La vía PI3K como diana: abordaje y nuevas estrategias en resistencias

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1 La vía PI3K como diana: abordaje y nuevas estrategias en resistencias Ana Maria Gonzalez-Angulo, M.D. Associate Professor Section Chief, Clinical Research and Drug Development Breast Medical Oncology Systems Biology Valencia, Spain 4/2013

2 PI3K pathway Meric-Bernstam and Gonzalez-Angulo, J Clin Oncol 2009

3 PI3K pathway adaptor RTK PTEN PIP2 PIP3 p85 p110 Ras enos p53 Mdm2 NF B Bad IKK Forkhead AKT GSK-3 PDK1 Tuberin Hamartin Rac Bcl-XL Bim Fas-ligand p130 Rb2 p27 KIP1 Cyclin D1 Myc Rheb mtor 4E-BP1 S6K1 Ribosomal S6 Cell Survival Cell Cycle Cell Growth Protein Synthesis

4 PI3K pathway: metabolism Gonzalez-Angulo and Meric-Bernstam, Clin cancer Res 2009

5 PI3K pathway: angiogenesis Stoeltzing, Meric-Bernstam, Ellis, Cancer Cell 2006

6 Not all tumors are made the same: Different aberrations may require inhibitions at different levels

7 PI3K Pathway: genetic target in Growth Factors breast Cancer HER2 RAS PTEN PI3K INPP4B LKB1 Gene % Mutation % Amp/Del HER AKT AMPK PIK3CA KRAS 4 TSC 1/2 PTEN 4 8 INPP4B 55 (TN) mtor AKT1 3 S6K Tumor suppressor gene Oncogene Modified from W. Sellers at AACR 2011 Onc*Base and Beroukhim et al, Nature 2010

8 PI3K Pathway: Aberrations Growth Factors HER2 RAS PTEN BAD FOXO PI3K AKT TSC1/2 Are specific PI3K pathway genetic alterations predictive of target or therapeutic dependence? mtor S6K Tumor suppressor gene Oncogene Modified from W. Sellers at AACR 2011

9 PI3K pathway: distinct cancer states Are there distinctive dependences? Modified from W. Sellers at AACR 2011

10 PIK3CA Mutations DO NOT invariable activate AKT DO NOT invariable require AKT DO require PIK3C alpha PIK3CA mutations Growth Factors HER2 PI3K RAS PTEN AKT PDK1 TSC1/2 mtor S6K Vasudevan et al, Cancer Cell 2009 Wee et al, PNAS 2008 Modified from W. Sellers at SABCS 2009

11 PTEN loss Growth Factors PTEN loss leads to Constitutive AKT activation AKT dependence (AKT1) PIK3C Beta dependence PTEN HER2 PI3K AKT RAS PDK1 TSC1/2 mtor S6K Vasudevan et al, Cancer cell 2009 Nakamura et al, MCB 2000 Jia et al, Nature 2008 Modified from W. Sellers at SABCS 2009

12 RTK activation RTK activation Leads to PIK3C Alpha dependence If HER2 signaling depends on alpha, why PTEN loss creates trastuzumab resistance? PTEN loss can convert alpha to beta dependence Zhao et al, PNAS 2008 Jia et al, Nature 2008 Wee et al PNAS 2008 Modified from W. Sellers at SABCS 2009

13 PI3K Pathway: PIK3CA Mutations Growth Factors HER2 PI3K RAS Are specific PI3K pathway genetic alterations predictive of target or therapeutic dependence? PTEN BAD FOXO AKT TSC1/2 mtor PIK3CA mutation Confers dependence on PIK3C alpha RTK amplification Confers dependence on PIK3C alpha PTEN loss Confers dependence to PIK3C beta (probably more complex story) S6K Tumor suppressor gene Oncogene MEK/Erk activation as a consequence Modified from W. Sellers at AACR 2011

14 Biological justification of targeting the pathway in all breast cancer subtypes

15 Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signaling LTED cells exhibit increased PI3K/mTOR pathway activation PI3K pathway inhibition suppresses LTED cell growth, and prevents the emergence of hormoneindependent cells Miller et al, J Clin Invest 2010

16 Resistance to endocrine therapy in ER+ breast cancer is dependent upon PI3K signaling Miller et al, J Clin Invest 2010

17 Temsirolimus Reverses TAM resistance in Akt- Expressing Breast Cancer by Restoration of Apoptotic Response Control Temsirolimus Tam Tam + Temsirolimus WT MCF-7 MyrAkt1 MCF7 De Graffenried et al, Clin Cancer Res 2004

18 Temsirolimus Reverses TAM resistance in Akt- Expressing Breast Cancer by Restoration of Apoptotic Response Control Temsirolimus Tam Tam + Temsirolimus WT MCF-7 MyrAkt1 MCF7 De Graffenried et al, Clin Cancer Res 2004

19 Phase II neoadjuvant everolimus (RAD001) breast cancer study Newly diagnosed, untreated patients with ER + localized breast cancer likely to benefit from hormonal therapy Palpable tumor: > 2 cm diameter S C R E E N R A N D O M I Z E N = 138 N = 132 Letrozole 2.5 mg/d RAD mg/d Letrozole 2.5 mg/d Placebo 16 weeks Surgery Tumor biopsies (pretreatment) Tumor biopsies (day 15) Tumor samples (surgery) Baselga et al. J Clin Oncol 2009

20 Ki67d15 Cell cycle response (Ki-67) correlates with clinical response: role of PIK3CA mutations Day 15 Ki-67 score correlated with clinical response Reduction in Ki-67 at Day 15 Patients with PIK3CA exon 9 mut less responsive to letrozole as sensitive to everolimus + letrozole 80 0 PIK3CA e9 PIK3CA e20 mutant only mutant only PIK3CA wt only CR PR NC PD Everolimus + letrozole Letrozole Baselga et al. J Clin Oncol 2009

21 TAMRAD Schema Randomized Phase II Metastatic patients with prior exposure to AI A : Tamoxifen, 20 mg/d (TAM) B : Tamoxifen 20 mg/d + RAD mg/d (TAM + RAD) Stratification: Primary or secondary hormone resistance Primary: Relapse during adjuvant AI; progression within 6 months of starting AI treatment in metastatic setting Secondary: Late relapse ( 6 months) or prior response and subsequent progression to metastatic AI treatment No crossover planned Bachelot M, et al SABCS 2010

22 BOLERO-2 Schema N = 724 Postmenopausal ER+ HER2- ABC refractory to letrozole or anastrozole 2 1 Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) PFS OS ORR Bone Markers Safety PK Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-over Baselga et al. N Engl J Med 2012

23 # of Mutations PI3K Mutation Spectrum in BOLERO-2 NGS Population 230 patients with NGS data (187 Primary and 43 Metastatic samples) Total Sequenced population: 47% of Primary and 58% of Metastatic samples harbor a PIK3CA mutation Metastasis Primary Exon #Primary #Mets ABD RBD C2 Helical Kinase PIK3CA Primary: Exon 9 40%, Exon 20 44% Metastatic: Exon 9 20%, Exon 20 68% Total % Baselga et al. AACR 2013

24 H Score PTEN IHC: H Scores Overlayed With NGS Data on PTEN 11/19 (58%) with an H Score of 5 or less harbor an alteration of PTEN Tumor Samples with Matching NGS data Bi-allelic deletion Frameshift mutation InDel Missense mutation Nonsense mutation (Empty) Baselga et al. AACR 2013

25 PTEN Downregulation and Active PI3K Signaling Confer Trastuzumab Resistance in Cell Culture and in human HER2+ disease Berns K et al. Cancer Cell 2007

26 The PI3K Inhibitor GDC-0941 Inhibits the Growth of Both Trastuzumab-Sensitive and - Insensitive HER2-Amplified Cells Breast Cancer Cells resistant to Trastuzumab due to PTEN loss are sensitive to GDC-0941 Junttila et al, Cancer Cell 2009

27 Biomarker analysis in CLEOPATRA: a phase III, placebo controlled study of pertuzumab in HER2 positive, first-line metastatic breast cancer CLEOPATRA can only assist with prediction of the effect of adding pertuzumab to trastuzumab /chemotherapy, not HER2 therapies overall Baselga, et al. SABCS 2012

28 PIK3CA mutation associated with poorer prognosis (both arms) Mutations in PIK3CA were not associated with resistance to pertuzumab patients derived similar additional benefit independent of PIK3CA mutational status Baselga, et al. SABCS 2012

29 Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy 47 patients PR: 7/47 (15%) SD > 6 months: 9/47 (19%) Median PFS: 4.1 month Toxcicities: Fatigue, infection, and mucositis Morrow et al. J Clin Oncol 2011

30 Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy Morrow et al. J Clin Oncol 2011

31 Everolimus in HER2-positive MBC BOLERO 1 BOLERO 3

32 Neoadjuvant Systemic Therapy Courtesy A. Buzdar Liedtke et al. J Clin Oncol 2008

33 IGFBP2 Stathmin S6 AKT LKB1 Evidence of PI3K activation in primary resistant TNBC (cross-validated) Multivariable CoxPH model for all patients Protein HR 95% CI P value AKT IGFBP LKB S <0.01 Stathmin <0.01 Risk Score= *AKT *IGFBP *LKB *S *Stathmin AUC=0.856 Gonzalez-Angulo et al. (Submitted)

34 SUMMARY PI3K and MAPK Pathways RTK NF1 GDP RAS GTP KRAS IQGAP3 BRAF PI3K INPP4B ARAF PTEN GTP ERAS MEK AKT = mutation = mrna up ERK mtor FBXW7 = mrna dn = AMP = DEL Cell Proliferation S6K Cell Survival O'Shaughnessy, et al. SABCS 2011

35 Inhibition of MEK results in compensatory increase in PI3K/Akt, particularly in cells with loss of PTEN Mirzoeva et al. Clin. Cancer Res 2008 Saal et al. Nat. Genetics 2007 Modified from. Arteaga at SABCS 2009

36 Combined inhibition of PI3K and MEK is effective in all basal-like preclinical breast cancer models Modified from. Arteaga at SABCS 2009 Hoeflich et al. Clin Cancer Res 2009

37 Response to MEK/AKT inhibitors TN Breast Cancer Before treatment After 2 months treatment Dramatic response in one patient at 2 months Molecular analysis: Activated MAPK and PI3K pathways Gonzalez-Angulo AM (On-going study)

38 Conclusions The PI3K pathway is important in cancer growth through various important mechanisms PI3K pathway activation is an important mechanism for all subtypes of breast cancer, both in cancer growth and in therapy resistance Further translational studies are needed to clarify the different mechanisms of pathway activation, thus it can be targeted appropriately Clinical trials to evaluate the role PI3K pathway inhibitors at different levels of the pathway are needed We need more investigators like Dr. Arteaga to help us make sense of this pathway and to teach us how to design the good translational studies

39 Mentorship G.N. Hortobagyi G.B. Mills F. Meric-Bernstam Gonzalez-Angulo s Lab S. Liu X. Meng C. Phan H. Chen E. Tarco Meric-Berstam s Lab A. Akcakanat G. Singh Acknowledgements Collaborators MDACC Systems Biology K. Hale J. Mendelsohn Transcriptional Profiling L. Pusztai W.F. Symmans Tumor Bank A. Sahin BMO L. Hsu Surgical Oncology E. Mittendorf Funding By NIH MDACC Physician-Scientist Start up Funds Komen for the Cure BCRF Texas Fed of Business and Professional Women Commonwealth Foundation for Cancer Research AACR SU2C Dream Team ACS Clayton Foundation PI of Investigator Initiative Trials with Novartis, BMS, GSK, Abraxis, Roche Dx, Genomic Health Inc, Merck. Lab MTAs with NIH, Merck, Exelixis, Novartis, Xcovery, EMD Serono, Genentech, Bayer Bioinformatics K. Coombes Y. Ji Z. Ju W. Liu Biostatistics D. Berry K. Do X. Lei T and H&N G. Blumenschein Phase I Razelle Kurzrock Collaborators Outside MDA C. Perou, L. Carey I. Krop R. Bernards, H. Horlings A. Lluch, J. Ferrer C. Arteaga J. Baselga J. Tabernero, J. Rodon J. Gray M. Ellis C. Hudis, N. Rosen C. Sotiriou P. Lorusso AL. Borresen-Dale F. Andre M. Pollak

40 Thank you!!!!