mTOR抑制劑在癌癥治療中的用

1、mtor inhibitors (mtor抑制劑抑制劑)in cancer therapyruirong yuan, md, phdoncology, novartis &va medical center, umdnjmtor mammalian target of rapamycin (哺乳動(dòng)物雷帕霉素靶蛋白)a central regulator of cell growth and metabolism (控制細(xì)胞的生長(zhǎng)和代謝控制細(xì)胞的生長(zhǎng)和代謝) mtor is an intracellular serine-threonine kinase (絲氨絲氨酸酸-蘇氨酸激酶蘇氨酸

2、激酶) mtor is downstream of growth factor/nutrient and pi3k/akt signalling pathway (信號(hào)通路中的下游分子信號(hào)通路中的下游分子) mtor is a central regulator of protein synthesis activated by mutations in cancernutrientsgrowth factorsigf, egf, vegf etcpi3kglucose, amino acids, etc aktmtor(哺乳動(dòng)物雷帕霉素靶蛋白)mtor pathway activationp

3、roteinsynthesisgrowth factors cell growth &proliferationbioenergeticsangiogenesismtorpi3kegfigfvegfaktraserablampkrastsc1tsc2ptenlkb1regulators of mtor activity mtor activating mtor deactivatingmutations of pi3k, akt, ras, gfrs, tsc1/2, pten.) may result in inappropriate activation of the pathwa

4、y and loss of control of functions normally regulated by mtoractivation of mtor can result in loss of cell growth control and enhanced cell metabolism in cancer cells (無(wú)限制的癌細(xì)胞無(wú)限制的癌細(xì)胞生長(zhǎng)和擴(kuò)散生長(zhǎng)和擴(kuò)散)mtor activationincreased synthesis of multiple proteins, including:hypoxia-inducible factors (hifs, 低氧低氧誘導(dǎo)誘

5、導(dǎo)因子因子): expression of angiogenic growth factors (eg, vegf/ pdgf) (rcc)cyclin d1: promotes progression through the cell cycle (mcl)proteins necessary to transport nutrients (amino acids and glucose) into the cellmtor-linked pathway activation in selected cancersbreastnetcolorectallungrenal cellp-akt,

6、 42%pten, 15%41%her2, 30%36%pi3-k, 18%26%tsc1/tsc2igf-1/igf-1rvhlras, 50%p-akt, 46%pten, 35%pi3-k, 20%32%egfr, 70%egfr, 32%60%p-akt, 23%50%ras, 30%pten, 24%tgfa a/tgfb b1, 60%100%vhl, 30%50%igf-1/igf-ir, 39%-69%p-akt, 38%pten, 31%tsc1/tsc2nf-k kb, 33%lymphomaalk p-aktnf-k kbcyclin d1rapamycin (sirol

7、imus)-雷帕霉素雷帕霉素 isolated in 1975 on the island of rapa nui approved for prevention of kidney transplant rejection in the us and europe found to have broad anticancer activity against a panel of human cancer cell lines by the u.s. nci in the 1980s rapamycin derivatives with improved pharmacokinetic pr

8、operties clinical development of mtor inhibitors as anticancer agentsclinical development of mtor inhibitors(derivates of rapamycin ) temsirolimus (cci-779, torisel, wyeth pharmaceuticals) everolimus (rad001, afinitor, novartis) deforolimus (ap23573, ariad pharmaceuticals and merck & co)mtor inh

9、ibition: similar mechanism of action mtor inhibition (similar mechanism of action)mtor inhibitors: derivates of rapamycinformulation, and administration: different temsirolimus: administered intravenously deforolimus: administered intravenously everolimus: administered orallymrccstandards for rcc th

10、erapy by phase iii trial after asco 2007 settingtreatment- navepreviously treatedgood or intermediate risk*poor risk*prior cytokine prior vegfr-tki prior mtor inhibitorphase iiisunitinibbevacizumab + ifn-a atemsirolimussunitinibsorafenib?*mskcc risk statusrad001(everolimus)ooo hooonoooooo hooh 10 mg

11、/ 5 mgeverolimus (rad001) (口服口服mtor抑制劑抑制劑) rapamycin derivative selective inhibitor of mtor metabolized by cyp3a4 isozyme, t1/2 30 hours crosses bloodbrain barrier biomarker-guided monotherapy dose selection 10 mg/day 70 mg/week everolimus (rad001, afinitor) in rccrationale about 75% of clear cell c

12、arcinomas, the function of the von hippel lindau (vhl) gene is lost, causing accumulation of hif (低氧低氧誘導(dǎo)誘導(dǎo)因子因子)/expression of vegf and pdgf. other proteins in the pi3k-akt-mtor pathway are often deregulated in rcc unmet medical needs for patients who have failed vegft-tki therapy everolimus has both

13、 antiangiogenic and antiproliferative activity; response were observed in previously treated mrcc (uncontrolled phase ii study)better inhibition of p70s6 kinase with daily schedule01234567tumor050100time, daysinhibition of p70s6 kinase activity, % 5020703010510daily dosing, mgweekly dosing, mgcontin

14、uous target inhibition is predicted to be achievable through the use of daily dosing schedulestanaka et al., manuscript in preparation 2007.phase ii trial of rad001 in mrcc (amato)jac et al. asco, 2007. abstract 5107n=37n=39median = 11.17+(2.00 31.53+) monthsmedian = 24.17+ monthsprogression-free su

15、rvivaloverall survivaltime (months)time (months)objectives (end point)primary: pfssecondary: safety; response; patients reported outcome; osrecord-1 (renal cell cancer treatment with oral rad001 given daily) 隨機(jī)iii期試驗(yàn):比較rad001與安慰劑 (phase iii, double-blind, randomized trial of rad001+ bsc vs placebo+b

16、sc)record-1 phase iii study design(隨機(jī)iii期試驗(yàn):比較rad001與安慰劑) 410 patients randomized between september 2006 and october 2007 second interim analysis cut-off: october 15, 2007, based on 191 pfs events independent data monitoring committee recommended termination of studyrandomization2:1placebo + bscupon

17、 disease progressioninterim analysisinterim analysisn=410 stratification prior vegfrtki: 1 or 2舒尼替尼舒尼替尼或索拉非尼治療后或索拉非尼治療后進(jìn)展的患者進(jìn)展的患者 mskcc risk group: favorable, intermediate, or poor=finalanalysiseverolimus + bscplacebo + bsceverolimus + bscplacebo + bsc(n=138)rad001 + bsc(n=272)透明細(xì)胞癌透明細(xì)胞癌treatment gi

18、ven in 28-day cyclesprogression-free survival by treatment central radiology review100806040200024681012probability, %hazard ratio = 0.30 95% ci 0.22, 0.40median pfseverolimus: 4.0 moplacebo: 1.9 molog rank p value 0.001 everolimus (n = 272) placebo (n = 138) months延長(zhǎng)無(wú)進(jìn)展生存期延長(zhǎng)無(wú)進(jìn)展生存期motzer rj, et al.

19、asco 2008 and lancet 2008; 372: 44956progression-free survival by treatment investigator assessment100806040200probability (%)024681012monthshazard ratio = 0.3195% ci 0.23, 0.41median pfseverolimus: 4.6 moplacebo: 1.8 molog rank p value 0.001 everolimus (n = 272) placebo (n = 138) probability, %motz

20、er rj, et al. asco 2008 and lancet 2008; 372: 44956subgroup analysis of progression-free survival central radiology review1. motzer et al. j clin oncol. 2004;22:454-463.hrncentral review0.30410investigator review0.31410mskcc riskfavorable0.35118intermediate0.25231poor0.3961prior txsorafenib only0.29

21、119sunitinib only0.30184both0.28107age 65 yrs0.32259 65 yrs0.29151sexmale0.29317female0.3693regionu.s. & canada0.24130europe0.37251japan & australia0.102900.41.01.4hazard ratioeverolimus benefitplacebo benefit1.20.80.60.21motzer rj, et al. asco 2008 and lancet 2008; 372: 44956treatment-relat

22、ed adverse events*stomatitis (口腔炎口腔炎) asthenia / fatigue (疲勞疲勞)rash (皮皮 疹疹)diarrhea (腹瀉腹瀉)anorexia (厭食厭食)nausea (惡心惡心)mucosal inflammationvomiting coughedema peripheralinfectionspneumonitisdyspneaeverolimus%, (n = 269)all grades403725171615141212101088grade 3 3 3 1 1 1 0 1 0 0 0 3 3 1placebo%, (n =

23、135)all grades82443682443202grade 3 0 1 0 0 0 0 0 0 0 0 0 0 0* 10% of everolimus patients and additional selected aes.significant difference between sum of grade 3/4 events for everolimus and placebo groups (p .05) .conclusions everolimus prolongs progression-free survival in rcc patients after progression on vegfr-tki therapies everolimus is the first and only