Dr. José Baselga - Simposio Internacional 'Terapias oncológicas avanzadas'
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Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
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Dr. José Baselga - Simposio Internacional 'Terapias oncológicas avanzadas'
- 1. 10/19/2014 1 Avances en el tratamiento de precisión en cáncer Jose Baselga www. MSKCC.org 2014. Simposio Internacional Fundación Areces LB Alexandrov et al. Nature 500, 1‐7 (2013) doi:10.1038/nature12477 Prevalence of somatic mutations across human cancer types Melanoma Lung Squamous Lung Adenocarcinoma Bladder Lung small Cell Oesophagus Colorectum Cervix Head and neck Stomach Uterus Liver Kidney clear cell Kidney Papillary Ovary Prostate Myeloma Lymphoma B Cell Glioma Low Grade Breast Pancreas Giloblastoma Neuroblastoma CLL Thyroid Kidney Chromophobe AML Medulloblastoma ALL Pilocytic Astrocytoma
- 2. 10/19/2014 2 The Vision for “Precision Medicine” in Cancer Genotype first, select target, monitor early response 4 Haber, Gray, Baselga, Cell, 2011 Therapies for HER2-positive breast cancer Baselga. Nat Rev Cancer 2009 Trastuzumab Pertuzumab T-DM1 Lapatinib, Neratinib HSP-90 Inhib
- 3. 10/19/2014 3 Trastuzumab enhances overall survival in HER2 + metastatic breast cancer Herceptin® + CT CT alone p<0.05 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 45 50 Time (months) Probability of survival 18 27 1. Slamon DJ, et al. N Engl J Med 2001;344:783–789; 2. Smith IE, et al. Anticancer Drugs 2001;12(Suppl. 4):S3–S10
- 4. 10/19/2014 4 San Antonio Breast Cancer Symposium – Henry B. Gonzalez Convention Center – December 4–8, 2012 Ptz+T+D Pla+T+D 0 5 10 15 20 25 30 35 40 100 90 80 70 60 50 40 30 20 10 0 Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 7 CLEOPATRA: Significant improvement in median PFS1,2 (and OS)3 with pertuzumab D, docetaxel; Ptz, pertuzumab; T, trastuzumab PFS time (months) HR = 0.62 95% CI 0.51, 0.75 p < 0.001 12.4 18.5 Independently-assessed PFS (%) n at risk Ptz+T+D 402 345 267 139 83 32 10 0 0 Pla+T+D 406 311 209 93 42 17 7 0 0 3 ); Baselga J, et al. N Engl J Med 2012; 366: 109–119; Final OS Analysis Median follow-up 50 months (range 0–70 months) 8 OS (%) 100 90 80 70 60 50 40 30 20 10 0 HR 0.68 95% CI = 0.56, 0.84 p = 0.0002 0 10 20 30 40 50 60 70 Time (months) ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab. Ptz + T + D Pla + T + D 371 318 268 226 104 28 1 350 289 230 179 91 23 0 n at risk Ptz + T + D Pla + T + D 402 406 40.8 months 56.5 months Δ 15.7 months
- 5. 10/19/2014 5 Next‐Generation Sequencing is Transforming Molecular Diagnostics • Allows for sequencing many genes at once • Single test: more efficient workflow and use of tissue • Survey greater fraction of genome • Can interrogate entire exons • Not limited to hotspots • Suitable for tumor suppressor genes • Enables rapid addition of newly identified biomarkers • Can detect additional types of genomic alterations • Copy number alterations • Structural rearrangements • Greater sensitivity for low allele frequency events MSK‐IMPACT™: Integrated Mutation Profiling of Actionable Cancer Targets Capture DNA for 341 cancer genes “Next gen” Sequencing (HiSeq 2500) Prepare DNA from Tumor and Normal cells Align to genome and analyze Won et al., Journal of Visualized Experiments, Oct 2013 Somatic Alterations (specific to tumor): Sequence Mutations Copy Number Gains and Losses Select Rearrangements MSK Confidential 6
- 6. 10/19/2014 6 Selection of 341 Key Cancer Genes Gene Selection Committee: Representatives from Pathology, Medical Oncology, Radiation Oncology, HOPP, and Computational Biology Additional Input from solid tumor teams, phase I and immunotherapy clinics, CMBT, and clinical genetics service ABL1 BARD1 CD79B DDR2 ESR1 FOXP1 IKBKE MAP2K1 MUTYH PALB2 POLE RET SMARCB1 TNFRSF14 AKT1 BBC3 CDC73 DICER1 ETV1 FUBP1 IKZF1 MAP2K2 MYC PARK2 PPP2R1A RFWD2 SMARCD1 TOP1 AKT2 BCL2 CDH1 DIS3 ETV6 GATA1 IL10 MAP2K4 MYCL1 PARP1 PRDM1 RHOA SMO TP53 AKT3 BCL2L1 CDK12 DNMT1 EZH2 GATA2 IL7R MAP3K1 MYCN PAX5 PRKAR1A RICTOR SOCS1 TP63 ALK BCL2L11 CDK4 DNMT3A FAM123B GATA3 INPP4A MAP3K13 MYD88 PBRM1 PTCH1 RIT1 SOX17 TRAF7 ALOX12B BCL6 CDK6 DNMT3B FAM175A GNA11 INPP4B MAPK1 MYOD1 PDCD1 PTEN RNF43 SOX2 TSC1 APC BCOR CDK8 DOT1L FAM46C GNAQ INSR MAX NBN PDGFRA PTPN11 ROS1 SOX9 TSC2 AR BLM CDKN1A E2F3 FANCA GNAS IRF4 MCL1 NCOR1 PDGFRB PTPRD RPS6KA4 SPEN TSHR ARAF BMPR1A CDKN1B EED FANCC GREM1 IRS1 MDC1 NF1 PDPK1 PTPRS RPS6KB2 SPOP U2AF1 ARID1A BRAF CDKN2A EGFL7 FAT1 GRIN2A IRS2 MDM2 NF2 PHOX2B PTPRT RPTOR SRC VHL ARID1B BRCA1 CDKN2B EGFR FBXW7 GSK3B JAK1 MDM4 NFE2L2 PIK3C2G RAC1 RUNX1 STAG2 VTCN1 ARID2 BRCA2 CDKN2C EIF1AX FGF19 H3F3C JAK2 MED12 NKX2‐1 PIK3C3 RAD50 RYBP STK11 WT1 ARID5B BRD4 CHEK1 EP300 FGF3 HGF JAK3 MEF2B NKX3‐1 PIK3CA RAD51 SDHA STK40 XIAP ASXL1 BRIP1 CHEK2 EPCAM FGF4 HIST1H1C JUN MEN1 NOTCH1 PIK3CB RAD51B SDHAF2 SUFU XPO1 ASXL2 BTK CIC EPHA3 FGFR1 HIST1H2BD KDM5A MET NOTCH2 PIK3CD RAD51C SDHB SUZ12 YAP1 ATM CARD11 CREBBP EPHA5 FGFR2 HIST1H3B KDM5C MITF NOTCH3 PIK3CG RAD51D SDHC SYK YES1 ATR CASP8 CRKL EPHB1 FGFR3 HNF1A KDM6A MLH1 NOTCH4 PIK3R1 RAD52 SDHD TBX3 ATRX CBFB CRLF2 ERBB2 FGFR4 HRAS KDR MLL NPM1 PIK3R2 RAD54L SETD2 TERT AURKA CBL CSF1R ERBB3 FH ICOSLG KEAP1 MLL2 NRAS PIK3R3 RAF1 SF3B1 TET1 AURKB CCND1 CTCF ERBB4 FLCN IDH1 KIT MLL3 NSD1 PIM1 RARA SH2D1A TET2 AXIN1 CCND2 CTLA4 ERCC2 FLT1 IDH2 KLF4 MPL NTRK1 PLK2 RASA1 SHQ1 TGFBR1 AXIN2 CCND3 CTNNB1 ERCC3 FLT3 IFNGR1 KRAS MRE11A NTRK2 PMAIP1 RB1 SMAD2 TGFBR2 AXL CCNE1 CUL3 ERCC4 FLT4 IGF1 LATS1 MSH2 NTRK3 PMS1 RBM10 SMAD3 TMEM127 B2M CD274 DAXX ERCC5 FOXA1 IGF1R LATS2 MSH6 PAK1 PMS2 RECQL4 SMAD4 TMPRSS2 BAP1 CD276 DCUN1D1 ERG FOXL2 IGF2 LMO1 MTOR PAK7 PNRC1 REL SMARCA4 TNFAIP3 7 Case Example: Breast Cancer Patient Several Important Alterations Found Using MSK‐IMPACT Mutations FGFR2 ERBB2, CDK12 Copy Number Alterations 8
- 7. 10/19/2014 7 NEW KNOWLEDGE & INNOVATION DIAGNOSTIC MOLECULAR PATHOLOGY LAB 13 22,613 10,500 2012 10,000,000 Number of Genes Tested Number of Assays Tested 1,000,000 100,000 10,000 1,000 100 2013 2014 4,413 2,585,500 LOG SCALE Tumor DNA Sequencing cBioPortal: Cohort‐Level Display (current) MSK Confidential 11
- 8. 10/19/2014 8 cBioPortal: Patient‐Level Display (current) MSK Confidential 12 Cancer Genome: Transforming Power for Drug Development › Analysis of mutations and search for correlations with response to therapy in trials from phase I to III › Conduct of clinical trials targeted at driver mutations —the “Basket Studies” › Identification of novel mechanism of acquired resistance › Study tumor heterogeneity in context to evolution to response to therapy › N of 1 studies in responding patients to conventional therapies, including chemotherapy
- 9. 10/19/2014 9 Clinical Trials are “Targeted”: Need for Genomic Data • Only 2% standard “cytotoxics” • Many genomic targets are low prevalence (< 5%) disease of interest • Genomic data needed for • Eligibility • Biomarker development • Genomic data associated with response to immunotherapy Drug Class/Target for Open Phase I‐I/II Studies, MSKCC 2013* Cytotoxic Only 2% PI3K 9% mTOR/TORC 7% MEK 3% BRAF 3% HSP90 4% ALK 2% PARP 5% TKI, VEGF 9% TKI, Other 5% HER 3% HSP90 4% Antibody Drug Conjugate Monoclonal Antibody Other Targeted Hedgehog 2% Proteasome 2% 3% 22% 4% Radio‐Emitter 2% Vaccine 6% *Division of Solid Tumor, 85 Unique Protocols MSK Confidential 13 Basket Studies • First generation studies are underway: – PI3K, AKT, FGFR, ERBB2, BRAF, mTOR • Second generation will add complexity: – i.e. BRAF + EGFR MAbs
- 10. 10/19/2014 10 Vemurafenib Basket Study Schema V600 BRAF Mutation Identified Locally Lung Cancer Ovarian Cancer Colon Cancer Cholangio‐ Carcinoma Breast Cancer Multiple Myeloma Other Solid Tumors Treatment with Vemurafenib (and Cetuximab in colorectal cancer) until progression or intolerable side effects Primary Endpoint: Overall response rate (at 8 weeks) Secondary Endpoint: Progression Free Survival Centralized retrospective testing of all tumors to confirm V600 BRAF mutation Vemurafenib Waterfall Plot ( D. Hyman, MSKCC) GBM Anaplastic Thyroid Histiocytosis Pancreatic Colorectal NSCLC PD PR uPR* 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% ‐10.00% ‐20.00% ‐30.00% ‐40.00% ‐50.00% ‐60.00% ‐70.00% ‐80.00% ‐90.00% *‐Vem+Cetux CR PR CR CR PR PR PR PR PR PR SD SD SD SD PD PD ‐100.00%
- 11. 10/19/2014 11 On Study Progression Toxicity 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Pancreatic NSCLC NSCLC Multiple Myeloma Multiple Myeloma Histicytosis Histicytosis Histicytosis Histicytosis Histicytosis Histicytosis Histicytosis Histicytosis Histicytosis GBM GBM Colorectal Colorectal Anaplastic thyroid Anaplastic thyroid Anaplastic thyroid Anaplastic thyroid Vemurafenib Time on Study (D. Hyman, MSKCC) Months Consent Withdrawal
- 12. 10/19/2014 12 Erdheim Chester Disease Baseline 2 months A Case for Basket Trials: Mutations are Infrequent Mutation Frequency 48 studies analyzed, 7851 unique tumors (ERBB2) • Low prevalence (<5%) of mutation of interest across tumor types • Single‐histology studies with prospective centralized screening are impractical Data from MSK cBio.org
- 13. 10/19/2014 13 Distribution of ERBB2 Mutations Across Cancer Types A775_G776insYVMA S310F D769Y L755S P780_Y781insGSP V842I R869H R678Q R487W Source: Life Technologies/Compendia BioscienceTM. Data is taken from Oncomine® Gene Browser and includes >28,800 patient samples subjected to whole exome sequencing. Neratinib Basket Study Schema HER2 Mutation Identified Bladder Cancer Colon Cancer Endometrial Cancer Gastric Cancer Ovarian Cancer Other Solid Tumors HER3 Mutation Identified All Solid Tumors Treatment with Neratinib until progression or intolerable side effects Primary Endpoint: Overall response rate (at 8 weeks) Secondary Endpoints: PFS, OS Multinational Study, MSKCC Lead Site MSKCC Central Repository for All Biospecimens EGFR Mutation Identified Primary Brain Tumor
- 14. 10/19/2014 14 Distribution of ERBB2 Mutations in Patients Enrolled in Basket Study PUMA-NER-5201 Receptor_L Furin-Like Receptor_L Furin-Like TM Tyrosine Kinase Domain Kidney Data cutoff 26‐AUG‐2014 † # † D277G R970Q S310F or S310Y V842I # V777L L755S G776V or G776AinsVGC A775_G776 InsYVMA or Y772_A775InsYVMA or A774_G775AVYM D251fs*1 #, † Coexisting mutations in same patient N319D Bladder CRC Breast NSCLC Ovarian Ampullary Gastroesophageal ERBB2 Mutation Type Incidence Missense Substitutions 69.2% (18/26) Insertions / Deletions 26.9% (7/26) Frameshift 3.8% (1/26) Tumor Legend D769H R678Q 12 bp exon 20 insertion
- 15. 10/19/2014 15 PI3K pathway in Breast Cancer PI3K AKT mTOR • Most frequent activating gene mutation in breast cancer • ER + and HER2 + • PI3K inhibitors in clinical development TCGA consortium, Nature, 2012
- 16. 10/19/2014 16 PI3K pathway and downstream signaling in cancer p85 PIP2 PIP3 PIP3 PDK1 AKT mTORC1 Proliferation Apoptosis Growth Cell cycle arrest Metabolism Translation PTEN Addition of Everolimus (EVE) to Exemestane (EXE) More Than Doubled Median Progression Free Survival (PFS) 100 80 60 40 20 0 HR = 0.45 (95% CI: 0.38–0.54) Log‐rank P value: < 0.0001 EVE + EXE: 7.82 months PBO + EXE: 3.19 months 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120 Time, weeks Probability of Event, % PFS Local* PFS Central* HR = 0.38 (95% CI: 0.31–0.48) Log‐rank P value: < 0.0001 EVE + EXE: 11.01 months PBO + EXE: 4.14 months 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 100 80 60 40 20 0 Probability of Event, % Time, weeks Abbreviation: CI, confidence interval; HR, hazard ratio; PBO, placebo; PFS, progression‐free survival. *Piccart M, et al. ASCO 2012; Abstract 559. Baselga J et al. N Engl J Med. 2012
- 17. 10/19/2014 17 PI3K pathway inhibitors in clinical trials 4EBP1 PI3K Rheb TORC1 S6K S6 PIP3 Tuberin PTEN TORC2 Akt PDK1 eIF4E‐F‐G 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Furet, et al. 2013, Bioorg Med Chem Lett Fritch, et al. 2014, Mol Cancer Ther BYL719, a selective PI3Kα inhibitor Kinase Kinase Glo IC50 (nM) Cellular Assay PI3Kα 5 74 PI3Kβ 1156 2249 PI3Kδ 290 1249 PI3Kγ 250 Vps34 >9100 mTOR >9100 >10,000 BYL719 PIK3CA WT PIK3CA Mut 0.0 Proliferation relative to DMSO (%) P<0.0001
- 18. 10/19/2014 18 Clinical activity of BYL719 in patients with PIK3CA mut. Best % change from baseline SD SDSD UNK SD PD PD PD PD SD PD PDPD PD UNK PDPDPD SD SD PD SDSD SD SD SD PD SD SD SD SD SD PD SDSD SD PD SDSD SD SD SD PD SD SD SD UNK SD SD SDPDPD 100 80 60 40 20 0 –20 –40 –60 –80 *Patients with missing best percentage from baseline and unknown best overall response are not included. PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown. n=72* SD SD PD UNK SD SD SD PR PR SD SD PR SD SD SDSD SDSD PR SD Breast Colorectal Head and neck Other Ovarian –100 PI3K pathway inhibitors in clinical trials 4EBP1 PI3K Rheb TORC1 S6K S6 PIP3 Tuberin PTEN TORC2 Akt PDK1 eIF4E‐F‐G
- 19. 10/19/2014 19 GDC‐0032, a PI3Kα,δ,ϒ inhibitor, more potent in PIK3CAmut mutant cancer cells SW48 isogenic lines (PIK3CAmut vs. PIK3CAwt) 12000 9000 6000 3000 KPL4 (PIK3CAH1047R breast CA) 0 -10 -9 -8 -7 -6 GDC-0032 [M] Cell Viability Parental PIK3CAE545K PIK3CAH1047R PIK3CAwt PIK3CAmut PIK3CAwt PIK3CAmut HER2 PIK3CAmut/HER2 10 1 0.1 GDC-0032 EC50 (M) 0.01 Solid tumors Breast tumor cell lines Preliminary efficacy with GDC‐0032 treatment • Trend for increased GDC‐0032 anti‐tumor activity in patients with PIK3CAmut tumors Data as of 30 Nov 2012
- 20. 10/19/2014 20 Cancer Genome: Transforming Power for Drug Development › Analysis of mutations and search for correlations with response to therapy in trials from phase I to III › Conduct of clinical trials targeted at driver mutations —the “Basket Studies” › Identification of novel mechanism of acquired resistance › Study tumor heterogeneity in context to evolution to response to therapy › N of 1 studies in responding patients to conventional therapies, including chemotherapy Resistance to PI3K inhibitors • Primary – Co‐existence of genetic alterations • Acquired under selective therapy pressure • Adaptive activation of compensatory pathways
- 21. 10/19/2014 21 Tumor heterogeneity and targeted therapies resistance • Tumor heterogeneity and acquired resistance to treatment via the emergence and growth of resistant clonal subpopulations is one of the major challenges • A systematic approach to interrogate tumors at the time of progression is required Right IDC ER+/PR+/Her2- T1cN0M0 ~ 4 years ~ 2 years 10 months Standard of care therapy BYL719 clinical trial Death and autopsy Patient clinical history and outcome BYL719 2 months BYL719 2 months BYL719 2 months BYL719 2 months BYL719 2 months RECIST PARTIAL RESPONSE RECIST PARTIAL RESPONSE RECIST PARTIAL RESPONSE RECIST PARTIAL RESPONSE RECIST PROGRESSION PIK3CA E542K Standard of care therapy Metastatic lesions
- 22. 10/19/2014 22 Understanding Acquired Resistance to BYL719 Baseline 6/3/2011 Cycle 8 ‐ 1/30/2011 Stable periaortic lymph node Cycle 10 ‐ 3/26/2012 Stable periaortic lymph node Baseline 6/3/2011 Cycle 8 ‐ 1/30/2011 No lung lesions Cycle 10 ‐ 3/26/2012 New lung lesion and new b/l pleural effusions 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Sample Location Pathology Review 1 L ovary mass 75% tumor 2 Peri‐aortic LN 50% tumor, some lysis 3 Liver posterior 65% tumor 4 Lung left lower lobe 75% tumor 5 Bone, T spine 65% tumor 6 Lung right upper lobe 55% tumor 7 Liver dome 70% tumor, necrosis 8 Lung right middle lobe 15% tumor, some necrosis 9 Uterus 55% tumor 10 Liver left lobe 70% tumor, necrosis 11 Peri‐esophageal lesion 35% tumor 12 Lung left upper lobe 75% tumor 13 Subcarinal LN 70% tumor 14 Liver central 15% tumor, necrosis and lysis 15 Peri‐adrenal mass left 40% tumor 16 Lung right lower lobe 65% tumor 17 Mesenteric mass 40% tumor 18 Liver left lower 50% tumor 19 Liver normal 99% normal but with node infiltration 20 Normal muscle normal 21 Normal spleen normal 22 Spinal cord no tumor Rapid Autopsy on Progression to Therapy
- 23. 10/19/2014 23 A three-step approach to discover mechanisms of resistance to BYL719 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1. WGS of new lesion and primary PROGRESSION RESPONDING Cycle 8 Cycle 10 Cycle 8 Cycle 10 2. WES of new, responding lesions and primary 3. Targeted exome sequencing of all metastases and primary Targeted exome sequencing reveals multiple PTEN alterations in all resistant lesions Primary MUTATION AMPLIFICATION DELETION Primary Non-responding Non-responding Responding Responding
- 24. 10/19/2014 24 Resistance to PI3K inhibitors • Primary • Acquired under selective therapy pressure • Adaptive activation of compensatory pathways – Persistent mTOR activation – Activation of ER upon PI3K inhibition PI3K α inhibitor PI3K α inhibitor Ras HER2/HER3 4EBP1 Raf Erk Rsk PI3K TORC1 S6K Rheb S6 PIP3 Tuberin MEK Akt PDK1 Ras HER2/HER3 4EBP1 Raf Erk Rsk PI3K TORC1 S6K Rheb S6 PIP3 Tuberin MEK Akt PDK1 Sensitive Resistant
- 25. 10/19/2014 25 pS6 (240/4) is downregulated in the tumors who regress upon treatment with BYL719 Non responding tumors Responding tumors Untreated (pre) (4) (5) (6) (1) (2) (3) BYL719 (post) Levels of pS6 (240/4) relative to pre-treatment (%) 150 p=0.046 100 50 No tumor response Tumor response 0 Untreated (pre) BYL719 (post) (‐1.5%) (‐0.9%) (+7.8%) (‐34.8%) (‐26.3%) (‐24.9%) (%)‐ Best response Elkabets et al. Science Transl Med. 2013 Re‐activation of mTORC1 is associated with relapse to treatment with BYL719 Patient #4 Patient #6 pS6 (240/4) H-Score 0 -26.3 -7.8 350 300 250 200 150 100 50 0 % change from baseline pS6 (240/4) H-Score 0 -34.8 -18.3 150 100 50 0 % change from baseline Elkabets et al. Science Transl Med. 2013
- 26. 10/19/2014 26 PI3K α inhibitor PI3K α inhibitor Ras HER2/HER3 4EBP1 Raf Erk Rsk PI3K TORC1 S6K Rheb S6 PIP3 Tuberin MEK Akt PDK1 Ras HER2/HER3 4EBP1 Raf Erk Rsk PI3K TORC1 S6K Rheb S6 PIP3 Tuberin MEK Akt PDK1 Sensitive Resistant + mTOR inhibitor HER2/HER3 Sensitive Ras 4EBP1 Raf Erk Rsk PI3K TORC1 S6K Rheb S6 PIP3 Tuberin MEK Akt PDK1 Resistance to PI3K inhibitors • Primary • Acquired under selective therapy pressure • Adaptive activation of compensatory pathways – Persistent mTOR activation – Activation of ER upon PI3K inhibition
- 27. 10/19/2014 27 PI3Kα inhibition induces a transcriptome switch towards a more luminal (ER‐driven) phenotype Ctrl BYL-719 0.4 0.3 0.2 0.1 0.0 Enrichment Luminal signature Enrichment after BYL‐719 MCF7 BYL-719 1 M Ctrl 4h 8h12h 24h 48h Patient Derived Xenograft PI3Kα inhibition increases ERα target‐gene expression 3 2 1 Control BYL 0 y Relative ER transcriptional activity ** 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Fold Enrichment PR promoter 12 10 8 6 4 2 0 Fold Enrichment CREB1 promoter 2.5 2.0 1.5 1.0 0.5 Control 4h 8h 12h 24h 48h 0.0 PR Time (h) of exposure to drug Relative mRNA levels ** ** ** ** 2.5 2.0 1.5 1.0 0.5 Control 4h 8h 12h 24h 48h 0.0 GREB1 Time (h) of exposure to drug Relative mRNA levels ** ** ** ** MCF7
- 28. 10/19/2014 28 4 3 2 1 Control GDC0032 GDC0941 0 PR Expression in MCF-7 Relative mRNA levels ** ** 5 4 3 2 1 Control GDC0032 GDC0941 0 GREB1 Expression in MCF-7 Relative mRNA levels ** ** ERα induction and activity is also observed with other PI3K inhibitors Tumors from patients treated with BYL‐719 present a change in gene expression towards a more luminal/ER dependent signature
- 29. 10/19/2014 29 ER PI3K AKT mTOR PI3K AKT mTOR ER ER ER Adding SERDs to PI3K inhibitors prevents ERα transcriptional activity 2.5 2.0 1.5 1.0 0.5 Control FUL V BYL BYL+FULV 0.0 PR MCF-7 Relative mRNA levels ** ** ** 2.5 2.0 1.5 1.0 0.5 Control FULV BYL BYL+FULV 0.0 GREB1 MCF-7 Relative mRNA levels ** ** ** 2.0 1.5 1.0 0.5 Control FUL V BYL BYL + FULV 0.0 Luciferase assay MCF-7 Relative ER transcriptional activity ** ** ##
- 30. 10/19/2014 30 Combination of BYL‐719 and fulvestrant in vivo Control BYL719 Fulv Combination 0 5 10 2.5 2.0 1.5 1.0 0.5 0.0 15 20 25 Fold change in tumor size from Day 0 Days of treatment ER PI3K AKT mTOR PI3K AKT mTOR ER ER ER PI3K AKT mTOR ER ER ER Working model
- 31. 10/19/2014 31 Anti‐tumor Activity of GDC‐0032 and Fulvestrant Combination SABC 2013 Traditional Oncology Decision‐Making Process Decision
- 32. 10/19/2014 32 Today’s Need For A Cognitive Solution Decision Today’s Need For A Cognitive Solution
- 33. 10/19/2014 33 MSK Teaches Oncology to IBM Watson Cognitive Computing Clinical Data Integration Collegial Dialoguing Genomics Advisor Patient Decision Aides Clinical Trials Matching New Research Prompts
- 34. 10/19/2014 34 Acknowledgments: Maurizio Scaltriti Pau Castel Ana Bosch Haley Ellis Natasha Morse Moshe Elkabets Zach Zumsteg Javier Carmona Eneda Toska Samuel Brooks Farzeen Aslam MGH Dejan Juric Mari Mino-Kenudson Tiffany Huynh Dennis Sgroi Steven Isakoff Ashraf Thabet Leila Elamine Mardis Lab Malachi Griffith Obi Griffith Benjamin Ainscough Elaine Mardis Novartis Cornelia Quadt Malte Peter Alan Huang Berger Lab Helen Won Ronak Shah Michael Berger Lowe Lab Saya Ebessen Scott Lowe Solit Lab Gopa Iyer David Solit Neal Rosen Sarat Chandarlapaty Zhiquiang Li