. ASS1 expression is of particular interest because prior studies have demonstrated its potential association with BC stage and recurrence. In regard to chemoresistance, we found that aberrant expression or induced stimulation of SAT1 restored cisplatin sensitivity in the cell culture system. We also found that the addition of exogenous arginine deiminase through administration of ADI-PEG 20 (pegylated arginine deiminase) increased ASS1 expression and enhanced cisplatin’s apoptotic effects. 結果:氨基酸和多胺代謝催化劑的基因高度甲基化,發現會導致ASS1和SAT1的表達大大下降。 ASS1的表達特別讓人感到有興趣,因為之前的研究已證明ASS1的表達與膀胱癌細胞(BC)的期別和復發有極大的關聯。在關於對化療藥的抗性,在細胞培養系統裡,我們發現SAT1的異常表達或誘導刺激SAT1表達,可恢復對cisplatin的敏感性。我們還發現通過注射ADI-PEG 20(聚乙二醇化精氨酸脫亞胺酶),可以增加ASS1的表達(●應該是正常細胞的ASS1表達)並增強cisplatin讓癌細胞凋亡的作用。 ●就是說ADI-PEG 20應該可以讓BC病人,對cisplatin比較不會有抗藥性,從而增強cisplatin讓癌細胞凋亡的能力。
Conclusions: Our study demonstrates a novel mechanistic link between the epigenetic perturbation of SAT1 and ASS1 and cancer metabolism in cisplatin-resistant bladder cancer cells. These findings suggest potential utility of SAT1 and ASS1 as predictive biomarkers in re-sensitizing bladder cancer to chemotherapy and personalizing therapy. 結論:我們的研究證實了一個新的聯結機制→在對cisplatin有抗藥性的膀胱癌細胞中,擾亂SAT1、ASS1以及癌症代謝的表觀遺傳基因之間的關聯性。從這些發現建議,使用SAT1和ASS1作為預測性生物標誌,可以讓膀胱癌細胞對化療藥物恢復敏感性,以及做為量身定作的個人化治療是非常具有潛力的。
Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 (Tremelimumab) in Patients With Muscle-Invasive, High-Risk Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Neoadjuvant Chemotherapy ClinicalTrials.gov Identifier: NCT02812420 Sponsor: M.D. Anderson Cancer Center--------------------大聯盟平台老闆! Collaborator: MedImmune LLC Information provided by (Responsible Party): M.D. Anderson Cancer Center Brief Summary: The goal of this clinical research study is to learn if the combination of durvalumab and tremelimumab is safe and tolerable when given to patients with bladder cancer before surgery to remove the bladder. This is an investigational study. Tremelimumab and durvalumab are not FDA or commercially available for the treatment of bladder cancer. The use of these drugs are considered investigational. Up to 35 participants will be enrolled in this study. All will take part at MD Anderson.
Study design Study Type : Interventional (Clinical Trial) Estimated Enrollment : 15 participants Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 (Tremelimumab) in Patients With Muscle-Invasive, High-Risk Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Neoadjuvant Chemotherapy Actual Study Start Date : March 7, 2017 Estimated Primary Completion Date : March 2020 Estimated Study Completion Date : March 2021 現在加入,不早也不遲!剛剛好!
簡介DNA甲基化及胺基酸代謝與膀胱癌(BC)的相關性 膀胱癌(BC)是全球第二大常見的泌尿生殖系統惡性腫瘤,也是美國第四大常見癌症。大多數患者被診斷為可治療的細胞癌或非肌層浸潤性膀胱癌(NMIBC)。然而,大約20-30%的NMIBC病例最終發展成為肌肉浸潤性膀胱癌(MIBC)。甚至在根治性膀胱切除術後,這些患者中約有50%在兩年內還是會發生轉移。此外,對輔助化療無反應的MIBC患者預後較差。 不幸的是,目前還沒有明確定義和可用的預後標記,可以識別這些高風險患者。因此,為了開發新的診斷技術,需要對將造成化療抗性的患者族群,進行全面的分子生物理解。迫切需要能夠預測,患者對鉑類藥物治療反應的標誌物的鑑定,以改善那些具有較高抗藥性風險的BC患者的預後。已經證明表觀遺傳調節在膀胱腫瘤發生中起著重要的作用。最近,通過分析DNA甲基化譜,已經鑑定了三種不同的BC患者亞型。 依賴基因沉默通過胞嘧啶(cytosine)甲基化發生表觀遺傳調節,被認為是治療抗性的特徵。癌症特異性DNA甲基化主要發生在CpG島,位於基因的啟動子區域並導致下游基因的沉默。目前,兩種DNA甲基轉移酶(DNMT)抑製劑(5- azacytidine及其變體,5-aza-CdR)已被FDA批准用於治療高危險骨髓增生異常症候群,也在進行human solid tumor的臨床試驗中。除DNA甲基化外,還有其他影響基因的相關表觀遺傳機制表達水平,包括組蛋白修飾(histone modification)和核小體定位(nucleosome positioning)。這些過程共同作用,創造了表觀遺傳,表觀遺傳直接影響基因表達過程。基於DNA甲基化和核小體可及性(佔據)的染色質結構,在該基因中發揮關鍵作用,在基因的轉錄起始位點調節基因表達。最近使用分子動力學模擬的計算模型,揭示了表觀遺傳DNA甲基化對核小體穩定性的潛在影響,並證明了CpG有助於核小體定位的也可以是DNMT1。這些發現表明,監測染色質可及性,DNA甲基化和組蛋白修飾對於更好地理解BC中的治療反應至關重要。 自從Otto Warburg博士90年前首次觀察到,代謝重編程已被接受為癌症的標誌。考慮到這一點,針對癌症相關氨基酸新陳代謝作為一種潛力療法進行了測試。 在這項研究中,我們試圖了解順鉑耐藥BC細胞中代謝重編程的表觀遺傳改變。我們的實驗結果表明,癌症特異性兩個編碼基因的表觀遺傳沉默代謝酶,亞精胺/精胺N1-乙酰轉移酶(SAT1)和精氨基琥珀酸合成酶1(ASS1),與順鉑耐藥密切相關,並且在T24 BC細胞中被表觀遺傳基因調節。兩個酶都與精氨酸代謝有關:ASS1催化精氨酸生物合成的最後一步。另一方面,SAT1,分解代謝spermidine and spermine,這兩個是衍生自精氨酸,步驟是精氨酸到鳥氨酸arginine to ornithine,鳥氨酸到腐胺ornithine to putrescine,腐胺與亞精胺putrescine to spermidine,亞精胺與精胺spermidine to spermine.
還是欣賞下面這篇吧~~ Arginine lowering enzymes against cancer: a techno-commercial analysis through patent landscape 精氨酸降低酶對抗癌症:通過專利領域的技術商業分析 醫學期刊:Expert Opinion on Therapeutic Patents (影響係數=2.867) ●老揚:這是一家專門發表、回顧、分析醫療專利的專家意見的期刊 發表時間:09/Aug/2018 類型:專家回顧 Funding資金 This paper was not funded. 這篇論文沒有資助。 ●老揚:就是說這篇論文跟北極星公司沒有關係,不是北極星公司花錢找人寫的!
Introduction: Rise in incidence of various cancers and growing adoption of biological therapy to avoid side effects of conventional cancer therapies is driving the growth of the cancer bio-therapy market globally. One such therapy available for the treatment of certain tumors employs arginine-lowering enzymes (ALEs). Several patents have been filed in this technology domain and many phase I/II clinical trials of the ALEs especially arginine deiminase (ADI) are underway. 簡介:各種癌症的發病率持續成長上升,為避免常規癌症療法的副作用,生物治療的採用越來越多,且推動癌症生物療法的市場也在全球性地增長。精氨酸降低酶(ALEs)就是可用於治療其中某些腫瘤的療法。在ALEs技術領域中,許多Phase I / II臨床中已經提交了若干專利,尤其是精氨酸脫亞胺酶(ADI)的試驗正在進行中。
Areas covered: Patents and clinical trials in the domain of ALEs for the treatment of cancer were studied with an objective to understand technology trends, targeted areas, key players and inventors involved. 涵蓋的領域:研究用於治療癌症的ALE領域的專利和臨床試驗,其目的是為了解技術趨勢、目標領域、主要參與者和發明者的介入。
Expert opinion: Amongst the various arginine depleting enzymes, ADI is the most promising enzyme for cancer therapy. ADI based cancer therapy holds potential in treating liver, skin, lung, gastrointestinal and blood cancer. ADI-PEG20 has proved to be very effective when used as a component of combination therapy in a first-line treatment. Polaris group holds the worldwide rights, for ADI-PEG 20 and is the leading player in developing ADI as a therapeutic agent. Many clinical studies, especially in a combinatorial approach, are underway whose success will pave the way for ADI-PEG to the multimillion cancer market. 專家觀點:在各種精氨酸消耗酶中,ADI是最有希望的酶癌症治療。以ADI為主幹的癌症治療,在治療肝臟,皮膚,肺,胃腸道和血癌方面都深具潛力。已經證明ADI-PEG20在聯合用藥治療時,是非常有效的一線治療。 Polaris集團擁有ADI-PEG 20的全球版權,並且是開發ADI作為治療劑的領先者。許多臨床研究,尤其是正在進行中的聯合用藥方向,其成功將為ADI-PEG鋪平道路,達到數以百萬計的癌症治療市場。
文中最後一段值得細讀 5. Expert opinion專家意見 Arginine deprivation through enzymes is currently under clinical investigations. The market potential of this therapy depends on its clinical success. Arginine deprivation approach for the treatment of cancer shows potential in making its own share in ~USD137 billion cancer drug market. 通過酶去除精氨酸目前正在進行臨床研究。這種療法的市場潛力取決於其臨床成功。用於治療癌症的精氨酸剝奪方法顯示在~1370億美元的抗癌藥物市場上佔有一席之地的潛力。
Its high potential in drug market can be speculated considering the fact that it specifically targets the cancer cells sparing the normal cells which are able to replenish the amino acids by their usual machinery. Till now phase-I/II clinical trial results have proved that ADI-PEG 20 shows promising results when used as a component of combination therapy in a first-line treatment. 可以推測它在藥物市場方面的潛力很大,因為它專門針對癌症細胞,又保留了能夠通過常規機制補充氨基酸的正常細胞。現在Phase I/II臨床試驗結果證明,當ADI-PEG 20作為聯合治療的成員時,結果顯示ADI-PEG 20是非常有希望的。
However, higher and sustained dosage is required to promote longer arginine depletion. ADI-PEG 20 has been tested in combination with Nexavar, nabpaclitaxel or gemcitabine. A limited number of assignees are active in this domain because of stronghold of Polaris group on the technology. 但是,需要更高和持續的劑量促進更長的精氨酸消耗。ADI-PEG 20已經與nabpaclitaxel or gemcitabine聯合測試。由於Polaris集團在這項技術的強力掌控,在這個領域活躍的公司數量非常有限。
Polaris acquired Phoenix Pharmacologics and TDW Pharmaceuticals, Inc. on December 31, 2008, to strengthen its patent portfolio. 為加強其專利組合,Polaris公司於2008年12月31日收購了Phoenix Pharmacologics和TDW Pharmaceuticals。
If the clinical trials are successful then in a short span of time, Polaris group might be competing with the key players like Novartis, Amgen, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Eli Lilly, Seattle Genetics, Spectrum Pharmaceuticals or Celgene to increase their share of cancer market. 如果臨床試驗成功,那麼在短時間內,Polaris集團就可與Novartis, Amgen, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Eli Lilly, Seattle Genetics, Spectrum Pharmaceuticals or Celgene等關鍵公司競爭,以增加其在癌症市場的份量。
The major share of the global cancer biological therapy market will continue to remain with monoclonal antibodies, vaccines, cancer growth blockers (Tyrosine kinase inhibitors, Proteasome inhibitors, and mTOR inhibitors), blood cell growth factors and cytokines. 癌症生物治療市場的全球主要份量,將繼續保持在單核抗體,疫苗,癌症生長阻斷劑(酪氨酸激酶抑製劑,蛋白酶體抑製劑和mTOR抑製劑),血細胞生長因子和細胞因子。
There are certain improvements required at the molecular level of enzymes to effectively treat cancer. These improvements relate mainly to reducing immunogenicity of the enzyme, increasing the short half-life, increasing production, quick purification and increasing the activity of enzymes at physiological conditions. 要有效治療癌症,在酶的分子層級方面需要一些改良。這些改良主要涉及降低酶的免疫原性,增加短半衰期,增加產量,快速淨化和增加酶在生理條件下的活性。
The advances in protein engineering technology have opened new dimensions in this regard and the pharmacokinetic and pharmacodynamic properties of the enzymes have been improved. PEGylation significantly increases plasma half-life but it compromises the activity of the enzyme. 在蛋白質工程技術的進步方面,已開闢了新的維度。酶的藥物代謝動力學和藥效學特性也已得到改善。聚乙二醇化顯著增加血漿半衰期,但它會影響酶的活性。
To combat this problem new method of albumin binding fusion protein is introduced in some patents. The use of erythrocytes to deliver ADI is another approach that is utilized to enhance the plasma half-life. There is a need for more such studies to establish the effectiveness of this new technology. 為了解決這個問題,在一些專利中有介紹到以白蛋白結合融合蛋白的新方法。使用紅血球來傳遞ADI是強血漿半衰期的另一種方法增。需要更多此類研究來確定新方法的有效性。 ●老揚:這個部分可參考收錄第18篇,北極星公司做了多少改良!
耐大,英文很好就應該為廣大的星友付出一點自己的時間和智慧,下次再這樣偷懶,就要被打屁屁囉~~ Polaris Announces Drs. James Allison and Padmanee Sharma Joining its Scientific Advisory Board Polaris宣布Drs. James Allison和Padmanee Sharma加入其科學顧問委員會 Source Press Release Company Polaris Group
Date July 08, 2018
來源新聞稿 Polaris集團公司 日期2018年7月8日
SAN DIEGO, July 8, 2018 /PRNewswire/ -- Polaris Pharmaceuticals, Inc. (a subsidiary of Polaris Group ), a biopharmaceutical company focused on developing novel drugs for cancer, announced that James Allison, Ph.D. and Padmanee Sharma, M.D., Ph.D. have joined its Scientific Advisory Board. 聖地亞哥,2018年7月8日/美通社-PR Newswire / - Polaris Pharmaceuticals,Inc。(Polaris集團的子公司)是一家專注於開發新型癌症藥物的生物製藥公司,宣布James Allison,Ph.D.和Padmanee Sharma,M.D.,Ph.D.已加入其科學顧問委員會。
As one of the world’s most renowned scientists, Dr. Allison’s fundamental research on the mechanisms governing T cell responses inspired the development of an antibody against CTLA-4 that became ipilimumab , the first drug ever shown to increase survival for patients with metastatic melanoma and received approval from the FDA in 2011. 作為世界上最著名的科學家之一,Allison博士對T細胞反應機制的基礎研究激發了抗CTLA-4抗體的發展,該抗體為ipilimumab,這是有史以來第一種提高轉移性黑色素瘤患者生存率的藥物,並於2011年獲得FDA的批准.。
Dr. Allison is a member of both the National Academies of Sciences and Medicine of the USA, and has received numerous prestigious awards. Allison博士是美國國家科學院和醫學院的成員,並獲得了許多著名的獎項。
His current work seeks to improve immune checkpoint blockade therapies and identify new targets to unleash the immune system in order to eradicate cancer. 他目前的工作旨在改善免疫檢查點封鎖治療,並確定釋放免疫系統以消除癌症的新目標。
Dr. Allison is currently Professor and Chair of the Department of Immunology and the Executive Director of the Immunotherapy Platform, and a Director of the Parker Institute for Cancer Immunotherapy at the University of Texas MD Anderson Cancer Center, where he also holds the Vivian Smith Distinguished Chair in Immunology. Allison博士目前是免疫學系教授兼主任,免疫治療平台執行主任,以及德克薩斯大學MD安德森癌症中心Parker癌症免疫治療研究所所長,並在那裡擔任Vivian Smith Distinguished免疫學主席。
As a trained medical oncologist and immunologist, Dr. Sharma focuses her research work on investigating mechanisms and pathways within the immune system that are responsible for tumor rejection and clinical benefit. She is the Principal Investigator of multiple immunotherapy clinical trials and conducts translational laboratory studies related to these trials. Her studies enable development of novel immunotherapy strategies for the treatment of cancer patients. Dr. Sharma is a Professor in the Departments of Genitourinary Medical Oncology and Immunology, the Scientific Director for the Immunotherapy Platform, and also the Co-Director of Parker Institute for Cancer Immunotherapy at the University of Texas MD Anderson Cancer Center. 作為一名訓練有素的腫瘤內科醫生和免疫學家,Sharma博士的研究重點是研究免疫系統中負責腫瘤排斥和臨床獲益的機制和途徑。她是多個免疫療法臨床試驗的首席研究員,並進行與這些試驗相關的轉化實驗室研究。她的研究有助於開發治療癌症患者的新型免疫治療策略。 Sharma博士是泌尿生殖醫學腫瘤學和免疫學系的教授,免疫治療平台的科學主任,以及德克薩斯大學MD安德森癌症中心Parker癌症免疫治療研究所的聯合主任。
This is a wonderful opportunity to help develop further the unique arginine inhibition mechanism of ADI-PEG 20 , as well as other agents in their portfolio, said Dr. Allison. Arginine is a key regulator of various cellular processes. Combining arginine deprivation with immunotherapies , as well as cytotoxic agents, adds another mechanism of attack to our anti-cancer armamentarium. ●“這是一個很好的機會,有助於進一步發展ADI-PEG 20的獨特精氨酸抑制機制,以及其產品
●MD anderson的效率非常快,因為這三個團隊的clinical trial本來就已經在進行中了,現在只要再開一組聯ADI的就好,不需要再另外設計實驗!所以老揚查了一下clinical trial的資料,以下是MD anderson主導的prostate cancer
Tremelimumab + Durvalumab Chemotherapy Naive CRPC ClinicalTrials.gov Identifier: NCT03204812 Sponsor: M.D. Anderson Cancer Center Collaborator: MedImmune LLC Information provided by (Responsible Party): M.D. Anderson Cancer Center Brief Summary: The goal of this clinical research study is to study the safety and tolerability of durvalumab and tremelimumab when given to patients with metastatic (has spread) castration-resistant prostate cancer. This is an investigational study. Tremelimumab and durvalumab are not FDA approved or commercially available. They are currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work in more detail. Up to 27 participants will be enrolled in this study. All will take part at MD Anderson.
Study design Study Type : Interventional (Clinical Trial) Estimated Enrollment : 27 participants Intervention Model: Single Group Assignment Intervention Model Description: This is an open-label, single center, pilot study. Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Pilot Trial to Explore the Link Between Immunological Changes, Efficacy, Safety and Tolerability of Durvalumab (MEDI4736) Plus Tremelimumab in Chemotherapy-naïve Men With Metastatic Castration-resistant Prostate Cancer (CRPC) Actual Study Start Date : July 14, 2017 Estimated Primary Completion Date : July 2019 Estimated Study Completion Date : July 2020
Advanced soft tissue sarcoma 相當罕見的癌別,僅佔癌症比例的不到1%,且組織型態超過100種, 一半以上是因為p53 突變 一線用藥為doxorubicin+ifosfamide or pazopanib alone 二線用藥為gemcitabine + docetaxel 在korea, 二線用藥gemcitabine + docetaxel為off-label use
茲列舉 Korea, 20家醫學中心, 2009~2014年收治228例, 其中可分析數為218位的結果分析 Gemcitabine and Docetaxel Combination for Advanced Soft Tissue Sarcoma: A Nationwide Retrospective Study 這218位有兩種注射處方模式 1. a single cycle of gemcitabine 1,000 mg/m2 intravenously (D1, D8) and docetaxel 35 mg/m2 intravenously (D1, D8) every 21 days 2. gemcitabine 900 mg/m2 intravenously (D1, D8) and docetaxel 75-100 mg/m2 intravenously (D1) every 21 days.
ADI+Gem+Doc的注射模式類似韓國的第2種,差別在Doc給藥的時間點是第8天,而韓國的資料是第1天給藥 Gemcitabine will be given intravenously at a dose of 900 mg/m2 over 90 minutes on Days 1 and 8 of each cycle. Docetaxel will be given intravenously at a dose of 75 mg/m2 over 60 minutes on Day 8 of each cycle.
同行比一比 荷蘭→以Keytruda or Opdivo治療Uveal melanoma (UM)眼黑色素癌的統計 M. K. van der Kooij et al. Anti-PD1 treatment in metastatic uveal melanoma in the Netherlands Acta Oncologica 2017 n=17 PFS=2.3months(72天, 95%CI 50.8-93.2天) mOS=9.6months(269天, 95%CI 167-370天)
美國及西班牙9家醫療機構→以Keytruda or Opdivo治療Uveal melanoma (UM)眼黑色素癌的統計 Algazi et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122:3344–3353. n=56 PFS=2.6months(95% CI, 2.4-2.8 months) mOS=7.6months(95% CI, 0.7-14.6 months) ORR= 3.6% (95% CI, 1.8%-22.5%)-----------2/56=56個只有2個PR or CR SD= 9% (_6 months) --------5/56=56個只有5個SD 從ORR+SD可以推出 Keytruda or Opdivo 的DCR=7/56 (12.5%) vs. ADI+PEM+CIS 的DCR=7/10 (70%)
(4)在PD-L1表達低的晚期癌症組,病人腫瘤PD-L1的表達需低於50%才符合進入本試驗的條件。此類病人在使用免疫療法新藥治療時,一般療效比較不明確。而本試驗的目的就是探討此類病人在先使用ADI-PEG 20之後,是否可以提升免疫療法新藥的療效。在本組目前可評估的八名病患中,已在三位罹患不同晚期癌症的病患身上看到部分腫瘤反應,腫瘤反應率為37.5%(3/8),這三位病患均已接受過多種系統性藥物治療,分別為第三線治療的粘膜黑色素瘤、第五線治療的膽管癌和第四線治療的食道癌。 ●PD-L1表達低於50%的晚期癌症組目前可評估的8名病患中,ORR=37.5%(3/8) 這3個分別是3rd line mucosal melanoma, 4th line esophagus ca., 5th line cholangiocarcinoma
2018/06/04的英文新聞稿 Preclinical data indicated that ADI-PEG 20 could up-regulate PD-L1 expression, turning immune ’cold’ tumors to express PD-L1 and thus more receptive to programmed death inhibition with agents such as pembrolizumab. We are gratified to see this same scenario occur in patients, said John Bomalaski. “臨床前數據表明,ADI-PEG 20能夠上調PD-L1的表達,把對免疫”冷反應“的腫瘤轉化為表達PD-L1,從而更容易接受anti PD1,如Keytruda之類的免疫療法。我們很高興看到這相同的情景發生在患者身上,“John Bomalaski說。 ●this same scenario ●this same scenario ●this same scenario
●3K大、各位星友大,this same scenario已經說明了一切!
2018/06/05 Money DJ的新聞稿有再提供一點訊息 3rd line mucosal melanoma→PD-L1原表達為0% 4th line esophagus ca. →PD-L1原表達為20% 5th line cholangiocarcinoma→PD-L1原表達為<1% 但是,為什麼還是不直接說PD-L1低表達的,打完ADI後PD-L1 expression就平均上升了多少?
Ans. 各位可不要在關鍵處犯糊塗!這個能說嗎?能這麼便宜的就說出來嗎?想知道嗎?誠意拿出來!什麼誠意? 1. 後續的case,把Keytruda的藥送過來 2. 來簽保密協定 3. 誠意到了就可以了!到了就可以了!到了就可以了!
ASCO 2018/06/04 HNSCC--------ADI+Keytruda A phase Ib study of ADI-PEG 20 plus pembrolizumab in advanced solid cancers
Background: Arginine deprivation with pegylated arginine deiminase (ADI-PEG 20) has been shown to upregulate tumor programmed death-ligand 1 (PD-L1) expression and T cell infiltration. Current phase Ib study is to explore the feasibility of combining ADI-PEG 20 with pembrolizumab in patients with advanced solid tumors. 之前的研究已顯示用(ADI-PEG 20)可上(PD-L1)表達和T細胞浸潤。 目前的phase Ib旨在探索將ADI-PEG 20與pembrolizumab (keytruda)結合用於晚期實體瘤患者的可行性。
Methods: Eligibility criteria included treatment-failure patients with measurable lesions. Pre-treatment tumor biopsy was required. In the “3 + 3” designed dose-escalation part, patients were enrolled to receive ADI-PEG 20 36 mg/m2 at day 1, 8 and 15, and pembrolizumab (1 mg/kg or 200 mg) at day 1, every 3 weeks to determine the maximum tolerated dose (MTD) of pembrolizumab for expansion cohort study. In the expansion cohort part, patients with platinum-failed HNSCC would receive both ADI-PEG 20 and pembrolizumab (at MTD) from day 1; while patients in translation cohort who were required to have < 50% PD-L1 expressing tumors would receive 3 doses of weekly ADI-PEG 20 and a post-ADI-PEG 20 biopsy before the start of combination treatment. The primary endpoint was safety and tolerability. Secondary endpoints included progression-free survival, overall survival, response rate, and the changes of tumorous PD-L1 expression and T-cell infiltration after treatment with ADI-PEG 20 with and without pembrolizumab. 合格納入研究的標準,包括曾治療失敗者且有可測量到病變的病人。治療前需要接受切片檢查。在“3 + 3”設計的劑量遞增部分(dose-escalation)中,患者被納入在第1,8和15天接受ADI-PEG 20 36mg / m 2,並且在第1天及每3週接受keytruda(1mg / kg或200mg),以確定用於expansion cohort的最大耐受劑量(MTD)。
Results: The recruitment of dose-escalation cohorts was completed between July 2017-January 2018. There was only one dose-limiting toxicity, grade 3 hepatitis, observed in a patient in 1 mg/kg dose level; while none in the 200 mg dose level. Among them, two (22.2%) had partial response (PR) and four (44.4%) had stable disease. The two PRs were in thymus cancer and nasopharyngeal carcinoma, with both having 100% tumor baseline PD-L1 expression. The most common grade 3/4 adverse event (AE) was neutropenia, which occurred in seven patients. For serious AEs, two had neutropenic fever lasting less than one week in the third week, and one had tumor bleeding because of tumor progression in the eighth week. The expansion cohorts are enrolling. 在2017年7月至2018年1月之間完成了劑量遞增組群(dose-escalation cohorts)的招募。在1mg / kg劑量的患者中觀察到只有一位有3級肝炎的劑量限制毒性; 而在200mg劑量則沒有發生劑量限制毒性。 其中2例(2/9=22.2%)有部分緩解(PR),4例(4/9=44.4%)病情穩定(SD)。 兩位PR的病人是,胸腺癌和鼻咽癌,兩位的PD-L1表達在baseline時就是有100%的表達。
ASCO 208/06肝癌HCC---ADI+Folfox6 ADI-PEG 20 and FOLFOX6: A phase 1 study in pts (pts) with advanced hepatocellular carcinoma (HCC). Abstract Disclosures Background: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways, and preclinical data indicate that pairing pegylated arginine deaminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. Methods: An open-label phase 1 trial of ADI-PEG 20 and FOLFOX6 for treatment-refractory HCC and other advanced gastrointestinal (GI) tumors was based on a 3 + 3 dose escalation design. The primary objectives were to define, safety, tolerability, and the recommended phase 2 dose (RP2D). An HCC expansion cohort was used to define best overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and exploration of pharmacodynamics and immunogenicity. Eligible patients were treated with intravenous FOLFOX6 biweekly at standard doses and ADI-PEG 20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m2 (Cohort 2 and RP2D expansion). Results: 27 pts enrolled—23 advanced HCC (and 4 other GI). HCC cohort: median age 64 (44-77) years old/70% male/100% Child Pugh A/57% non-viral/70% extrahepatic disease/39% portal vein involvement/43% ≥ 2 lines of treatment. No dose-limiting toxicities were observed and the RP2D for ADI-PEG 20 was 36 mg/m2 weekly with FOLFOX6. Common adverse events (AEs) any grade: thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. 以上沒什麼特別的地方,就不做評論了。
Among 23 HCC pts------23位病人中 the most frequent treatment related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%).
Arginine levels= (Mean ± SEM, baseline 81.7 ± 8.2, week 1 0.8 ± 0.2µM) were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. 這裡只看到用藥後一週的Arginine被剝離的濃度
The degree of arginine depletion, presence of antibodies, and archived tumoral argininosuccinate synthetase-1 levels did not correlate with response. ●從這句更可知,Arginine被剝離的時間與濃度、有無產生抗體等與腫瘤的反應都沒有關係!
Conclusions: Concurrent ADI-PEG-20 and FOLFOX6 is safe with favorable efficacy compared to historic controls. The HCC cohort has been expanded further into a phase II study of the combination in the third-line. Clinical trial information: NCT02102022 ●唯一可惜的是三線用藥,收案不易,但是數據越來越好、勝算越來越大了,值得等待!
Uveal melanoma (UM)眼黑色素癌,是非常罕見又無藥可治的癌症!在歐洲的發生率僅4.4例/百萬! 荷蘭→以Keytruda or Opdivo治療的統計 M. K. van der Kooij et al. Anti-PD1 treatment in metastatic uveal melanoma in the Netherlands Acta Oncologica 2017 n=17 PFS=2.3months(72天, 95%CI 50.8-93.2天) mOS=9.6months(269天, 95%CI 167-370天)
美國及西班牙9家醫療機構→以Keytruda or Opdivo治療的統計 Algazi et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016;122:3344–3353. n=56 PFS=2.6months(95% CI, 2.4-2.8 months) mOS=7.6months(95% CI, 0.7-14.6 months) ORR= 3.6% (95% CI, 1.8%-22.5%) SD= 9% (_6 months)
來看看被認為會是最有效治療Uveal melanoma的→BMS目前進行到Phase 2的Opdivo+Yervoy進行中的研究 1. NCT02626962--Opdivo+Yervoy一線治療轉移性眼黑色素癌 Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma (GEM1402) 贊助者Sponsor: Grupo Español Multidisciplinar de Melanoma---看不懂這是什麼鬼文字,應該是歐洲的什麼黑色素癌基金會之類的吧! Actual Enrollment : 48 participants Intervention Model: Single Group Assignment Masking: None (Open Label) Actual Study Start Date : April 2016 Estimated Primary Completion Date : February 2020 Estimated Study Completion Date : February 2020
2. NCT01585194--Opdivo+Yervoy不管曾經接受過幾線治療的轉移性眼黑色素癌 Phase II Study of Nivolumab in Combination With Ipilimumab for Uveal Melanoma 贊助者Sponsor: M.D. Anderson Cancer Center-----聰明的你可以告訴老揚,為什麼加入這個平台這麼重要了嗎? Estimated Enrollment : 39 participants Intervention Model: Single Group Assignment Masking: None (Open Label) Actual Study Start Date : November 2012 Estimated Primary Completion Date : November 2019 Estimated Study Completion Date : November 2019
Polaris Signs Collaboration Agreement with MD Anderson Cancer Center to Join its Immunotherapy Platform for Clinical Trials and Preclinical Research
SAN DIEGO, May 10, 2018 /PRNewswire/ -- Polaris Group announced that it has signed a multiyear strategic Collaboration Agreement with MD Anderson Cancer Center to utilize its Immunotherapy Platform, led by world-renowned immunotherapy pioneer Dr. James Allison, Dr. Padmanee Sharma, and Dr. Patrick Hwu, to design clinical studies and monitor biomarkers in immune functions associated with the therapies. 聖地亞哥,2018年5月10日電/新華美通/ - 北極星集團宣布與MD安德森癌症中心簽署多年戰略合作協議,利用由世界知名免疫治療先驅 James Allison博士,Padmanee博士領導的免疫療法平台Sharma和 Patrick Hwu博士設計臨床研究並監測與治療相關的免疫功能的生物標誌物。
As one of the ten research platforms that support the Cancer Moon Shots ProgramTM, MD Anderson’s Immunotherapy Platform conducts preclinical research to assess feasibility and efficacy of new treatments; it also monitors immune function changes as a result of clinical therapies through cellular and molecular analysis of patient samples in hope of discovering biomarkers for personalized medicine. 作為支持Cancer Moon Shots Program TM的10個研究平台之一,MD Anderson的免疫治療平台開展臨床前研究以評估新治療的可行性和有效性; 它還通過對患者樣本進行細胞和分子分析的臨床療法監測免疫功能變化,以期發現個人化醫療的生物標誌物。
We are very excited to join MD Anderson’s Immunotherapy Platform and be part of its cutting-edge pre-clinical and clinical research programs in the immunotherapy area, said Dr. Bor-Wen Wu, CEO of Polaris Group. We believe the unique mechanism of action of ADI-PEG 20 may complement that of the existing immunotherapy drugs, hence potentially achieve higher overall efficacy as combination therapy. We look forward to having a fruitful collaboration on our journey to develop more effective treatments, and the exploration of other immunotherapy targets. “我們非常高興能夠加入MD安德森的免疫治療平台,並成為免疫治療領域最先進的臨床前和臨床研究項目的一部分,” 北極星集團首席執行官Bor-Wen Wu博士說。“我們相信ADI-PEG 20的獨特作用機制可能與現有免疫治療藥物的作用相輔相成,因此可能實現更高的綜合療效,我們期待在開發更有效治療的過程中取得卓有成效的合作,並與其他免疫治療靶點的探索“。
About ADI-PEG 20 關於ADI-PEG 20
ADI-PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI-PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI-PEG 20. ADI-PEG 20是北極星集團開發的一種生物製劑,用於治療攜帶主要代謝缺陷的癌症,使其無法內部合成精氨酸。因為精氨酸對蛋白質合成和細胞存活至關重要,這些癌細胞變得依賴精氨酸的外部供應來生存和生長。ADI-PEG 20旨在消除精氨酸的外部供應,導致精氨酸依賴性癌細胞死亡,同時使患者的正常細胞不受傷害。已報導多種癌症具有高度的精氨酸依賴性並且可能用ADI-PEG 20治療。
About Polaris Group 關於北極星集團
Polaris Group specializes in the research and development of protein drugs to treat cancer and other debilitating diseases. In addition to the ADI-PEG 20 program, Polaris Group is developing other therapeutic agents including a small molecule drug program that utilizes a rational structure-based approach to design novel compounds that inhibit the biological function of cancer-related protein tar
●●●2018/02的新聞 Bristol-Myers Squibb and Nektar Therapeutics Announce Global Development & Commercialization Collaboration for Nektar’s CD122-biased Agonist, NKTR-214
Bristol-Myers Squibb to pay Nektar upfront= 18.5E鎂, 包括10E鎂現金及828萬股的Nektar股票(以每股$102.60的價錢買) 總簽約金→36億鎂! 很離譜的是,後續Nektar可以分潤65%,BMS反而只有35%!
Amino Acid Uptake Measured by [18F]AFETP Increases in Response to Arginine Starvation in ASS1-Deficient Sarcomas ASS1缺陷型肉瘤中,用[18F] AFETP測量氨基酸攝取,增加對精氨酸飢餓的反應
Rational: In a subset of cancers, arginine auxotrophy occurs due to the loss of expression of argininosuccinate synthetase 1 (ASS1). This loss of ASS1 expression makes cancers sensitive to arginine starvation that is induced by PEGylated arginine deiminase (ADI-PEG20). Although ADI-PEG20 treatment is effective, it does have important limitations. Arginine starvation is only beneficial in patients with cancers that are ASS1-deficient. Also, these tumors may metabolically reprogram to express ASS1, transforming them from an auxotrophic phenotype to a prototrophic phenotype and thus rendering ADI-PEG20 ineffective. Due to these limitations of ADI-PEG20 treatment and the potential for developing resistance, non-invasive tools to monitor sensitivity to arginine starvation are needed. 原理:在部分癌症中,由於ASS1的表達缺失而發生精氨酸缺陷。 ASS1表達的這種缺失使得癌症對由PEG(ADI-PEG20)誘導的精氨酸飢餓敏感(就是ADI-PEG20這個藥對該種癌症有效的意思)。雖然ADI-PEG20治療是有效的,但它有重要的限制。精氨酸飢餓只對患有ASS1缺陷的癌症患者有益。此外,這些ASS1缺陷的腫瘤可能代謝重新編排以表達ASS1(就是會產生抗藥性),將它們從營養缺陷型轉化為原營養型,從而使ADI-PEG20無效。由於ADI-PEG20治療的這些限制和潛在的抗藥性,需要發展監測對精氨酸飢餓敏感性的非侵入性工具。
Methods: Within this study, we assess the utility of a novel positron emission tomography (PET) tracer to determine sarcomas reliant on extracellular arginine for survival by measuring changes in amino acid transport in arginine auxotrophic sarcoma cells treated with ADI-PEG20. The uptake of the 18F-labeled histidine analogue, (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (AFETP), was assessed in vitro and in vivo using human-derived sarcoma cell lines. In addition, we examined the expression and localization of cationic amino acid transporters in response to arginine starvation with ADI-PEG20. 方法:在本研究中,我們用創新型的正子造影(PET)追蹤劑,評估測量用ADI-PEG20治療過的→精氨酸營養缺陷型肉瘤細胞中,氨基酸轉運的變化,來確定必須依賴細胞外精氨酸才能存活的肉瘤的效用。用標記有氟18組胺酸類似物的攝取量----(S)-2-氨基-3- [1-(2- [18 F]氟乙基)-1H- [1,2,3]三唑-4-基]丙酸( AFETP)----在體外(in vitro, 試管)和體內(in vivo,在活體內,如動物或人)使用源自人類的肉瘤細胞株做評估。此外,我們用ADI-PEG20檢測了帶陽離子的氨基酸轉運蛋白,在反應精氨酸飢餓時的表達和定位,。
Results: In vitro studies revealed that in response to ADI-PEG20 treatment, arginine auxotrophs increase the uptake of L-[3H]arginine and [18F]AFETP due to an increase in the expression and localization to the plasma membrane of the cationic amino acid transporter CAT-1. Furthermore, in vivo PET imaging studies in mice with arginine-dependent osteosarcoma xenografts showed increased [18F]AFETP uptake in tumors 4 days after ADI-PEG20 treatment compared to baseline.
Conclusion: CAT-1 transporters localizes to the plasma membrane as a result of arginine starvation with ADI-PEG20 in ASS1-deficient tumor cells and provides a mechanism for using cationic amino acid transport substrates such as [18F]
第一篇 Poster Board: #274 • Abstract 4085 ADI-PEG 20 and FOLFOX6: A phase 1 study in pts (pts) with advanced hepatocellular carcinoma (HCC). James J. Harding, MD - First Author Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College Sun, Jun 03, 8:00 AM - 11:30 AM Location: Hall A POSTER SESSION Gastrointestinal (Noncolorectal) Cancer Track(s): Gastrointestinal (Noncolorectal) Cancer
第二篇 Poster Board: #382 • Abstract 2556 A phase Ib study of ADI-PEG 20 plus pembrolizumab in advanced solid cancers. Kwang-Yu Chang, MD, PhD - First Author National Institute of Cancer Research, National Health Research Institutes Mon, Jun 04, 8:00 AM - 11:30 AM Location: Hall A POSTER SESSION Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Track(s): Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
第三篇 Poster Board: #415 • Abstract 2589 Phase 1 study of pegargiminase combined with cisplatin and pemetrexed in patients with ASS1-deficient uveal melanoma. Pui Ying Chan, MBBS - First Author Barts Health NHS Trust Mon, Jun 04, 8:00 AM - 11:30 AM Location: Hall A POSTER SESSION Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Track(s): Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
第四篇查不到,應該就是吳博說的比poster低一個等級,只是publish在目錄上之類的. A phase 1 expansion study of pegargiminase, cisplatin and pemetrexedin argininosuccinatesynthetase1-negative recurrent high grade gliomas(HCGs).
●老揚:「請看法說第2頁的最後一句 There is complete confidentiality for research projects of different platform member companies; however, the Directors of the platform will recommend collaborations between member companies when they see sound scientific rationale to support such collaboration 不同平台會員公司的研究項目有完全的保密性; 然而,該平台的主席會建議成員公司之間的合作,當他們看到強而有力的科學理由來支持這種合作!
謝謝賓馳大提供Cancer Research Institute (CRI)與James Allison博士的訪談內容,老揚稍微潤飾後,收錄於此版!原文也可在下面的網址閱讀。 cancerresearch.org/immunotherapy/stories/scientists/james-p-allison,-ph-d
The University of Texas at MD Anderson Cancer Center Houston, TX
The Texas T Cell Mechanic ●●Once you’ve generated T cells that can recognize cancer, you’ve got them basically for the rest of your life.●● 一旦你的身體產生了可以識別癌症的T細胞,基本上,你的的餘生已經擁有了它們(因為已經有記憶了)。
James Allison, Ph.D., knows his T cells. For the past 30 years, he’s studied them inside and out, learning what makes them run and hum. From his laboratory have emerged some of the most important discoveries in immunology. James Allison博士完全了解他的T細胞。在過去的30年中,他一直在透徹地研究他們,了解是什麼讓T細胞奔跑和嘶喊。他的實驗室已經出現了免疫學方面的一些最重要的發現。 ●老揚:「檢測ASS1的assay,也是出自James Allison的實驗室!」
In the early 1980s, Allison was one of the first to identify the T cell receptor—the part of a T cell that binds to antigen and functions as the T cell’s ignition switch. A few years later, in 1992, he showed that a molecule called CD28 functions as the T cell’s gas pedal. Then, in 1995, when no one else was even thinking there would be such a thing, he identified the T cell’s brakes, in the process opening up a whole new vista in cancer treatment. 在二十世紀八十年代早期,Allison是第一批鑑定T細胞受體的學者之一 → T細胞受體是與T細胞結合的T細胞的一部分,並作為T細胞的點火開關。幾年之後,1992年,他表明,一種名為CD28的分子作為T細胞的加速踏板。然後,在1995年,甚至沒有人認為會有這樣的事情時,他確定了T細胞的剎車機制,在這個過程中開闢了癌症治療的全新視野。
Known as checkpoint blockade, the treatment approach uses antibodies to block the action of this braking molecule, called CTLA-4. By “taking the brakes off”the immune response, the treatment enables a more powerful anti-cancer response. 就是廣為人知的→阻斷檢查點,治療方法是使用抗體來阻斷這種剎車分子的作用,稱為CTLA-4。 通過“免除剎車”的免疫反應,治療可以產生更強大的抗癌反應。
Some of the most dramatic clinical responses seen in recent years have occurred with checkpoint blockade antibodies, including ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). Fittingly, in 2013, Science magazine named cancer immunotherapy the “breakthrough of the year,” citing Allison’s work in particular. 近年來出現的一些最引人注目的臨床反應發生在阻斷檢查點的抗體,包括(抗CTLA-4)和nivolumab(Opdivo,抗PD-1)。 在2013年,“科學”雜誌將癌症免疫治療命名為“年度突破”,特別引用了James Allison的發現。
Allison is currently chairman of immunology at The University of Texas MD Anderson Cancer Center in Houston, Texas. He serves as director of CRI’s Scientific Advisory Council, a position he assumed in 2011, when Lloyd J. Old, M.D., retired (pictured together on right). Allison目前是德州休斯敦德克薩斯大學MD安德森癌症中心的免疫學主席。 當Lloyd J. Old醫師在2011年退休時,Allison繼承Dr. Old的職位擔任CRI科學顧問委員會主席。 ●老揚:「Dr.Lloyd J. Old醫師就是ADI的發明人,也被稱為現代免疫學之父!現在了解Dr. Old & Allison之間的關係了嗎?除了ADI在吳博的領導下,不斷地改良精進至已可佔癌症治療的一席之地外,Allison在CTLA-4的研發上,對世人的貢獻已經奠定無法磨滅的地位了,那對當初這位亦師亦友的Dr. Old研發的ADI呢?要不要助一臂之力,在人世間留下更多的佳話?且問君,人生→所謂何求?」
For such a high-powered scientist, Allison is surprisingly down-to-earth. He speaks in the drawl of his native Texas, enjoys a good BBQ, and plays harmonica in a garage band called The Checkpoints, composed of other immunologists. 對於這樣一個強大的科學家來說,Allison親民的表現令人驚訝。 他有德克薩斯州原住民的口音,熱愛燒烤食物,並在由其他免疫學家組成的名為“檢查站”的車庫樂隊演奏口琴。
We spoke to Dr. Allison about his research, his love of science, and his hopes for the future of cancer treatment. 我們與艾莉森博士談了他的研究成果、他對科學的熱愛、以及他對未來癌症治療的希望
Phase III Randomized Study of Second Line ADI-PEG 20 Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma Phase 3二線療法的隨機研究 ADI-PEG 20單一療法治療末期肝癌失敗的生聚教訓 (看看科學家的精神) 5 April 2018剛剛發表在Annals of Oncology (非常嚴謹的期刊) 事隔三年後才發表,為什麼?為了→找到原因並擇其不善者而改之!------對這群偉大的科學家們........敬禮!
先複習一下,當初的數據 ADI-PEG 20 18mg/m2 weekly IM 實驗組vs. 對照組= 424:211 70%(299人)曾用Sorafenib vs. 69% (146人) 曾用Sorafenib 16%(68人)對雷沙瓦不耐受vs. 17% (36人) 對雷沙瓦不耐受 曾接受過一種化療→ 實驗組73% (311) vs. 對照組79% (167) ●●●曾接受過兩種以上化療→實驗組27% (113) vs. 對照組21% (44)
慘痛的教訓 Median OS= 7.8月(實驗組): 7.4月(對照組)-- (hazard ratio = 1.022 [95% CI, 0.847-1.233], p= 0.884) Median PFS= 2.6月(實驗組): 2.6月(對照組)-- (hazard ratio =1.175 [95% CI, 0.964-1.432], p= 0.075)
Subgroup的寶貴經驗 只要Arg depletion>7wks Median OS→ 12.5月(>7wks組): 6.3月(<7wks組)--P<.001
在Discussion中有很重要的幾點討論,收錄於此 1. Strategies to prolong ADI-PEG 20 induced arginine suppression include: 延長ADI-PEG 20誘導精氨酸抑制的策略包括: (a) an increased dose of ADI-PEG 20 (36 mg/m2) 以後的試驗,增加ADI-PEG 20的劑量至36mg / m 2 ●老揚:難怪現在的都已改用36mg / m 2
(b) combination with cytotoxic agents which may blunt the immune response to ADI-PEG 20 與可以鈍化ADI-PEG 20免疫反應的細胞毒性劑(化療)聯合用藥 ●老揚:所以才有了後來的ADI+Folfox, ADI+Cis+Pem.......等聯藥
(c) developing a new ADI that would not be so quickly neutralized by antibodies 開發一種不會被抗體迅速中和的新ADI ●老揚:所以才有了後來的ADI第2代,第3代 (ADI+Trail).....等
This latter approach is currently under investigation, and would mirror the success observed with asparaginase from Erwinia chrysanthemi in patients with acute lymphocytic leukemia (ALL) who have developed antibodies to E. coli asparaginase, as well as by developing a new formulation 後一種方法(不會被抗體迅速中和的新ADI)目前正在研究中,使用來自菊歐文氏菌(Erwinia chrysanthemi)的天冬酰胺酶觀察到的成功,已反映在產生抗大腸桿菌天冬酰胺酶的急性淋巴細胞性白血病(ALL)患者中,而且正在通過開發新的製劑 ●老揚:太謙虛了,不是正在通過,是專利(第2代、第3代)都送出申請了!
While this study was ongoing an experiment was conducted across multiple HCC cell lines which demonstrated an increase in ASS1 expression in some cell lines treated with sorafenib. 雖然這項研究正在進行中,但在多個HCC細胞系中進行了實驗,顯示在用sorafenib處理的一些細胞系中,ASS1表達增加了。 ●老揚:所以三年後才真正正式揭曉答案→兇手確實是sorafenib!
Considering that 86% of patients received prior sorafenib, up-regulation of ASS1 expression may have contributed to the lack of efficacy in the patient population in this study. 考慮到86%的患者先前曾接受sorafenib治療,在本研究中,ASS1表達的上調,可能導致患者缺乏療效。
At the time of the design of the study, the 4 months median OS anticipated for the placebo group seemed reasonable. 在研究設計時,安慰劑組預期能活4個月(mOS)似乎是合理的。
In retrospect, it would be hard to justify nowadays with improved performance status and a favorable Child-Pugh population selected for clinical trials. 回想起來,現在很難證明,選擇用較好的ECOG(如ECOG 1)和較適合的Child-Pugh族群(如狀況比較好的Child-Pugh A),是有利於臨床試驗的。
The reported herein 7.4 months median OS for the placebo group is commensurate with current data 本文報導的安慰劑組mOS 7.4個月,與當前的數據相當。
Capitalizing on the attributes that may help potentiate the efficacy of ADI-PEG 20 would be critical. 利用可能有助於增強ADI-PEG 20功效的特性,將是至關重要的。
Another arginine deprivation approach in HCC has been investigated with pegylated recombinant human arginase 在HCC,另一種用聚乙二醇化的重組人類精氨酸酶,剝奪精氨酸的方法,已經在研究了。
In summary, ADI-PEG 20 at the dose of 18 mg/m2 proved to be ineffecti
A novel biologic ADI-TRAIL fusion protein benefits from structural and functional complementarity of its components arginine deiminase and TRAIL, induces cancer cell apoptosis in vitro, and inhibits tumor growth in vivo 題目:「一種創新的生物融合蛋白→ADI+TRAIL,受益於精氨酸脫亞胺酶和TRAIL組成的結構和功能互補性,其在體外會誘導癌細胞凋亡,且在體內可抑制腫瘤生長」
Abstract TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have shown good safety profile and efficacy in preclinical cancer models. TNF(一種關於腫瘤細胞凋亡的因子)相關凋亡的誘導配體(簡稱TRAIL),它的受體激活劑在臨床前試驗癌症模型分析顯示,可以安全且有效地誘導腫瘤細胞凋亡。
However, clinical success has been limited due to poor PK and/or development of resistance to death receptor-induced apoptosis. 然而,由於PK較差 和/或 對死亡受體誘導的細胞凋亡的抗性發展,使得臨床上的成功受到限制 ●老揚:「PK的意思就是說→pharmacokinetics藥物動力學!」
To address these issues we have conceived and produced a fusion protein of arginine deiminase (ADI) and TRAIL. 為了解決這些問題,我們構想並製成了精氨酸脫亞胺酶(ADI)和TRAIL的融合蛋白。
ADI is an enzyme that converts arginine into citrulline. ADI是一種將精氨酸轉化為瓜氨酸的酶。
Arginine deprivation can inhibit growth of arginine auxotrophic cancers that lack key enzymes enabling normal cells to produce arginine from citrulline. 精氨酸剝奪可以抑制有精氨酸缺陷型癌症的生長,這些癌症→缺少可以使正常細胞從瓜氨酸產生精氨酸的關鍵酶。。
ADI is currently being evaluated in clinical trials and is well-tolerated. ADI目前正在進行臨床試驗評估,且耐受性良好。
We (and others) observed synergy between ADI and TRAIL in inducing apoptosis in a number of cancer cell lines including those that are otherwise resistant to rhTRAIL. 我們(和其他人)在ADI和TRAIL之間,觀察到在許多癌細胞株,包括那些對rhTRAIL具有抗性的癌細胞株,都會對誘導細胞凋亡產生協同作用(ADI+TRAIL合併後更具優勢的意思)。 ●老揚:「rhTRAIL= recombinant human tumor necrosis factor-related apoptosis-inducing ligand,重組人類TNF相關凋亡的誘導配體,是一種目前超熱門的,治療腫瘤的蛋白藥物!有興趣的可以搜尋了解!」
We have explored potential mechanisms of synergy and will present our findings. 我們探索了潛在的協同機制,並將介紹我們的研究結果。
Using in silico modeling we predicted structural complementarity between ADI and TRAIL with each modality stabilized when part of the fusion protein. 使用電腦模擬,我們預測到ADI和TRAIL之間的結構互補性,其中,每一種結構的形態,當具有部份融合蛋白時,都很穩定。 ●老揚:「這個意思就是說,第2代的ADI是Hexamer (6個鍵結)的聚合物,TRAIL是Trimer (3個鍵結)的聚合物,6+3這個超級大的大分子聚合物,重新排列組合,不管是什麼樣的組合形態,只要相互間有部分的融合蛋白時,結構都很穩定!」 ●數學好的算算看,6+3排列組合可以有多少結構組合?那得有多少種產品?只能欽佩北極星養了一票鬼才!----台灣生技投資人不懂這些,但是老揚相信→大藥廠懂! ●這應該就是吳博曾說過的:「也可以叫它做→第3代的ADI吧!」 ●看到這些,對北極星和吳博還沒有信心的,老揚也只能說→此,汝命也!
We were able to produce multiple ADI-TRAIL fusion protein variants and have tested their activity in enzymatic and cell-based assays. 我們能夠生產多種ADI-TRAIL融合蛋白變體,並對這些酶和基於細胞的測定中,測試了它們的活性。
Our experimental data confirmed in silico predictions of the structural advantages for ADI and TRAIL in the fusion protein. 我們的實驗數據證實了,在電腦上預測ADI+TRAIL融合蛋白的結構優勢。
ADI enzymatic activity improved when part of the fusion protein and the fusion protein appeared to have higher potency than the combination of the two separate proteins in inducing cancer cell death. 當部分融合蛋白和融合蛋白,在誘導癌細胞死亡上,呈現出比兩種單獨蛋白質的組合具有更高的效力時,ADI的酶活性也得到改善。
In mice ADI-TRAIL fusion protein exhibited extended half-life and was efficacious in HCT116 xenograft model, superior to rhTRAIL administered at the same molar amounts. 小鼠中,ADI-TRAIL融合蛋白展現出
Metabolic consequences of arginine deprivation in ASS1-deficient cancers 缺乏ASS1的癌症中剝奪精氨酸的代謝結果
Background背景 Argininosuccinate Synthetase 1 (ASS1) is silenced in ∼90% of sarcomas. 約90%的肉瘤都缺乏ASS1
Loss of this urea cycle enzyme causes cells to become dependent upon extracellular arginine for continued cell growth and proliferation. 失去了這個尿素循環酶(=ASS1),會導致細胞必須依賴,細胞外精氨酸來維持生長和增殖所需的能量
Upon arginine starvation, ASS1(-) sarcoma cells undergo autophagy, increase their glutamine dependence and undergo growth arrest. 精氨酸飢餓後,缺乏ASS1的肉瘤細胞會發生自噬,並發生生長停滯,所需能量會依賴以增加glutamine的方式來提供。------所以抑制glutamine也是另一種癌症的代謝治療。
In order to identify potentially exploitable synthetic lethal targets arising from the induction of autophagy following arginine deprivation, we investigated the metabolic alterations caused by arginine deprivation resulting from treatment with PEGylated arginine deiminase (ADI-PEG20). 為了鑑定由剝奪精氨酸後,誘導肉瘤細胞自噬而引起的,可開發的合成致死靶點(就是要研究更多不同的代謝抑制途徑,希望徹底把癌細胞的營養途徑阻斷),我們研究了以(ADI-PEG 20)治療而導致剝奪精氨酸的代謝改變。
Mass spectroscopy was performed and revealed a significant increase in the level of serine biosynthesis from glucose which resulted from the up regulation of PHGDH. 什麼樣的代謝改變呢? 在進行質譜分析後發現,由葡萄糖引起的serine生物合成水平會顯著增加,而這樣的增加是因PHGDH的上調(上升)所引起的
When paired with ADI-PEG20 treatment, inhibition of serine metabolism results in significant cell death. 當與ADI-PEG20聯合治療時發現,抑制serine代謝會導致顯著的癌細胞死亡。
With recent studies showing the importance of serine biology in cancer, as well as recent generation of a small molecule PHGDH inhibitor to the rate limiting enzyme in serine biosynthesis, this newly identified synthetic lethality proves to be an exploitable therapeutic option for ASS1 deficient sarcomas. 最近的研究顯示了serine生物學在癌症中的重要性,以及新一代小分子PHGDH抑製劑對serine生物合成中的限速酶的影響,對缺乏ASS1的肉瘤而言,這種新鑑定的合成致死性(用PHGDH抑製劑抑製serine的合成),被證明了是一種可開發的治療選擇。
Methods: The cell lines were with ADI-PEG20 for three days and subjected to metabolite extraction and capillary electrophoresis mass spectrometry (CE-MS). Similarly, additional samples were cultured for 2 days, with or without ADI-PEG20, and subsequently treated with U-C13 labeled glucose for an additional 24 hours before being subjected to metabolite extraction. Cell death was measured by propidium iodide fluorescent activated cell sorting after inhibition of serine metabolism by the small molecule inhibitor of PHGDH (CBR-5884) or genetic knockdown of key enzymes, with and without ADI-PEG20. 方法學老揚就先不談了,跟投資人沒有太大關係。
Results結果 Upon treatment with ADI-PEG20 and subsequent arginine deprivation induced autophagy, the radiolabeled glucose derived component of a vast majority of metabolites decreased significantly. 在用ADI-PEG20治療,精氨酸剝奪誘導癌細胞自噬後,絕大多數用放射性標記的葡萄糖衍生的組成成分(代謝物)會顯著降低。
The pathway with the largest increase in metabolic flux was serine biosynthesis, including subsequent conversion into glycine. 代謝量增加最多的途徑是serine生物合成,包括隨後轉化而成的Glycine(甘氨酸)。
Significant changes in the enzyme responsible for the rate limiting step of serine biosynthesis, phosphoglycerate dehydrogenase (PHGDH), as well as serine catabolism were induced upon arginine deprivation. 磷酸甘油酸脫氫酶(PHGDH)會顯著地改變serine生物合成的限速酶,同樣地剝奪精氨酸會誘導serine分解代謝。
Cell death levels were significantly higher in samples when inhibition of PHGDH was paired with ADI-PEG20 treatment. 當抑制PHGDH與ADI-PEG20聯合治療時,樣品中的癌細胞死亡會顯著地上升。
Conclusions結論 Starvation mediated by arginine depri
Argininosuccinate Synthetase-1 (ASS1) Loss in high-Grade Neuroendocrine Carcinomas of the Urinary Bladder: Implications for Targeted Therapy with ADI-PEG 20 在膀胱癌中的高階神經內分泌癌中-缺乏ASS1對用ADI-PEG 20靶向治療的意義 Sounak Gupta & Divya Sahu & John S. Bomalaski & Igor Frank & Stephen A. Boorjian & Prabin Thapa & John C. Cheville & Donna E. Hansel ●注意第三位作者→Bomalaski為北極星的董事兼執行副總經理,其他大多是來自Mayo Clinic的專家!!!
摘要 High-grade neuroendocrine carcinomas (HGNECs) of the urinary bladder encompass small cell (SCNEC) and large cell neuroendocrine carcinomas (LCNEC). 膀胱癌中的高階神經內分泌癌(HGNECs)包括小細胞(SCNEC)和大細胞神經內分泌癌(LCNEC)。
Currently, recommended initial management is with systemic chemotherapy, followed by consolidative therapy with either radical cystectomy or radiotherapy in patients with localized disease. 目前推薦的初始治療方法是全身化療,然後伴隨根治性膀胱切除術或局部放射治療的聯合療法。
Nevertheless, survival in this setting remains poor. We therefore evaluated the potential to modify arginine metabolism as an alternative, targeted therapy approach in these carcinomas. 然而,這種情況下的存活率仍然很差。因此,我們評估了修飾精氨酸代謝的可能性,作為這些癌症中替代的靶向治療方法。
In humans, arginine is a semi-essential amino acid and its synthesis enzyme argininosuccinate synthetase (ASS1) represents the rate-limiting step in arginine biosynthesis. 在人體中,精氨酸是半必需氨基酸,其合成酶精氨基琥珀酸合成酶(ASS1)代表精氨酸生物合成中的限速步驟。
Neoplasms that show low to absent ASS1 expression require extracellular arginine for cancer cell survival, and thus can be targeted using arginine-degrading enzymes such as pegylated arginine deiminase (ADI-PEG 20). 腫瘤的ASS1表達,若顯示從低表達至沒有表達,則表示其需要細胞外精氨酸用於癌細胞存活,因此可以使用精氨酸降解酶如----聚乙二醇化精氨酸脫亞胺酶(ADI-PEG 20)進行靶向治療。
An initial study by our group of 19 patients demonstrated that a high percentage of SCNEC lack ASS1 expression. 從本次實驗中患者中的19例患者的初步研究可證實,有很高比例的小細胞神經內分泌癌SCNEC缺乏ASS1表達。
Herein, we evaluated an expanded cohort of 74 radical cystectomy patients with HGNEC, including 63 SCNEC, 5 LCNEC, and 6 mixed morphology HGNEC patients. 在此,我們擴展長期追蹤評估了74名接受根治性膀胱切除術的HGNEC患者,其中包括63名SCNEC,5名LCNEC和6名混合形態的NEC。
ASS1 expression was assessed through immunohistochemistry. ASS1表達是透過免疫組織化學評估
Fifty-eight (of 74, 78%) patients with HGNEC showed absent ASS1 expression, including all patients with LCNEC and mixed morphology (11 of 11, 100%). 74位HGNEC患者中有58例(78%)患者缺乏ASS1表達,這58例中也包括所有5位LCNEC患者和6位混合型患者(11例中有11例,100%)。
Ten-year survival from disease-specific death was not statistically significant between ASS1-expressing and ASS1-deficient cases (p = 0.75). 因疾病而死亡的10年存活率→在有ASS1表達和缺ASS1表達之間沒有統計學上顯著的差異(p = 0.75)。----就是說ASS1缺乏與否,在接受ADI-PEG 20治療前,其本身和存活率是無關的,並不會因為ASS1 loss的就會死的快一點!但是同樣地,這也完全不影響ADI-PEG 20的治療!
Our results show that HGNEC of the bladdermay be candidates for arginine deprivation therapy using drugs such as ADI-PEG 20. 我們的研究結果表明,HGNEC膀胱可能是使用ADI-PEG 20等藥物進行精氨酸剝奪治療的候選者。
Further studies are needed to validate these findings and to determine the therapeutic efficacy of such agents. 後續需要進一步的研究,來驗證這些發現並確定這些藥物的治療功效。
自從免疫療法問世以來、臨床醫師等待副作用處理的guideline、應該都快望穿秋水了!ASCO+NCCN總算在2018/02/14發表了!蒼生之幸! Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline 免疫檢查點抑製劑治療患者免疫相關不良事件的處置方式:美國臨床腫瘤學會臨床實踐指南
Purpose目的 To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. 為提高認識、概述策略、並提供免疫檢查點抑製劑(ICPi)治療患者免疫相關不良事件建議管理的指導原則。
Methods方法 A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. 召集了血液腫瘤學、皮膚病學、胃腸病學、風濕病學、肺病學、內分泌學、泌尿學、神經病理學、血液學、急救醫學、護理學、臨床試驗和宣傳的多學科、多組織專家小組,以製定臨床實踐指南。指南制定包括對文獻和非正式共識過程進行系統性的評估。 系統評價著重於2000年至2017年發表的指南、系統評價和系統性分析、隨機對照試驗和病例係列。
Results結果 The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. 系統評價確認後納入了204份合格的出版物。 許多證據包括對觀察數據、共識指南、病例係列和病例報告的系統評價。 由於缺乏有關免疫相關不良事件管理的高質量證據,以下建議都是基於專家們的共識達成的。
Recommendations建議 Recommendations for specific organ system–based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. 介紹了針對特定器官系統毒性診斷和處理的建議。 儘管根據受影響器官系統的處置方式不同,但一般情況下,如果只是第1級的免疫毒性,應繼續ICPi治療,只要嚴格密切監測就好,除非有神經、血液和心臟毒性等副作用。
ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. 如果是第2級的免疫毒性,ICPi療法可能暫停,除非症狀恢復至第1級或更低的等級時才可恢復使用ICPi療法。可以施打皮質類固醇。
Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. 第3級毒性通常需要暫停ICPis並開始使用高劑量皮質類固醇(prednisone 1〜2 mg / kg / d或methylprednisolone 1〜2 mg / kg / d)。皮質類固醇應至少施打4至6週後再逐漸減量。一些難治性病例可能需要infliximab(anti-TNF療法---老揚)或其他免疫抑制治療(如Mycophenolate 1g BID or 500mg BID---老揚)。 ●沒有遇過嚴重併發症的醫師是無法了解的,高劑量皮質類固醇打到手發抖,因為大多數醫師這輩子沒有幫病人打過,如此多又如此久的類固醇!ASCO+NCCN已經很保守了→1〜2 mg / kg / d,現在我們在臨床上都是從4 mg / kg / d開始打,4週後才開始慢慢減量到2mg,1mg,0.5mg.
In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacemen
~2018/01/18 ASCO MPM (肺間皮癌)guideline(治療準則)悄悄地誕生了 Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline
KEY RECOMMENDATIONS主要建議 ●Chemotherapy化療 Recommendation 1.1: Chemotherapy should be offered to patients with mesothelioma because it improves survival and quality of life (Type of recommendation: evidence based; Evidence quality: intermediate; Strength of recommendation: strong). ●MPM的病人,應提供化療,因為可以促進生存率及增進生活品質。 參考資料 Arnold DT, Hooper CE, Morley A, et al: The effect of chemotherapy on health-related quality of life in mesothelioma: Results from the SWAMP trial. Br J Cancer 112:1183-1189, 2015 ●The SWAMP (South West Area Mesothelioma and Pemetrexed) trial 評估生活品質 58位一線pemetrexed/platin化療 vs. 15位 best supportive care (BSC) 結論:化療的生活品質比BSC好 (P = .006)!
Recommendation 1.2: In asymptomatic patients with epithelial histology and minimal pleural disease who are not surgical candidates, a trial of close observation may be offered prior to the initiation of chemotherapy (Type of recommendation: informal consensus; Strength of recommendation: moderate). ●沒有症狀、epithelial type MPM及僅有輕微胸膜疾病但不適合接受手術的病人,接受化療前,可以先提供有密切觀察的臨床研究。
Recommendation 1.3: Selected patients with a poor performance status (PS 2) may be offered single-agent chemotherapy or palliative care alone. Patients with a PS of 3 or greater should receive palliative care (Type of recommendation: evidence based; Evidence quality: low; Strength of recommendation: moderate). ●ECOG 2(Performance status 2,PS2)的MPM病人,可以提供單一化療或palliative care(安寧緩和症狀治療)。ECOG大於等於3的MPM病人,就接受palliative care(安寧緩和症狀治療)就好了。 參考資料 Muers MF, Stephens RJ, Fisher P, et al: Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): A multicentre randomised trial. Lancet 371:1685-1694, 2008 ●The MS01 phase III trial active symptom control (ASC) vs. mitomycin/vinblastine/cisplatin or vinorelbine n= 409 previously untreated MPM-----一線治療 mOS= 7.6 months vs. 8.5 months (HR, 0.89;P = 0.29)----不達標!
Recommendation 2.1: The recommended first-line chemotherapy for patients with mesothelioma is pemetrexed plus platinum. However, patients should also be offered the option of enrolling in a clinical trial (Type of recommendation: evidence based; Evidence quality: high; Strength of recommendation: strong) ●一線化療建議用藥為pem+cis. 但是應該建議病人加入臨床研究! 以下為FDA核准藥證的研究 參考資料 Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21: 2636-2644, 2003
●single-blind, RCT phase 3 cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) vs. cisplatin n=456 previously untreated patients with MPM mOS= 12.1 vs. 9.3 months (P = .020;HR, 0.77) ----達標! MPFS= 5.7 vs. 3.7months; P = .001----達標! ORR= 41.3% vs. 16.7%; P , .001----達標! ●注意是epithelial type居多的一線治療,其中Cis+Pem組 Sarcomatoid type的病人= 18/226(8%)→ORR=4/18(22.2%)●個案數太少,不具代表性●; Mixed type的病人= 37/226(16.4%)→ORR????→在appendix有交代,但是文獻有點舊,老揚的軟體查不到,若有人查得到還請分享!
參考資料 van Meerbeeck JP, Gaafar R, Manegold C, et al: Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: An intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 23:6881-6889, 2005
Bottomley A, Gaafar R, Manegold C, et al: Short-term treatment-related symptoms and quality of life: Results from an international randomized phase III study of cisplatin with or without raltitrexed in patients wit
Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non–Small Cell Lung Cancer JAMA oncology doi:10.1001/jamaoncol.2017.4771 Published online January 11, 2018.
G 3/4 AE= 13.1% vs. 35.1% 特徵屬性 White= 196 (81.7%) vs. 104 (86.0%)→ total 300 (83.1%) Asian= 29 (12.1%) vs. 14 (11.6%)→ total 43 (11.9%)-------重點一,亞洲人很少! tobacco use= 191 (79.6%) vs. 85 (70.2%)→ total 276 (76.5)--重點二! Oral cavity= 108 (45.0%) vs. 67 (55.4%)→ total 175 (48.5%)---口腔---重點三之一! Pharynx= 92 (38.3%) vs. 36 (29.8%)→ total 128 (35.5%)---咽喉---重點三之二!
●Keytruda- Keynote 040 ----------只有subgroups達標!!! Keytruda vs. methotrexate 40mg/m2 Qwk, docetaxel 75mg/m2 Q3wks, or cetuximab (n=247:248)[keytruda 200mg Q3wks]
mOS (ITT)= 8.4 months (95% CI, 6.5-9.4) vs. 7.1 months (95% CI, 5.9-8.1) (HR, 0.81 [95% CI, 0.66-0.99]; one sided p = 0.0204); with pre-specified p-value required for statistical significance of 0.0175; 12-month OS= 37.3% vs. 27.2%----不達標,因為是one sided p value, 要小於0.0175才達標!
以下兩組subgroups有達標! mOS (PD-L1 CPS ≥1)= 8.7 months (95% CI, 6.9-11.4) vs. 7.1 months(95% CI, 5.7-8.6) (HR, 0.75 [95% CI, 0.59-0.95]; p = 0.0078); 12-month OS= 40.1% vs. 26.7% mOS (PD-L1 TPS ≥50%)=11.6 months (95% CI, 8.3-19.5) vs. 7.9 months (95% CI, 4.8-9.3) (HR, 0.54 [95% CI, 0.35-0.82]; p = 0.0017); 12-month OS= 46.6% vs. 25.8%
ORR (ITT)=14.6% vs. 10.1%(p = 0.0610) ORR (PD-L1 CPS ≥1)= 17.3% vs. 9.9% (p = 0.0171) ------- subgroups有達標! ORR (PD-L1 TPS ≥50%)= 26.6% vs. 9.2% (p = 0.0009) ------- subgroups有達標!
Treatment-related adverse events (TRAEs)= 155 (63.0%) vs. 196 (83.8%) Discontinuation due to TRAEs= 15 patients (6.1%) vs. 12 patients (5.1%) Deaths due to treatment related AE= 4 patients (1.6%)vs. 2patients (0.9%) ●免疫療法的併發致死率,雖然只有1.6%,但是臨床血液腫瘤科醫師只要遇到一個,壓力就很大了!
四、PD-L1 regulates cisplatin chemoresistance in head and neck squamous cell carcinoma一文中主要表明,對順鉑具有化學抗性的HNSCC cell line進行順鉑治療,將導致PD-L1的表現增加。而對順鉑具敏感性的cell line 中PD-L1表現度則沒影響。作者們觀察到對順鉑具抗藥性的腫瘤細胞上的PD-L1會透過調控MRN(MRE11-RAD50-NBS1)complex(在DNA修復中扮演重要角色)中的NBS1來增進DNA修復,使得腫瘤細胞展現抗藥性。當使用小分子干擾核糖核酸(siRNA)使具順鉑抗藥性的腫瘤細胞降低PD-L1表現時,細胞變得對順鉑具有敏感性。因此作者們認為PD-L1為細胞對順鉑具抗藥性的關鍵因子。如果我們抑制腫瘤細胞上PD-L1的表現,使其無法與MRN complex產生交互作用,導致腫瘤細胞DNA因化療產生的雙股斷裂無法被修復,將可增進順鉑的治療效果。
五、Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis一文作者們認為PD-1/PD-L1接合後腫瘤細胞可能會利用患者的免疫系統獲得傳統化療的抗藥性(本文使用的化療藥劑是阿黴素,doxorubicin和歐洲紫杉醇, docetaxel,都與抑制細胞分裂有關)。因此作者們認為抑制PD-1/PD-L1接合的免疫療法與傳統化療合併使用,將有助於增進化療的效果。疑問:此結論是否能推展至Pemetrexed呢?先持保留態度。
今天(19/01/2018)的ASCO GI symposium有刊出一篇壁報,是關於影響精氨酸降解機轉的其中一環。 應該是醫師研究人員的個人投稿,因為沒有看到公司發新聞稿。
MicroRNA-1291 effects on pancreatic cancer (PC) cells sensitivity to arginine deprivation and chemotherapy through modulation of ASS1 and GLUT1. Presented Friday, January 19, 2018 MicroRNA-1291通過調節ASS1和GLUT1,來影響胰腺癌(PC)細胞對精氨酸降解及化療的敏感性。
Authors: Edward Jae-hoon Kim, Mei-Juan Tu, Zhijian Duan, Frank J Gonzalez, Richard J. Bold, Aiming Yu; UC Davis Comprehensive Cancer Center, Sacramento, CA; National Cancer Institute at the National Institutes of Health, Bethesda, MD
Background: Cancer cells are reprogrammed to become addicted to a continuous supply of nutritional glucose and semi-essential amino acids like arginine, to drive synthesis of critical macromolecules for proliferation, tumorigenesis and metastasis. This dependence on nutritional supply makes cancer cells potentially vulnerable to deprivation by agents like pegylated arginine deiminase (ADI-PEG) which converts arginine back to citrulline. However, this vulnerability depends on limited ability of cancer cells to make arginine. PC cells that express high levels of argininosuccinate synthase 1 (ASS1), the rate limiting enzyme in cellular arginine synthesis, appear to be resistant to ADI-PEG. Our recent study showed that miR-1291 modulates factors in nutrient metabolism including ASS1 and GLUT1. We have developed a novel method to bioengineer miR-1291 agents for treatment. The aim of the current study was to evaluate if miR-1291 could enhance efficacy of metabolism-targeting drugs in PC.
Methods: Cell proliferation was measured by CellTiter-Glo assay. Mature miR-1291 levels were determined by stem-loop reverse transcription real-time PCR assay. GLUT1 and ASS1 protein levels in miR-1291-treated pancreatic cancer cell lines were assessed by Western blot. Glucose uptake in AsPC-1 and PANC-1 cell lines was determined with a fluorescent probe, 2-NBDG. 細胞增殖通過CellTiter-Glo測定法測量。 成熟的miR-1291水平是通過PCR測定確定。 在miR-1291處理的胰腺癌細胞中,GLUT1和ASS1的蛋白質水平通過Western測量。 AsPC-1和PANC-1細胞中的葡萄糖攝取用熒光探針,2-NBDG測量。
Results: A bioengineered pre-miR-1291 was processed to high levels of mature miR-1291 in PC cells. L3.3 and PANC-1 cells endogenously express high levels of ASS-1 and are resistant to arginine deprivation by ADI-PEG. ASS1 protein was downregulated by miR-1291 in L3.3 and PANC-1 cells and sensitized pancreatic cancer cells to ADI-PEG. In addition, miR-1291 significantly downregulated the protein levels of GLUT1 in AsPC-1 cells, leading to a lower glucose uptake capacity and a greater sensitivity to chemotherapy. 在胰腺癌細胞中,將生物合成的pre-miR-1291製造成高水平的成熟miR-1291。 L3.3和PANC-1細胞,內源性地表達了高水平的ASS-1,使對ADI-PEG有抗性。 在L3.3和PANC-1細胞中,miR-1291可下調ASS1蛋白,讓胰腺癌細胞對ADI-PEG是敏感的。 此外,在AsPC-1細胞,miR-1291還可以顯著下調GLUT1蛋白水平,導致癌細胞對葡萄糖攝取能力降低, 使癌細胞對化療靈敏度提高。
Conclusions: Our results demonstrate that miR-1291 sensitizes PC cells to arginine deprivation and chemotherapy through downregulation of ASS1 and GLUT1. These results provide new insight into the mechanistic actions of miR-1291 and provide a new strategy for treatment of pancreatic cancer. 我們的研究結果發現,通過下調ASS1和GLUT1,miR-129
Lenvatinib phase3 的參考資料請看下面: Lenvatinib OS Noninferior, PFS Improved Versus Sorafenib for Unresectable HCC 4 Jun 2017 ASCO 標題說OS不比Nexavar差,PFS比Nexavar好!!!
●Lenvatinib(Lenvima)---Eisai日本---想要取代Nexavar一線用藥地位的進度● Lenvatinib(Lenvima)---Eisai日本---目前已「遞出申請」HCC藥證的進度 1. Japan (June 2017) 2. United States and Europe (July 2017) 3. China (October 2017)--- 2017/12/27CFDA先給了 Priority Review and Approval,近期可以密切追蹤,CFDA什麼時候會給藥證! 4. Taiwan (December 2017).
免疫療法呢? 單藥治療5家都拿到了NSCLC的2-L! ●免疫+雙化療只有Merck拿到了FDA 1-L, EMA不給! ●Roche應該會拿到FDA and EMA 1-L→T+Avastin+雙化療 (IMpower150) ●所以接下來只要病人的錢夠多,聯藥應該是Roche的天下, 但是真的很煩,後面都有一班天才在追趕!
●看看Merck要幹什麼!Keytruda+IDO+雙化療!預計2017/12開始收案! Pembrolizumab Plus Epacadostat Alone or With Platinum-based Chemotherapy Versus Pembrolizumab Plus Platinum-based Chemotherapy Plus Placebo in Metastatic Non-Small Cell Lung Cancer NCT03322566 Estimated Enrollment: 1062 Anticipated Study Start Date: December 1, 2017 Estimated Study Completion Date: December 30, 2022 Estimated Primary Completion Date: October 26, 2022 (Final data collection date for primary outcome measure)
●看看BMS要幹什麼!Opdivo+IDO+雙化療!預計2017/12開始收案! Nivolumab and Epacadostat With Platinum Doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Non-Small Cell Lung Cancer NCT03348904 Estimated Enrollment: 630 Anticipated Study Start Date: December 2017 Estimated Study Completion Date: April 2022 Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)
所以Roche這時除了T+雙化療的IMpower 132之外,將再多一個研究項目 ●T+ADI+雙化療就是要對付Merck and BMS,以保住目前的領先優勢!!! 因為Roche是看過ADI+CIS+PEM的數據後才加入的!英國的癌症中心應該也是看過ADI+CIS+PEM的數據後才願意給Dr. Peter Szlosarek研究經費的!