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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-1
Sirolimus
Everolimus
Temsirolimus
Ridaforolimus
(Deforolimus)
C-42
substitution
O-(2hydroxyethyl)
Dihydroxymethyl
propionate
Dimethylphosphi
nate
Molecular
weight
957.6
1029.6
989.6
Formula
913.5

Increase solubility

Increase bioavailability
Rapalogs-2
Sirolimus
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
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
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
mTOR inhibitors and transplant
Three signal of T-cell activation
N Eng J Med, 2004;351:3715
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
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
level and FKBP8
acid
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)
Thank you for
your attention !!