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1. mTOR Signaling and Drug
Development in Cancer

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
Sirolimus Everolimus Temsirolimus Ridaforolimus
(Deforolimus)
Formula
C-42 - O-(2- Dihydroxymethyl Dimethylphosphi
substitution hydroxyethyl) propionate nate
Molecular 913.5 957.6 1029.6 989.6
weight
 Increase solubility
 Increase bioavailability

7. Rapalogs-2
Sirolimus Everolimus Temsirolimus Ridaforolimus
(Deforolimus)
Brand Name Rapamune® Certican®, Torisel® Taltorvic®
Afinitor®
Formulation Oral Oral Intravenous Intravenous, Oral
Indication Prevent renal RCC, SEGA, RCC, MLC Metastatic soft
rejection Prevent tissue sarcoma or
renal/heart bone sarcoma
rejection
Max dose Not report 10 mg/day 225 mg/m2/wk 18.75 mg/day
x5d→100 mg/wk
x2wk
Half-life(t1/2) 46-78 hr 26-30 hr 9-27 hr 35-70 hr
Bioavailability Solution:18% ~30% - 16%
Tablet:14%
SEGA: subependymal giant cell astrocytoma

8. Pharmacologic properties
 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

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

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. mTORC1
 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

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
Thank you for
should be given to treat with the inhibitor for
the shortest period of time possible. (Weak)
your attention !!