mtor inhibitor in cancer

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mTOR Signaling and Drug Development in Cancer

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Page 1: mTOR inhibitor in cancer

mTOR Signaling and Drug Development in Cancer

Page 2: mTOR inhibitor in cancer

Nature Reviews Clinical Oncology 2010;7:209–19

2010 IF:10.787

Review article

Page 3: mTOR inhibitor in cancer

Outline

Introduction to mTOR inhibitors

mTOR signaling pathway

mTOR inhibitors and transplant

mTOR inhibitors and cancer

Current development of mTOR inhibitors

Conclusion

Page 4: mTOR inhibitor in cancer

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

Page 5: mTOR inhibitor in cancer

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)

Page 6: mTOR inhibitor in cancer

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

Page 7: mTOR inhibitor in cancer

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

Page 8: mTOR inhibitor in cancer

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

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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

Page 10: mTOR inhibitor in cancer

Management of Adverse Effects

Generally mild to moderate severity

Reversible with DC or dose reduction

Specific treatment for hyperlipidemia and hyperglycemia

Page 11: mTOR inhibitor in cancer

mTOR inhibitors in clinical development

Page 12: mTOR inhibitor in cancer

Introduction to mTOR inhibitors

mTOR signaling pathway

mTOR inhibitors and transplant

mTOR inhibitors and cancer

Current development of mTOR inhibitors

Conclusion

Page 13: mTOR inhibitor in cancer

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

Page 14: mTOR inhibitor in cancer

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

Page 15: mTOR inhibitor in cancer

Introduction to mTOR inhibitors

mTOR signaling pathway

mTOR inhibitors and transplant

mTOR inhibitors and cancer

Current development of mTOR inhibitors

Conclusion

Page 16: mTOR inhibitor in cancer

N Eng J Med, 2004;351:3715

mTOR inhibitors and transplantThree signal of T-cell activation

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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

Page 18: mTOR inhibitor in cancer

Introduction to mTOR inhibitors

mTOR signaling pathway

mTOR inhibitors and transplant

mTOR inhibitors and cancer

Current development of mTOR inhibitors

Conclusion

Page 19: mTOR inhibitor in cancer

PI3K/Akt/mTOR signaling pathway

Page 20: mTOR inhibitor in cancer

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

Page 21: mTOR inhibitor in cancer

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

Page 22: mTOR inhibitor in cancer

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

Page 23: mTOR inhibitor in cancer

Introduction to mTOR inhibitors

mTOR signaling pathway

mTOR inhibitors and transplant

mTOR inhibitors and cancer

Current development of mTOR inhibitors

Conclusion

Page 24: mTOR inhibitor in cancer

Dysregulation of PI3K/Akt/mTOR Signaling in Cancer

Nat. Rev. Drug Develop. 2006;5:671-88

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Clinical Trials of mTOR inhibitors in RCC

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Phase II Trials with Rapalogs

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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

Page 28: mTOR inhibitor in cancer

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

Page 29: mTOR inhibitor in cancer

Introduction to mTOR inhibitors

mTOR signaling pathway

mTOR inhibitors and transplant

mTOR inhibitors and cancer

Current development of mTOR inhibitors

Conclusion

Page 30: mTOR inhibitor in cancer

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

Page 31: mTOR inhibitor in cancer

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

Page 32: mTOR inhibitor in cancer

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 !!