Teresa Alonso GordoaServicio de Oncología Médica

Hospital Universitario Ramón y Cajal

VHL-HIFANGIOGENESIS

IMMUNOLOGY

EPIGENETIC ANDCHROMATIN MODIFIERS

VHL

METABOLICS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTOR

Genes Tumores conmutación (%)

VHL 52.3

PBRM1 32.9

SETD2 11.5

The Cancer Genome Atlas Research Network. Nature, 2013Brugarolas J. J Clin Oncol 2014

SETD2 11.5

BAP1 10.1

MTOR 6

TCEB1 0.7

PIK3CA 2.9

KDM5C 6.7

TP53 2.2

PTEN 4.3

VHLPBRM1

BAP1SETD2

Gerlinger M, et al. Nature Genetics, 2014

BAP1SETD2

VHL-HIFANGIOGENESIS

VHL-HIFANGIOGENESIS

IMMUNOLOGY

EPIGENETIC ANDCHROMATIN MODIFIERS

METABOLICS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTOR

VHLVHL

ELB

ELB ELCELC CUL

2CUL

2

RBX1RBX1

VCB-CR Complex

VHLVHL

ELB

ELB ELCELC CUL

2CUL

2

RBX1RBX1

SUBSTRATESSUBSTRATES

pVHL structure and VCB complex

OHOH OHOH

HIFαHIFαVCB-CR Complex

Proteosomal degradation

Gossage L, et al. Nature Reviews, 2015

HIFαHIFα

METABOLICS

VHL/HIF- OXYGEN SENSING

cyto

plas

m

nucl

eus

HIF1α Induction of HIF targetgenes

Induction of HIF targetgenesHIF1αHIF1α

HIF1βHIF1β

HRE Induction of HIF targetgenes

Induction of HIF targetgenes

VEGF IGF2 Glucosemetabolism

Angiogenesis Growth/Survival

Transport: GLUT1/3Glycolitic enzymes

Massari F, Cancer Treat Rev 2015

VHL-HIFANGIOGENESIS

IMMUNOLOGY

EPIGENETIC ANDCHROMATIN MODIFIERS

METABOLICS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTORPI3K/AKT/mTOR

PI3K/AKT/mTOR pathway

CELL GROWTH

METABOLISM

ANGIOGENESIS

Pal S and Quinn D. Cancer Treat Rev. 2013

CELL GROWTH

METABOLISM

ANGIOGENESIS

Alterations targetingcomponents of the

PI(3)K/AKT/MTOR pathwayin 28%

of the tumors

PI3K/AKT/mTOR pathway

The Cancer Genome Atlas Research Network. Nature, 2013

HIF1αHIF2α

INTERPLAY BETWEEN VHL AND mTORC1

4%

Burgarolas J. J Clin Oncol, 2014The Cancer Genome Atlas Research Network. Nature, 2013

2%

6%

VHL-HIFANGIOGENESIS

IMMUNOLOGY

EPIGENETIC ANDCHROMATIN MODIFIERS

EPIGENETIC ANDCHROMATIN MODIFIERS

METABOLICS

EPIGENETIC ANDCHROMATIN MODIFIERS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTOR

EPIGENETIC/CHROMATIN REMODELING

GENE LOCATION FREQUENCY FUNCTION

PBRM1 3p21 40% SWI/SNF chromatin remodeling (binding domain of PBAF complex)

SETD2 3p21 10-15% Histone methyltransferase for H3K36

KDM5C Xp11 6.7% Histone demethylase for H3K4

BAP1 3p21 10-15% Deubiquitinating enzyme for histone H2A and HCFC1

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, 2013.

EPIGENETIC/CHROMATIN REMODELING

Kapur P, et al. Lancet Oncol, 2013

EPIGENETIC/CHROMATIN REMODELING

The Cancer Genome Atlas Research Network. Nature, 2013

VHL-HIFANGIOGENESIS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTOR

METABOLICS

IMMUNOLOGYIMMUNOLOGY

EPIGENETIC ANDCHROMATIN MODIFIERS

IMMUNOLOGY AND IMMUNOTHERAPY

Carlo MI, Nature 2016

NOVEL IMMUNOTHERAPIES BEING STUDIED FOR mRCCNOVEL IMMUNOTHERAPIES BEING STUDIED FOR mRCC

Checkpoint inhibitorsCheckpoint inhibitors VaccinesVaccines Adoptive T-cell therapyAdoptive T-cell therapy T-cell agonistsT-cell agonists

CTLA inhibitors:- Ipilimumab- Tremelimumab

PD1-inhibitors:- Nivolumab- Pembrolizumab- Pidilizumab

PDL1 inhibitors:- Atezolizumab- Avelumab- Durvalumab- BMS-936559

Single peptide:- TroVax®- TG4010

Dendritic cell:- AGS-003

Multipeptide:- IMA901

CAR T cells

CIK cells

Cytokines:- IL2- IFNγ- IL21

Agonist antibodies:- CD137- OX40- CD27- GITR

IMMUNOLOGY AND IMMUNOTHERAPY

CTLA inhibitors:- Ipilimumab- Tremelimumab

PD1-inhibitors:- Nivolumab- Pembrolizumab- Pidilizumab

PDL1 inhibitors:- Atezolizumab- Avelumab- Durvalumab- BMS-936559

Single peptide:- TroVax®- TG4010

Dendritic cell:- AGS-003

Multipeptide:- IMA901

CAR T cells

CIK cells

Cytokines:- IL2- IFNγ- IL21

Agonist antibodies:- CD137- OX40- CD27- GITR

Carlo MI, Nature 2016

AND THE COMBINATION WITH ANTIANGIOGENIC AGENTS?

IMMUNOLOGY AND IMMUNOTHERAPY

Carlo MI, Nature 2016

ANTIANGIOGENICS OVER TUMOUR IMMUNEMICROENVIRONMENT

NCT00113217 Bevacizumab x 8 sem nefrectomía citoreductora N=42

NCT00715442 Sunitinib x 4 sem nefrectomía citoreductora N=39

NCT00126594 Sorafenib tras nefrectomía citoreductora/radical N=41

PRE-ANTI VEGF/R

ANTI VEGF/R NAÏVE

Liu X, et al. CancerImmunolRes, 2015

VHL-HIFANGIOGENESIS

IMMUNOLOGY

EPIGENETIC ANDCHROMATIN MODIFIERS

METABOLICSMETABOLICS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTOR

METABOLICS

VHLVHL

METMET

FLCNFLCN

Angiogenesis, ECM remodeling, genomic integrity, glycolyticenzyme expression, anabolic biosynthesis, cell cycle progression

Tumor cell proliferation, survival, invasion and angiogenesis

mRNA translation, protein synthesis and cellular growthFLCNFLCN

FHFH

SDHSDH

TSC1/TSC2TSC1/TSC2

Energy production, angiogenesis, cell growth, cell proliferation,oxidative stress

Energy production

mRNA translation, protein synthesis and cellular growth

mRNA translation, protein synthesis and cellular growth

Massari F, Cancer Treat Rev 2015

METABOLICS

Linehan WM, et al. Nature Rev Urol, 2010

METABOLICS

ENERGY SENSING PATHWAYS

WARBURG EFFECT

Vander Heiden, Science 2009

VHL-HIFANGIOGENESIS

IMMUNOLOGY

VHL-HIFANGIOGENESIS

METABOLICS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTOR

MOLECULAR SUBTYPES OF IMDC

MOLECULAR CLASSIFICATION AS PROGNOSTICFACTORS OR PREDICTIVE BIOMARKERS OF

RESPONSE TO TREATMENT

PROGNOSTIC CRITERIA

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

MOLECULAR SUBTYPESCHROMATIN REMODELING

Joseph RW, et al. J Urol, 2015Kapur P, et al. Lancet Oncol, 2013

The basis for amolecular geneticclassification of

ccRCC:PBRM1 & BAP1

BAP1 and BPRM1 mutation status in COMPARZ trial

mPFS mOS

BAP1 mutant 5,52m (HR1,29) 21,78m (HR1,57)

BAP1 WT 10,68m 31,61m

mPFS mOS

PBRM1 mutant 11,04m (HR0,73) 35,48m(HR0,64)

PBRM1 WT 8,25m 26,12mVoss M, et al. Poster discussion ASCO 2017

MOLECULAR AND IMDC/MSKCCCLASSIFICATIONS

N=54 mRCCN=54 mRCC

ccA, N=17

ccB, N=37

ccA, N=23

ccB, N=31

Clear Code34Clear Code34 8-gene signature model8-gene signature model

De Velasco G. The Oncologist 2017;22:286–292.

MOLECULAR SUBTYPES ANDRESPONSE TO TKI

SULONG:N=123 mccRCC treated with sunitinib first lineLR= PFS≥22 months and at least stable disease (97)PR= PFS ≤ 3 months (26)

SULONG:N=123 mccRCC treated with sunitinib first lineLR= PFS≥22 months and at least stable disease (97)PR= PFS ≤ 3 months (26)

HEYLHEYL

mRCC 1st line treatment

PR (N=8):Up-regulated in PR: miR-425-5pDown-regulated in PR:miR-139-3p, let-7d and let-7e

Tumor vs Healthy tissue:miR-135a, miR-200c, miR-187 and miR-21

Garrigos C, et al. ASCO 2017

mRCC 1st line treatment

PR (N=8):Up-regulated in PR: miR-425-5pDown-regulated in PR:miR-139-3p, let-7d and let-7e

Tumor vs Healthy tissue:miR-135a, miR-200c, miR-187 and miR-21

Garrigos C, et al. ASCO 2017

Puente J, et al. Oncotarget 2017

HEYL

miRNA628miRNA628 miRNA27bmiRNA27b

mRCC 1st line treatment

PR (N=8):Up-regulated in PR: miR-425-5pDown-regulated in PR:miR-139-3p, let-7d and let-7e

Tumor vs Healthy tissue:miR-135a, miR-200c, miR-187 and miR-21

Garrigos C, et al. ASCO 2017

mRCC 1st line treatment

PR (N=8):Up-regulated in PR: miR-425-5pDown-regulated in PR:miR-139-3p, let-7d and let-7e

Tumor vs Healthy tissue:miR-135a, miR-200c, miR-187 and miR-21

Garrigos C, et al. ASCO 2017

IMmotion150: A phase II of atezolizumab as monotherapy or in combination withbevacizumab compared to sunitinib in participants with untreated advanced RCC

MOLECULAR SUBTYPES ANDRESPONSE TO VEGFinh +/- IO

McDermott D, et al. IMmotion150 biomarkers: AACR 2017

IMmotion150: A phase II of atezolizumab as monotherapy or in combination withbevacizumab compared to sunitinib in participants with untreated advanced RCC

MOLECULAR SUBTYPES ANDRESPONSE TO VEGFinh +/- IO

McDermott D, et al. IMmotion150 biomarkers: AACR 2017

Angiogenesis Immune: T-effector Myeloid inflammation

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

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

N= 615Clear cell predominantHigh 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

R

N=309SUNITINIB 50mg/24h 4/2 for 1 year

N=306PLACEBO (50mg/24h 4/2) for 1 year

1:1

S-TRAC TRIAL

*Primary endpoint: Disease Free Survival

Stratified by:UISS risk groupsECOG PS (<2 vs 2)Country

*Primary endpoint: Disease Free Survival

Stratified by:UISS risk groupsECOG PS (<2 vs 2)Country

Rini BI, Lancet Oncol 2015Escudier B, Oral presentation at ASCO 2017

16-gene assay:Vascular: APOLD1, EDNRB, NOS3, PPAP2BImmune response: CEACAM1, CX3CL1,CCL5Cell growth/Division: EIF4EBP1, TUBB2A,LMNB1Inflammation: IL-6Reference genes: AAMP, ARF1, ATP5E,GPX1, RPLP1

Placebo (N=90) HR 4,24Sunitinib (N=103) HR 2,53

CONCLUSIONS

VHL-HIFANGIOGENESIS

IMMUNOLOGY

PATIENT SELECTIONPATIENT SELECTIONVHL-HIF

ANGIOGENESIS

METABOLICS

EPIGENETIC ANDCHROMATIN MODIFIERS

PI3K/AKT/mTOR

PATIENT SELECTION

TREATMENT STRATEGYTREATMENT STRATEGY

MUCHAS GRACIAS POR VUESTRA ATENCIÓN

Teresa Alonso GordoaServicio de Oncología Médica

Hospital Universitario Ramón y Cajaltalonso@oncologiahrc.com