Role of the mTOR Pathway in Endocrine Therapy- Resistant Breast Cancer Ana M. Gonzalez Ana M. Gonzalez-Angulo, M.D. Angulo, M.D. Associate Professor Associate Professor Breast Medical Oncology Breast Medical Oncology Systems Biology Systems Biology Sao Paulo, Brazil, 3/2012 Sao Paulo, Brazil, 3/2012
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Role of the mTOR Pathway in Endocrine Therapy- Resistant Breast … · 2012. 3. 15. · Modified from W. Sellers at SABCS 2009. PTEN loss HER2 PI3K PTEN Growth Factors RAS PDK1 PTEN
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Role of the mTOR Pathway in Endocrine Therapy-
Resistant Breast Cancer
Ana M. GonzalezAna M. Gonzalez--Angulo, M.D.Angulo, M.D.Associate ProfessorAssociate Professor
Breast Medical OncologyBreast Medical OncologySystems BiologySystems Biology
Sao Paulo, Brazil, 3/2012Sao Paulo, Brazil, 3/2012
PI3K PI3K pathwaypathway
Meric-Bernstam and Gonzalez-Angulo, J Clin Oncol 2009
Modified from W. Sellers at SABCS 2009Onc*Base and Beroukhim et al, Nature 2010
PI3K pathway: distinct cancer statesPI3K pathway: distinct cancer statesAre there distinctive dependences?Are there distinctive dependences?
Modified from W. Sellers at AACR 2011
PIK3CA mutationsPIK3CA mutations
HER2HER2
PI3KPI3K
PTENPTEN
Growth Growth FactorsFactors
RASRAS
PDK1PDK1
PIK3CA MutationsPIK3CA MutationsDO NOT invariable activate AKTDO NOT invariable activate AKTDO NOT invariable require AKTDO NOT invariable require AKTDO require PIK3C alphaDO require PIK3C alpha
mTORmTOR
S6KS6K
AKTAKT
TSC1/2TSC1/2
PDK1PDK1
Vasudevan et al, Cancer Cell 2009Wee et al, PNAS 2008Modified from W. Sellers at SABCS 2009
PTEN lossPTEN loss
HER2HER2
PI3KPI3K
PTENPTEN
Growth Growth FactorsFactors
RASRAS
PDK1PDK1
PTEN loss leads toPTEN loss leads toConstitutive AKT activationConstitutive AKT activationAKT dependence (AKT1)AKT dependence (AKT1)PIK3C Beta dependencePIK3C Beta dependence
mTORmTOR
S6KS6K
AKTAKT
TSC1/2TSC1/2
PDK1PDK1
Vasudevan et al, Cancer cell 2009Nakamura et al, MCB 2000Jia et al, Nature 2008Modified from W. Sellers at SABCS 2009
RTK activationRTK activationLeads to PIK3C Alpha dependenceLeads to PIK3C Alpha dependence
RTK activationRTK activation
If HER2 signaling depends on If HER2 signaling depends on alpha, why PTEN loss creates alpha, why PTEN loss creates trastuzumabtrastuzumab resistance?resistance?
PTEN loss can convert alpha to PTEN loss can convert alpha to beta dependencebeta dependence
Zhao et al, PNAS 2008Jia et al, Nature 2008Wee et al PNAS 2008Modified from W. Sellers at SABCS 2009
Resistance to endocrine therapy in ER+ breast Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signalingcancer is dependent upon PI3K signaling
PI3K pathway inhibition suppresses PI3K pathway inhibition suppresses LTED cell growth, and prevents LTED cell growth, and prevents the emergence of hormonethe emergence of hormone--independent cellsindependent cells
Miller et al, J Clin Invest 2010
Resistance to endocrine therapy in ER+ breast Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signalingcancer is dependent upon PI3K signaling
Miller et al, J Clin Invest 2010
Frequency of mutations in the Frequency of mutations in the PIK3CA, PIK3CA, and and AKT1AKT1genes in 547 human breast cancers and 41 breast genes in 547 human breast cancers and 41 breast
cancer cell linescancer cell lines
Tumor subtypeTumor subtype MutationMutation
PIK3CAPIK3CA catalytic catalytic domain*domain*
PIK3CAPIK3CA other other †† PIK3CAPIK3CA totaltotal AKT1AKT1 E17KE17K
All human breast tumorsAll human breast tumors 73/547 (13.3%)73/547 (13.3%) 44/547 (8.0%)44/547 (8.0%) 117/547 (21.4%)117/547 (21.4%) 6/418 (1.4%)6/418 (1.4%)
Human breast HRHuman breast HR++ 48/232 (20.7%)48/232 (20.7%) 32/232 (13.8%)32/232 (13.8%) 80/232 (34.5%)80/232 (34.5%) 6/232 (2.6%)6/232 (2.6%)
Human breast HER2Human breast HER2++ 13/75 (17.3%)13/75 (17.3%) 4/75 (5.3%)4/75 (5.3%) 17/75 (22.7%)17/75 (22.7%) 0/75 (0%)0/75 (0%)
Human breast TNHuman breast TN 12/240 (5.0%)12/240 (5.0%) 8/240 (3.3%)8/240 (3.3%) 20/240 (8.3%)20/240 (8.3%) 0/111 (0%)0/111 (0%)
All breast cancer cell linesAll breast cancer cell lines 7/41 (17.1%)7/41 (17.1%) 9/41 (22%)9/41 (22%) 16/41 (39%)16/41 (39%) 0/41 (0%)0/41 (0%)
Breast cancer cell lines HR+Breast cancer cell lines HR+ 1/12 (8.3%)1/12 (8.3%) 3/12 (25%)3/12 (25%) 4/12 (33.3%)4/12 (33.3%) 0/12 (0%)0/12 (0%)
Breast cancer cell lines HER2+Breast cancer cell lines HER2+ 2/10 (20%)2/10 (20%) 4/10 (40%)4/10 (40%) 6/10 (60%)6/10 (60%) 0/10 (0%)0/10 (0%)
Breast cancer cell lines Breast cancer cell lines TNTN 4/19 (21%)4/19 (21%) 2/19 (10.5%)2/19 (10.5%) 6/19 (31.6%)6/19 (31.6%) 0/19 (0%)0/19 (0%)
mTOR
PI3K pathway activationPI3K pathway activation
Courtesy of S. Johnston
TamTamTemsirolimusTemsirolimusControlControl
WTWTMCFMCF--77
Tam + TemsirolimusTam + Temsirolimus
TemsirolimusTemsirolimus Reverses TAM resistance in Reverses TAM resistance in AktAkt--Expressing Breast Cancer by Restoration of Expressing Breast Cancer by Restoration of
Apoptotic ResponseApoptotic Response
MyrAkt1MyrAkt1MCF7MCF7
MCFMCF--77
De Graffenried et al, Clin Cancer Res 2004
TamTamTemsirolimusTemsirolimusControlControl
WTWTMCFMCF--77
Tam + TemsirolimusTam + Temsirolimus
TemsirolimusTemsirolimus Reverses TAM resistance in Reverses TAM resistance in AktAkt--Expressing Breast Cancer by Restoration of Expressing Breast Cancer by Restoration of
Apoptotic ResponseApoptotic Response
MyrAkt1MyrAkt1MCF7MCF7
MCFMCF--77
De Graffenried et al, Clin Cancer Res 2004
RAD001 Added to Letrozole Causes RAD001 Added to Letrozole Causes GI Accumulation and Increased ApoptosisGI Accumulation and Increased Apoptosis
•• Newly diagnosed, untreated patients with ERNewly diagnosed, untreated patients with ER++ localized breast localized breast cancer likely to benefit from hormonal therapycancer likely to benefit from hormonal therapy
•• Palpable tumor: Palpable tumor: > 2 cm diameter> 2 cm diameter
RRAANN Letrozole 2.5 mg/dLetrozole 2.5 mg/d
RAD001 10 mg/dRAD001 10 mg/d
N = 138N = 138SSCC
Phase II Phase II neoadjuvantneoadjuvant everolimuseverolimus(RAD001) breast cancer study(RAD001) breast cancer study
Reduction in pS6240 and pS6235 reveals everolimusReduction in pS6240 and pS6235 reveals everolimus--treated patientstreated patients
--140140
--120120
--100100
--8080
--6060
--4040
--2020
Chang
e in
H S
core
(% P
ositive f
or K
i67)
Chang
e in
H S
core
(% P
ositive f
or K
i67)
Everolimus + letrozoleEverolimus + letrozole
LetrozoleLetrozole
Baselga et al. J Clin Oncol 2009
Cell cycle response (KiCell cycle response (Ki--67) correlates with clinical 67) correlates with clinical response: role of PIK3CA mutationsresponse: role of PIK3CA mutations
Reduction in KiReduction in Ki--67 at Day 15 67 at Day 15
Patients with PIK3CA Patients with PIK3CA exonexon 9 9 mutmutless responsive to less responsive to letrozoleletrozole as as sensitive to sensitive to everolimuseverolimus + + letrozoleletrozole
00
PIK3CA e9PIK3CA e9mutant onlymutant only
PIK3CA e20PIK3CA e20mutant onlymutant only
PIK3CA PIK3CA wt onlywt only
6060
8080
Day 15 Day 15 KiKi--67 score correlated 67 score correlated with clinical responsewith clinical response
TAMRAD SchemaTAMRAD SchemaRandomized Phase IIRandomized Phase IIMetastatic patients with prior exposure to AIMetastatic patients with prior exposure to AI
•• Stratification: Primary or secondary hormone resistanceStratification: Primary or secondary hormone resistance•• Primary: Relapse during adjuvant AI; progression within 6 Primary: Relapse during adjuvant AI; progression within 6
months of starting AI treatment in metastatic settingmonths of starting AI treatment in metastatic setting•• Secondary: Late relapse (≥ 6 months) or prior response Secondary: Late relapse (≥ 6 months) or prior response
and subsequent progression to metastatic AI treatmentand subsequent progression to metastatic AI treatment•• No crossover plannedNo crossover planned
Hazard Ratio (HR) = 0.53; 95% CI (0.35Hazard Ratio (HR) = 0.53; 95% CI (0.35--0.81)0.81)Exploratory logExploratory log--rank: rank: P = P = 0.00260.0026
Fulvestrant in ER positive breast cancer Fulvestrant in ER positive breast cancer with GDCwith GDC--0941 and GDC0941 and GDC--0980 0980 InhibitorsInhibitors
C2D1C2D1C1D1C1D1 C1D15C1D15DD--2828
RegistrationRegistration
“run“run--in”in”screeningscreening
FulvestrantFulvestrant500mg500mg
FulvestrantFulvestrant500mg500mg
Arm B Arm B -- GDCGDC--0980 (Daily)0980 (Daily)
C3D1C3D1
Arm C Arm C –– Placebo (Daily)Placebo (Daily)
FulvestrantFulvestrant500mg/Q4w500mg/Q4w
FulvestrantFulvestrant500mg/Q4w500mg/Q4w
D1D1--D28 D28 D1D1--D28 D28
NodeNode--positive HRpositive HR--positive and HER2positive and HER2--negative breast cancernegative breast cancer
Patients consent to studyPatients consent to study--sponsored RSsponsored RStesting if not already donetesting if not already done
RECURRENCE RECURRENCE
Number of positive nodes ?Number of positive nodes ?
11--3 positive3 positive4+ positive4+ positive
RS > 25RS > 2511--3 positive nodes and 3 positive nodes and
Phase III Randomized, placeboPhase III Randomized, placebo--controlled clinical trial evaluating the use of controlled clinical trial evaluating the use of adjuvant endocrine therapy +/adjuvant endocrine therapy +/-- everolimuseverolimus in patients with highin patients with high--risk, noderisk, node--
positive, hormone receptorpositive, hormone receptor--positive and HER2positive and HER2--neu normal breast cancer neu normal breast cancer
11--3 positive nodes and 3 positive nodes and RS > 25 or 4+ positive RS > 25 or 4+ positive
nodesnodes
A phase II A phase II neoadjuvantneoadjuvant trial of BEZtrial of BEZ--235 in 235 in combination with endocrine therapy in postcombination with endocrine therapy in post--menopausal patients with operable hormone menopausal patients with operable hormone
receptorreceptor--positive breast cancerpositive breast cancer
Breast Cons SurgeryBreast Cons SurgeryKiKi--6767TUNELTUNEL
PP--Akt, etcAkt, etcmicroarraysmicroarrays
RPPARPPA
2:1 randomization2:1 randomization
LetrozoleLetrozolePlaceboPlacebo
ConclusionsConclusions•• The PI3K pathway is one of the most important active signaling pathways in The PI3K pathway is one of the most important active signaling pathways in
cancer growth through various mechanismscancer growth through various mechanisms
•• Modulation of signal transduction pathway may modulate activity of Modulation of signal transduction pathway may modulate activity of endocrine therapy and influence outcome… Assuming of course that the endocrine therapy and influence outcome… Assuming of course that the tumor is “addicted” to the intended target!!tumor is “addicted” to the intended target!!
•• PI3K PI3K pathway activation is an important component in all subtypes of breast pathway activation is an important component in all subtypes of breast cancer, both in cancer growth and in therapy resistancecancer, both in cancer growth and in therapy resistancecancer, both in cancer growth and in therapy resistancecancer, both in cancer growth and in therapy resistance
•• The PI3K pathway is a common The PI3K pathway is a common mechanism of mechanism of endocrine therapy resistanceendocrine therapy resistance. . Benefit Benefit is is impressive.impressive.
Will Will be studied in the adjuvant be studied in the adjuvant settingsetting
•• Clinical Clinical trials to evaluate the role PI3K pathway inhibitors at different trials to evaluate the role PI3K pathway inhibitors at different levels of the pathway are ongoing and should have extensive correlative levels of the pathway are ongoing and should have extensive correlative components to be able to decipher the best use of these drugs according to components to be able to decipher the best use of these drugs according to the molecular aberrations of the the molecular aberrations of the tumorstumors
•• G.N. HortobagyiG.N. Hortobagyi•• G.B. MillsG.B. Mills•• F. MericF. Meric--BernstamBernstam
GonzalezGonzalez--Angulo’s LabAngulo’s Lab•• S. LiuS. Liu•• X. MengX. Meng•• C. PhanC. Phan•• H. H. ChenChen•• E. E. TarcoTarco
MericMeric--Berstam’s LabBerstam’s Lab•• A. AkcakanatA. Akcakanat
Collaborators MDACCCollaborators MDACC
Systems BiologySystems Biology•• KK. . HaleHale•• J. J. MendelsohnMendelsohnTranscriptional ProfilingTranscriptional Profiling•• L. PusztaiL. Pusztai•• W.F. Symmans W.F. Symmans Tumor BankTumor Bank•• A. SahinA. SahinBMOBMO•• L. HsuL. Hsu
Surgical OncologySurgical Oncology•• E. MittendorfE. Mittendorf
BioinformaticsBioinformatics•• K. Coombes K. Coombes •• Y. JiY. Ji•• Z. JuZ. Ju•• W. LiuW. LiuBiostatisticsBiostatistics•• D. BerryD. Berry•• K. DoK. Do•• X. LeiX. Lei
T and H&NT and H&N•• G. BlumenscheinG. BlumenscheinPhase IPhase I
•• C. Perou, L. CareyC. Perou, L. Carey•• I. KropI. Krop•• R. Bernards, H. HorlingsR. Bernards, H. Horlings•• A. Lluch, J. FerrerA. Lluch, J. Ferrer•• C. C. ArteagaArteaga•• J. BaselgaJ. Baselga•• J. J. TaberneroTabernero, , J. RodonJ. Rodon•• J. GrayJ. Gray•• M. EllisM. Ellis•• C. Hudis, N. RosenC. Hudis, N. Rosen•• C. C. SotiriouSotiriou•• P. P. LorussoLorusso•• AL. BorresenAL. Borresen--DaleDale•• A. AkcakanatA. Akcakanat
•• G. SinghG. Singh•• E. MittendorfE. Mittendorf Phase IPhase I
•• Razelle KurzrockRazelle Kurzrock
•• AL. BorresenAL. Borresen--DaleDale•• F. F. AndreAndre•• M. PollakM. Pollak
Funding ByFunding By•• NIHNIH•• MDACC PhysicianMDACC Physician--Scientist Start up FundsScientist Start up Funds•• Komen for the CureKomen for the Cure•• BCRFBCRF•• Texas Fed of Business and Professional WomenTexas Fed of Business and Professional Women•• Commonwealth Foundation for Cancer ResearchCommonwealth Foundation for Cancer Research•• AACR SU2C Dream TeamAACR SU2C Dream Team•• ACSACS•• Clayton Foundation Clayton Foundation
•• PI of Investigator Initiative Trials with Novartis, BMS, GSK, PI of Investigator Initiative Trials with Novartis, BMS, GSK, Abraxis, Roche Dx, Genomic Health Inc, Merck.Abraxis, Roche Dx, Genomic Health Inc, Merck.•• Lab MTAs with NIH, Merck, Exelixis, Novartis, Xcovery, Lab MTAs with NIH, Merck, Exelixis, Novartis, Xcovery, EMD Serono, Genentech, BayerEMD Serono, Genentech, Bayer