Teresa Alonso Gordoa Servicio de Oncología Médica Hospital Universitario Ramón y Cajal

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1 Teresa Alonso Gordoa Servicio de Oncología Médica Hospital Universitario Ramón y Cajal

2 IMMUNOLOGY VHL-HIF ANGIOGENESIS VHL EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS PI3K/AKT/mTOR

3 The Cancer Genome Atlas Research Network. Nature, 2013 Brugarolas J. J Clin Oncol 2014 Genes Tumores con mutación (%) VHL 52.3 PBRM SETD BAP MTOR 6 TCEB1 0.7 PIK3CA 2.9 KDM5C 6.7 TP PTEN 4.3

4 VHL PBRM1 BAP1 SETD2 Gerlinger M, et al. Nature Genetics, 2014

5 IMMUNOLOGY VHL-HIF ANGIOGENESIS EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS PI3K/AKT/mTOR

6 pvhl structure and VCB complex EL B RBX1 ELC VHL CUL 2 EL B RBX1 ELC VHL CUL 2 SUBSTRATES VCB-CR Complex OH OH HIFα Proteosomal degradation Gossage L, et al. Nature Reviews, 2015

7 METABOLICS nucleus cytoplasm VHL/HIF- OXYGEN SENSING HRE HIF1α Induction of HIF target genes HIF1β VEGF Angiogenesis Massari F, Cancer Treat Rev 2015 IGF2 Growth/ Survival Glucose metabolism Transport: GLUT1/3 Glycolitic enzymes

8 IMMUNOLOGY VHL-HIF ANGIOGENESIS EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS PI3K/AKT/mTOR

9 PI3K/AKT/mTOR pathway CELL GROWTH METABOLISM ANGIOGENESIS Pal S and Quinn D. Cancer Treat Rev Alterations targeting components of the PI(3)K/AKT/MTOR pathway in 28% of the tumors

10 PI3K/AKT/mTOR pathway HIF1α HIF2α The Cancer Genome Atlas Research Network. Nature, 2013

11 INTERPLAY BETWEEN VHL AND mtorc1 4% 2% 6% Burgarolas J. J Clin Oncol, 2014 The Cancer Genome Atlas Research Network. Nature, 2013

12 IMMUNOLOGY VHL-HIF ANGIOGENESIS EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS PI3K/AKT/mTOR

13 EPIGENETIC/CHROMATIN REMODELING GENE LOCATION FREQUENCY FUNCTION PBRM1 3p21 40% SWI/SNF chromatin remodeling (binding domain of PBAF complex) SETD2 3p % KDM5C Xp11 6.7% BAP1 3p % ARID1A 1p35 NR SWI/SNF chromatin remodeling (binding domain of BAF complex) SMARCA4 19p13 NR SWI/SNF chromatin remodeling (ATPase of BAF & PBAF complex) Liao L. Cancer Genetics, 2015; Brugarolas J. Cancer J, Histone methyltransferase for H3K36 Histone demethylase for H3K4 Deubiquitinating enzyme for histone H2A and HCFC1

14 EPIGENETIC/CHROMATIN REMODELING Kapur P, et al. Lancet Oncol, 2013

15 EPIGENETIC/CHROMATIN REMODELING The Cancer Genome Atlas Research Network. Nature, 2013

16 PI3K/AKT/mTOR VHL-HIF ANGIOGENESIS EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS IMMUNOLOGY

17 IMMUNOLOGY AND IMMUNOTHERAPY Carlo MI, Nature 2016

18 IMMUNOLOGY AND IMMUNOTHERAPY NOVEL IMMUNOTHERAPIES BEING STUDIED FOR mrcc Checkpoint inhibitors Vaccines Adoptive T-cell therapy CTLA inhibitors: - Ipilimumab - Tremelimumab Single peptide: - TroVax - TG4010 CAR T cells PD1-inhibitors: - Nivolumab - Pembrolizumab - Pidilizumab Dendritic cell: - AGS-003 PDL1 inhibitors: - Atezolizumab - Avelumab - Durvalumab - BMS Carlo MI, Nature 2016 Multipeptide: - IMA901 CIK cells T-cell agonists Cytokines: - IL2 - IFNγ - IL21 Agonist antibodies: - CD137 - OX40 - CD27 - GITR

19 IMMUNOLOGY AND IMMUNOTHERAPY AND THE COMBINATION WITH ANTIANGIOGENIC AGENTS? Carlo MI, Nature 2016

20 ANTIANGIOGENICS OVER TUMOUR IMMUNE MICROENVIRONMENT NCT Bevacizumab x 8 sem nefrectomía citoreductora N=42 PRE-ANTI VEGF/R NCT Sunitinib x 4 sem nefrectomía citoreductora N=39 NCT Sorafenib tras nefrectomía citoreductora/radical N=41 ANTI VEGF/R NAÏVE Liu X, et al. CancerImmunolRes, 2015

21 IMMUNOLOGY VHL-HIF ANGIOGENESIS EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS PI3K/AKT/mTOR

22 METABOLICS VHL Angiogenesis, ECM remodeling, genomic integrity, glycolytic enzyme expression, anabolic biosynthesis, cell cycle progression MET Tumor cell proliferation, survival, invasion and angiogenesis FLCN mrna translation, protein synthesis and cellular growth FH Energy production, angiogenesis, cell growth, cell proliferation, oxidative stress SDH Energy production TSC1/ TSC2 mrna translation, protein synthesis and cellular growth Massari F, Cancer Treat Rev 2015

23 METABOLICS Linehan WM, et al. Nature Rev Urol, 2010

24 METABOLICS ENERGY SENSING PATHWAYS WARBURG EFFECT Vander Heiden, Science 2009

25 IMMUNOLOGY VHL-HIF ANGIOGENESIS EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS PI3K/AKT/mTOR

26 MOLECULAR SUBTYPES OF IMDC MOLECULAR CLASSIFICATION AS PROGNOSTIC FACTORS OR PREDICTIVE BIOMARKERS OF RESPONSE TO TREATMENT

27 PROGNOSTIC CRITERIA Motzer RJ, et al. J Clin Oncol 1999 Heng D, et al. J Clin Oncol 2009

28 MOLECULAR SUBTYPES CHROMATIN REMODELING The basis for a molecular genetic classification of ccrcc: PBRM1 & BAP1 Joseph RW, et al. J Urol, 2015 Kapur P, et al. Lancet Oncol, 2013

29 BAP1 and BPRM1 mutation status in COMPARZ trial mpfs mos PBRM1 mutant 11,04m (HR0,73) 35,48m(HR0,64) PBRM1 WT 8,25m 26,12m Voss M, et al. Poster discussion ASCO 2017 mpfs mos BAP1 mutant 5,52m (HR1,29) 21,78m (HR1,57) BAP1 WT 10,68m 31,61m

30 MOLECULAR AND IMDC/MSKCC CLASSIFICATIONS N=54 mrcc Clear Code34 8-gene signature model cca, N=17 ccb, N=37 cca, N=23 ccb, N=31 De Velasco G. The Oncologist 2017;22:

31 MOLECULAR SUBTYPES AND RESPONSE TO TKI SULONG: N=123 mccrcc treated with sunitinib first line LR= PFS 22 months and at least stable disease (97) PR= PFS 3 months (26) mrcc 1st line treatment PR (N=8): Up-regulated in PR: mir425-5p Down-regulated in PR: mir-139-3p, let-7d and let7e HEYL mirna628 mirna27b Tumor vs Healthy tissue: mir-135a, mir-200c, mir187 and mir-21 Garrigos C, et al. ASCO 2017 Puente J, et al. Oncotarget 2017

32 MOLECULAR SUBTYPES AND RESPONSE TO VEGFinh +/- IO IMmotion150: A phase II of atezolizumab as monotherapy or in combination with bevacizumab compared to sunitinib in participants with untreated advanced RCC McDermott D, et al. IMmotion150 biomarkers: AACR 2017

33 MOLECULAR SUBTYPES AND RESPONSE TO VEGFinh +/- IO IMmotion150: A phase II of atezolizumab as monotherapy or in combination with bevacizumab compared to sunitinib in participants with untreated advanced RCC Angiogenesis McDermott D, et al. IMmotion150 biomarkers: AACR 2017 Immune: T-effector Myeloid inflammation

34 MOLECULAR SUBTYPES OF IMDC AND, IN THE ADJUVANT SETTING? - Risk assessment for disease recurrence utilizes various models, such as: - UCLA Integrated Staging System (UISS) - Mayo Clinic System (or Leibovich score) (SSIGN) - Currently used prognostic biomarkers: - Tumor biology - Risk of recurrence - Inter-observer variability

35 S-TRAC TRIAL N= 615 Clear cell predominant High risk modified UISS criteria: - pt3n0/x M0, any G, any ECOG PS - pt any N1-2 M0, any G, any ECOG PS - pt4n0/x M0, any G, any ECOG PS N=309 SUNITINIB 50mg/24h 4/2 for 1 year R 1:1 Stratified by: UISS risk groups ECOG PS (<2 vs 2) Country 16-gene assay: Vascular: APOLD1, EDNRB, NOS3, PPAP2B Immune response: CEACAM1, CX3CL1, CCL5 Cell growth/division: EIF4EBP1, TUBB2A, LMNB1 Inflammation: IL-6 Reference genes: AAMP, ARF1, ATP5E, GPX1, RPLP1 Rini BI, Lancet Oncol 2015 Escudier B, Oral presentation at ASCO 2017 N=306 PLACEBO (50mg/24h 4/2) for 1 year *Primary endpoint: Disease Free Survival Placebo (N=90) HR 4,24 Sunitinib (N=103) HR 2,53

36 CONCLUSIONS IMMUNOLOGY VHL-HIF ANGIOGENESIS PATIENT SELECTION EPIGENETIC AND CHROMATIN MODIFIERS METABOLICS PI3K/AKT/mTOR TREATMENT STRATEGY

37 MUCHAS GRACIAS POR VUESTRA ATENCIÓN Teresa Alonso Gordoa Servicio de Oncología Médica Hospital Universitario Ramón y Cajal talonso@oncologiahrc.com