1. mTOR Signaling and Drug Development in Cancer 財團法人台灣癌症臨床研究發展基金會

2.  Nature Reviews Clinical Oncology 2010;7:209–19  2010 IF:10.787  Review article

3. Outline  Introduction to mTOR inhibitors  mTOR signaling pathway  mTOR inhibitors and transplant  mTOR inhibitors and cancer  Current development of mTOR inhibitors  Conclusion

4. Background-1  Rapamycin – Triene macrolide antibiotic from S. hygroscopicus in a soil sample from Easter Island (Rapa Nui) in 1975 – Originally developed as antifungal agent – Sirolimus (Rapamune®) approved by FDA in 1999 as immunosuppressant used to prevent rejection in organ transplant

5. Background-2  mTOR inhibitors – Sirolimus, Everolimus, Temsirolimus, Ridaforolimus – mTOR kinase inhibitors  Immunosuppressive and antiproliferative properties  Clinical use  Immunosuppressant  Prevent kidney/heart rejection  Coronary stent coating  Cypher ®, Xience ®  Anticancer agent  Renal-cell carcinoma (RCC),  Mantle-cell lymphoma (MCL)

6. Rapalogs-1 SirolimusEverolimusTemsirolimusRidaforolimus (Deforolimus) Formula C-42 substitution -O-(2- hydroxyethyl) Dihydroxymethyl propionate Dimethylphosphi nate Molecular weight 913.5957.61029.6989.6  Increase solubility  Increase bioavailability

7. Rapalogs-2 SirolimusEverolimusTemsirolimusRidaforolimus (Deforolimus) Brand NameRapamune ® Certican ®, Afinitor ® Torisel ® Taltorvic ® FormulationOral IntravenousIntravenous, Oral IndicationPrevent renal rejection RCC, SEGA, Prevent renal/heart rejection RCC, MLCMetastatic soft tissue sarcoma or bone sarcoma Max doseNot report10 mg/day225 mg/m2/wk18.75 mg/day x5d→100 mg/wk x2wk Half-life(t1/2)46-78 hr26-30 hr9-27 hr35-70 hr Bioavailability Solution:18% Tablet:14% ~30%-16% SEGA: subependymal giant cell astrocytoma

8.  High blood-to-plasma ratio  Long plasma half-life  CYP450 metabolite –Drug-drug interaction  P-glycoprotein modulated oral absorption –Drug-drug interaction  Easily pass BBB –Effective in CNS Pharmacologic properties

9. Adverse Effects-1  Common AE: skin reactions, stomatitis, fatigue, diarrhea, thrombocytopenia, hyperlipidemia and hyperglycemia  Less common AE: renal toxicity, peripheral edema, interstitial pneumonitis and infections  Pneumonitis and infections are drug, dose, schedule related –Daily > weekly  Rare severe opportunistic infections

10. Management of Adverse Effects  Generally mild to moderate severity  Reversible with DC or dose reduction  Specific treatment for hyperlipidemia and hyperglycemia

11. mTOR inhibitors in clinical development

12.  Introduction to mTOR inhibitors  mTOR signaling pathway  mTOR inhibitors and transplant  mTOR inhibitors and cancer  Current development of mTOR inhibitors  Conclusion

13. mTOR  Protein kinase ubiquitous within cell  mTOR activation related to growth, nutrient, stress and energy signals leads to an increase protein synthesis  mTOR inhibit induce G1 cell cycle arrest and apoptosis in some cell line  PI3K/Akt signaling pathway  Upregulated by neoplasm

14. http://www.cellsignal.com/reference/pathway/mTor.html

15.  Introduction to mTOR inhibitors  mTOR signaling pathway  mTOR inhibitors and transplant  mTOR inhibitors and cancer  Current development of mTOR inhibitors  Conclusion

16. N Eng J Med, 2004;351:3715 mTOR inhibitors and transplant Three signal of T-cell activation

17. Rapalogs in solid organ transplant Sirolimus(Rapamune) 2 mg qd Everolimus(Certican) 0.75-1.5 mg q12h Adjuvent/alternative in combination Inhibit BK virus reactivation Reduce malignancy risk after transplant Regress mild PTLD, Kaposi sarcoma and nonmelanotic skin malignancy PTLD: Post-transplant Lymphoproliferative Disorders

18.  Introduction to mTOR inhibitors  mTOR signaling pathway  mTOR inhibitors and transplant  mTOR inhibitors and cancer  Current development of mTOR inhibitors  Conclusion

19. PI3K/Akt/mTOR signaling pathway

20.  Downstream signaling effectors and transcription factors  Influence cell proliferation, survival, angiogenesis, etc.  Rapalogs associate with FKBP12 complex block mTORC1  Rapalog-mediated mTORC1 inhibiton lead to ↑ mTORC2 activate Akt  Negative regulate by hypoxia, low amino acid level and FKBP8 mTORC1

21. mTORC2  Phosphorylate Akt at Ser473 and activate Akt  Rapalog-mediated mTORC1 inhibiton lead to ↑mTORC2 activate Akt  Potential resistance mechanism of rapalog  mTOR kinase inhibitor both inhibit mTORC1 and mTORC2

22. mTOR pathway feedback loops  S6K1 negative feedback insulin receptor  Rapalogs may induce other pathway such as mitogen-activated protein kinase (MAPK)  Limit antitumor effect of rapalogs

23.  Introduction to mTOR inhibitors  mTOR signaling pathway  mTOR inhibitors and transplant  mTOR inhibitors and cancer  Current development of mTOR inhibitors  Conclusion

24. Dysregulation of PI3K/Akt/mTOR Signaling in Cancer Nat. Rev. Drug Develop. 2006;5:671-88

25. Clinical Trials of mTOR inhibitors in RCC

26. Phase II Trials with Rapalogs

27. Limitation of mTOR inhibitors  Phosphorylation effects –mTORC2 formation sensitive in some cancer cell line –Poor correlation with antiproliferation was reported  Concentration-dependent effects –Some cell line such as lung, colon, prostate and breast –mTORC1 suppressed in low nanomolar concentration –mTORC2 suppressed in low micromolar concentration  Phosphatidic acid –Competitive mTOR –Determinant rapalogs sensitivity

28. mTOR inhibitors for cancer in future 1. Optimal drug administration 2. Markers of sensitivity and resistance 3. Combination of targeted agents 4. Development of more-effective mTOR inhibitors  mTOR kinase inhibitors

29.  Introduction to mTOR inhibitors  mTOR signaling pathway  mTOR inhibitors and transplant  mTOR inhibitors and cancer  Current development of mTOR inhibitors  Conclusion

30. Conclusion-1  mTOR is a central regulator of cell proliferation  In some tumor types, such as RCC and certain lymphomas, mTOR as key role in tumor cell proliferation and angiogenesis  Temsirolimus and everolimus are approved as monotherapy in advanced RCC

31. Conclusion-2  Temsirolimus also approved in MCL with notable improvement in PFS  Biomarkers to identify tumor types that are sensitive to mTOR inhibition  Combination target therapy augment anti-tumor activity and overcoming resistance PFS: progression-free survival

32. Recommendations In vivo concentration of endoxifen needed to maximally inhibit breast cancer proliferation is unknown Potent CYP2D6 inhibitors be avoided in women receiving tamoxifen (Strong) When the use of a drug known to potently inhibit CYP2D6 is necessary, consideration should be given to treat with the inhibitor for the shortest period of time possible. (Weak) Thank you for your attention !!