mtor signaling and drug development in cancer 財團法人台灣癌症臨床研究發展基金會
TRANSCRIPT
mTOR Signaling and Drug Development in Cancer
財團法人台灣癌症臨床研究發展基金會
Nature Reviews Clinical Oncology 2010;7:209–19
2010 IF:10.787
Review article
Outline
Introduction to mTOR inhibitors
mTOR signaling pathway
mTOR inhibitors and transplant
mTOR inhibitors and cancer
Current development of mTOR inhibitors
Conclusion
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
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)
Rapalogs-1Sirolimus Everolimus Temsirolimus Ridaforolimus
(Deforolimus)
Formula
C-42 substitution
- O-(2-hydroxyethyl)
Dihydroxymethyl propionate
Dimethylphosphinate
Molecular weight
913.5 957.6 1029.6 989.6
Increase solubility Increase bioavailability
Rapalogs-2Sirolimus Everolimus Temsirolimus Ridaforolimus
(Deforolimus)
Brand Name Rapamune® Certican®, Afinitor®
Torisel® Taltorvic®
Formulation Oral Oral Intravenous Intravenous, Oral
Indication Prevent renal rejection
RCC, SEGA, Prevent renal/heart rejection
RCC, MLC Metastatic soft tissue sarcoma or bone sarcoma
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%Tablet:14%
~30% - 16%
SEGA: subependymal giant cell astrocytoma
High blood-to-plasma ratioLong plasma half-lifeCYP450 metabolite
– Drug-drug interaction
P-glycoprotein modulated oral absorption– Drug-drug interaction
Easily pass BBB– Effective in CNS
Pharmacologic properties
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
Management of Adverse Effects
Generally mild to moderate severity
Reversible with DC or dose reduction
Specific treatment for hyperlipidemia and hyperglycemia
mTOR inhibitors in clinical development
Introduction to mTOR inhibitors
mTOR signaling pathway
mTOR inhibitors and transplant
mTOR inhibitors and cancer
Current development of mTOR inhibitors
Conclusion
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
http://www.cellsignal.com/reference/pathway/mTor.html
Introduction to mTOR inhibitors
mTOR signaling pathway
mTOR inhibitors and transplant
mTOR inhibitors and cancer
Current development of mTOR inhibitors
Conclusion
N Eng J Med, 2004;351:3715
mTOR inhibitors and transplantThree signal of T-cell activation
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
Introduction to mTOR inhibitors
mTOR signaling pathway
mTOR inhibitors and transplant
mTOR inhibitors and cancer
Current development of mTOR inhibitors
Conclusion
PI3K/Akt/mTOR signaling pathway
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
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
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
Introduction to mTOR inhibitors
mTOR signaling pathway
mTOR inhibitors and transplant
mTOR inhibitors and cancer
Current development of mTOR inhibitors
Conclusion
Dysregulation of PI3K/Akt/mTOR Signaling in Cancer
Nat. Rev. Drug Develop. 2006;5:671-88
Clinical Trials of mTOR inhibitors in RCC
Phase II Trials with Rapalogs
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
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
Introduction to mTOR inhibitors
mTOR signaling pathway
mTOR inhibitors and transplant
mTOR inhibitors and cancer
Current development of mTOR inhibitors
Conclusion
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
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
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)
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