CRC subtypes: from molecular signatures to therapeutic opportunities. Rodrigo Dienstmann, MD

Transcription

1 CRC subtypes: from molecular signatures to therapeutic opportunities Rodrigo Dienstmann, MD

2 No conflicts of interest.

3 REALITY Until recently, the evolution of biomarkers for matched targeted therapies in CRC has been restrictive. From a therapeutic perspective, only the RAS mutated vs. RAS wildtype disease classification had clinical utility.

4 PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi omics systems biomedicine adaptive (immune) drug

5 PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi omics systems biomedicine adaptive (immune) drug

6 PAST Vilar & Tabernero. Cancer Discov 2013

7 Matched Targeted Agent KRAS mutation BRAF mutation PIK3CA mutation MET overexpression MEK inhibitor BRAF inhibitor PI3K inhibitor MET inhibitor

8 Matched Targeted Agent Response rate KRAS mutation BRAF mutation PIK3CA mutation MET overexpression MEK inhibitor BRAF inhibitor PI3K inhibitor MET inhibitor <5% 1. DRUG? 2. PRIMARY-METASTASIS HETEROGENEITY?

9 Matched Targeted Agent BRAF mutation BRAF inhibitor MELANOMA - dabrafenib Hauschild et al, Lancet 2012

10 Is metastasis different from primary? Brannon et al, Genome Biol 2014

11 HOW TO IMPROVE CLINICAL BENEFIT FURTHER? Deeper biological understanding of the disease - Genomic - Transcriptomic - Immune-Stromal

12 CO-OCCURRING ALTERATIONS TCGA, Nature 2012

13 DYNAMICS OF TARGET INHIBITION

14 CLONAL SELECTION TEMPORAL HETEROGENEITY Misale et al, Cancer Discov 2014

15 Innate anti-egfr resistance MET ampl ERBB2 ampl PIK3CA/PTEN mut BRAF V600E mut Responsive upfront All wild-type RAS + PIK3CA mut RAS mut Dienstmann et al, Cancer J 2016

16 Innate anti-egfr resistance Acquired MET ampl ERBB2 ampl PIK3CA/PTEN mut BRAF V600E mut Responsive upfront All wild-type MEK1 mut, ERBB2 mut, others BRAF V600E mut MET ampl ERBB2 ampl RAS mut RAS + PIK3CA mut RAS + PIK3CA mut RAS mut EGFR mut 1/3 cases co-occurring alterations Dienstmann et al, Cancer J 2016

17 PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi omics systems biomedicine adaptive (immune) drug

18 *ctdna Dienstmann et al, J Clin Oncol 2013

19 Matched Targeted Agent KRAS, NRAS, BRAF, PIK3CA wild-type BRAF mutation ERBB2 amplification, KRAS wild-type EGFR mutation, RAS/BRAF wild-type Anti-EGFR mab BRAF inh + anti-egfr mab + MEK inh Anti-HER2 mab + pan-her inh Second generation anti-egfr mab

20 Resistance to anti-egfr mab Dienstmann et al, ASCO Ed Book 2015

21 Matched Targeted Agent KRAS wild-type NRAS wild-type BRAF wild-type EGFR mutation Second generation anti-egfr mab SYM004 * ** ** * * * * * * RAS/BRAF mutation * EGFR mutation Dienstmann et al, Cancer Discov 2015

22 Matched Targeted Agent ERBB2 amplification KRAS wild-type Anti-HER2 mab + pan-her inhibitor Siena et al, ASCO 2015

23 Matched Targeted Agent BRAF mutation BRAF inhibitor + anti-egfr mab + MEK inhibitor Van Cutsem et al, ESMO-WGIC 2015

24 Matched Targeted Agent NOVEL TARGETS ONCOGENIC DEPENDENCIES NTRK1 fusion Pan-TRK inhibitor De Braud et al, ASCO 2014

25 HOW TO IMPROVE CLINICAL BENEFIT FURTHER? Deeper biological understanding of the disease - Genomic - Transcriptomic - Immune-Stromal

26 Guinney, Dienstmann et al, Nat Med 2015 CRC subtypes: from molecular signatures to therapeutic opportunities

27 Guinney, Dienstmann et al, Nat Med 2015 CRC subtypes: from molecular signatures to therapeutic opportunities

28 Guinney, Dienstmann et al, Nat Med 2015 CRC subtypes: from molecular signatures to therapeutic opportunities

29 Guinney, Dienstmann et al, Nat Med 2015 CRC subtypes: from molecular signatures to therapeutic opportunities

30 Overall survival Relapse-free survival Guinney, Dienstmann et al, Nat Med 2015

31 CMS1 and CMS3 enrichment < EGFR overexpression < EGFR ligand overexpression > BRAF mut > NF1/MEK1/PIK3CA/PTEN mut > MSI and CIMP high CMS2 enrichment > EGFR overexpression > EGFR ligand overexpression > IRS2 amplification < BRAF mut Guinney, Dienstmann et al, Nat Med 2015

32 Mutation Methylation MAPK mutations Copy number Distal (Tumor Location) Proximal CRC subtypes: from molecular signatures to therapeutic opportunities Genomic Epigenomic Transcriptomic Driver genes Clinical MSI CMS1 CMS3 CIN CMS2 CMS4

33 Mutation Methylation MAPK mutations Copy number Distal (Tumor Location) Proximal CRC subtypes: from molecular signatures to therapeutic opportunities Microenvironment? Genomic Epigenomic Transcriptomic Driver genes Clinical MSI CMS1 CMS3 CIN CMS2 CMS4

34 Supervised immune and stromal infiltration analysis CMS1 CMS2 CMS3 CMS4 Becht et al, Clin Car Res 2016

35 Supervised immune infiltration analysis T cell chemokine T cell inhibition Myeloid cell chemokine Angiogenesis Immunosuppression Complement CMS1 CMS2 CMS3 CMS4 Becht et al, Clin Car Res 2016

36 Immune-activated Th1 cells Th1 cells dmmr MSI Hypermutation IFNγ CXCL9/10/13 Cancer cell PDL1 Macrophages Immune-ignorant Cancer cell Cytotoxic T cells NK cells IFNγ Immune-tolerant Inflamed TGFβ Complement MDSC Inflammation Th17 cells Macrophages Stromal cells Cancer cell TGFβ Cytotoxic T cells NK cells Stromal cells CCL2 Monocytes IL-17 CCL2 IL-23

37 Intra-CMS prognosis as per tumor infiltrating lymphocytes (TILs) QuanTILfy in 98 MSS samples Unpublished

38 Mutation count Methylation Fibroblasts Copy number Innate (Immune response) Adaptive MAPK mutations Distal (Tumor Location) Proximal CRC subtypes: from molecular signatures to therapeutic opportunities Genomic Epigenomic Transcriptomic Stroma Immune Microenvironment Driver genes Clinical MSI CMS1 CMS3 Highly immunogenic CIN CMS2 Poorly immunogenic CMS4 Inflamed (immunetolerant)

39 TAKE-HOME MESSAGE Transcriptomic classification of CRC is strongly associated with: i. pathway activation patterns; ii. immune and stromal contextures. Reflect the relationships between cancer cell phenotype and corresponding tumor microenvironment.

40 HYPOTHESIS Intrinsic gene expression subtyping plus immune and stromal characterization: - increase the biological understanding of the disease; - optimize patient stratification based on differences in outcome and response patterns to targeted agents.

41 PAST Single gene single marker single drug PRESENT Multi gene multi marker multi drug FUTURE Multi omics systems biomedicine adaptive (immune) drug

42

43 Low glucose + glutathione biosynthesis inhibitor Redox/ROS DNA damage Nature 2016 epub

44 Cancer Therapeutics Research Portal v2 Unpublished

45 BRAF mut-like cells are sensitive to vinorelbine Vecchione et al, Cell 2016

46 Predictive value hypotheses chemotherapies Strategy: repurposing of DNA damaging agents? microtubule inhibitors? KRAS mutated Metabolic CMS3 BRAF mut-like

47 OX40 agonist + TGFBR inhibitor in CMS4 in vivo model Triplett et al, Cancer Immunol Res 2015

48 OX40 agonist in hypermutated MSS in vivo model Gough et al, Cancer Res 2008

49 Predictive value hypotheses immune therapies CMS1 MSI Hypermutated PD1 blockade responsive Strategy: PD1 blockade + OX40 agonist?

50 Predictive value hypotheses immune therapies Mesenchymal TGFβ activated CMS4 Strategy: combination of immunostimulatory drugs and inhibitors of immune suppression? Strategy: epigenetic immune modulation and PD1 blockade? MEK inhibitors and PD1 blockade? Epithelial Canonical CMS2

51 Atezolizumab (PDL1 block) + cobimetinib (MEK inh) in mcrc Bendell et al, ASCO 2016

52 MoTriColor project

53 PAST Single gene single biomarker single drug PRESENT Multi gene multi biomarker multi drug FUTURE Genomic clonal perspective CO-OCCURRING ALTERATIONS DYNAMICS OF TARGET INHIBITION CLONAL SELECTION TEMPORAL HETEROGENEITY NOVEL ONCOGENIC DEPENDENCIES Multi omics systems biology adaptive (immune) drug Stromal immune perspective MICROENVIRONMENT SPATIAL HETEROGENEITY

54 PAST Single gene single biomarker single drug PRESENT Multi gene multi biomarker multi drug TARGET CLONAL EVOLUTION Genomic clonal perspective Intermittent use of targeted therapies, vertical inhibition of convergent pathway alterations, drugging truncal genomic events FUTURE Multi omics systems biology adaptive (immune) drug Stromal immune perspective Combining immune and targeted therapies TARGET MICROENVIRONMENT DEPENDENCIES

55 Differential benefit adjuvant oxaliplatin in NSABP C-07 trial 1,035 patients Song et al, JAMA Oncology 2016

56 TAKE-HOME MESSAGE Still unknown what combination of genomic features (mutation + MSI + gene expression + immune + stromal) will provide will provide the best prediction of drug response.

57 VHIO SAGE ICO Fiorella Ruiz, Ariadna Garcia, Cristina Viaplana, Marta Vilaro, Josep Tabernero Justin Guinney Susanna Aussó, Rebeca Sanz, Victor Moreno, Ramon Salazar