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Realizing society’s expectations of the cancer community

Realizing society’s expectations of the cancer community. cancer genomics. CTD 2. cancer therapeutics. Realizing society’s expectations of the cancer community. cancer genomics. CTD 2. cancer therapeutics. Anna Barker: Intro.

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Realizing society’s expectations of the cancer community

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  1. Realizing society’s expectations of the cancer community cancer genomics CTD2 cancer therapeutics

  2. Realizing society’s expectations of the cancer community cancer genomics CTD2 cancer therapeutics Anna Barker: Intro 1. Stuart Schreiber: Overview and small-molecule probes 2. William Hahn: LoF, GoF RNA 3. Andrea Califano: Systems analyses

  3. The NCI’s Cancer Target Discovery and Development Network “Towards patient-based cancer therapeutics” Andrea Califano, Daniela S. Gerhard, William C. Hahn, Scott Powers, Michael Roth, Stuart L. Schreiber, in review

  4. Relating a genetic feature of a cancer to the efficacy of a drug Philadelphia translocation: Janet Rowley imatinib matched small-molecule therapy chemotherapy overall survival (%) no treatment months after beginning treatment (Kaplan-Meier survival curve) Brian J Druker, Nature Medicine 15, 1149-1152 (2009)

  5. Relate cancer genetic features to drug efficacy comprehensively Philadelphia translocation: Janet Rowley imatinib matched small-molecule therapy chemotherapy overall survival (%) Can these type of dependencies, reflected by cancer genotype/drug efficacy relationships, be discovered comprehensively? no treatment months after beginning treatment (Kaplan-Meier survival curve) Brian J Druker, Nature Medicine 15, 1149-1152 (2009)

  6. Facilitate efficient paths for clinical development prospectively Philadelphia translocation: Janet Rowley imatinib matched small-molecule therapy chemotherapy overall survival (%) Patient populations, biomarkers, drug targets and resistance mechanisms are identified concurrently and from the outset. no treatment months after beginning treatment (Kaplan-Meier survival curve) Brian J Druker, Nature Medicine 15, 1149-1152 (2009)

  7. Cancer Target Discovery and Development (CTD2) Network probe acquired dependenciesvia RNA3-5 determine relevance (ID4; STK33; TBK1)1,4-5 probe acquired dependencies via proteins1,5 cancer genomics small-molecule probes (small-molecule probe set) small-molecule drugs1 cancer patients cancer genomics-based mouse models2,4 determinerelevance (STAT3; C/EBP in GBM)1,3 probe acquired dependencies via systems analyses3 Relate the genetic features of cancers to acquired cancer dependencies and identifysmall molecules that target the dependencies (1Broad; 2CSHL; 3Columbia; 4DFCI; 5UTSW)

  8. Cancer Target Discovery and Development (CTD2) Network probe acquired dependenciesvia RNA3-5 determine relevance (ID4; STK33; TBK1)1,4-5 probe acquired dependencies via proteins1,5 cancer genomics small-molecule probes (small-molecule probe set) small-molecule drugs1 cancer patients cancer genomics-based mouse models2,4 determinerelevance (STAT3; C/EBP in GBM)1,3 probe acquired dependencies via systems analyses3 Relate the genetic features of cancers to acquired cancer dependencies and identifysmall molecules that target the dependencies (1Broad; 2CSHL; 3Columbia; 4DFCI; 5UTSW)

  9. Small-molecule cancer probes against challenging targets growth, differentiation, survival factors Sonic Hedgehog, HB-EGF DDR1 membrane receptors (targets of small molecules whose functions have been modulated in cells) GPCRs, kinases, etc. transcription factors NFkB, GATA1, Myc, C/EBPa, HOXA13; HDAC6, JMJD2C

  10. From opportunistic to disciplined: modulating challenging targets Advances exploited by CTD2 and enabling a disciplined approach to cancer drug discovery: • innovations innext-generation synthetic chemistry that reach ‘undruggable’ targets or processes. • innovations in cell culturing and screening in physiologically relevant conditions (tumor microenvironment) Sonic Hedgehog • innovations in determining the targets and mechanisms of small-molecule probes and drugs. SHH signaling

  11. Cancer Target Discovery and Development (CTD2) Network probe acquired dependenciesvia RNA3-5 determine relevance (ID4; STK33; TBK1)1,4-5 probe acquired dependencies via proteins1,5 cancer genomics small-molecule probes (small-molecule probe set) small-molecule drugs1 cancer patients cancer genomics-based mouse models2,4 determinerelevance (STAT3; C/EBP in GBM)1,3 probe acquired dependencies via systems analyses3 Relate the genetic features of cancers to acquired cancer dependencies and identifysmall molecules that target the dependencies (1Broad; 2CSHL; 3Columbia; 4DFCI; 5UTSW)

  12. Small-molecule probes of ID4: an ovarian cancer oncogene Loss-of-Function Genes essential for ovarian cancer proliferation Cancer GenomeAnnotation ID4 Cross reference with genes in amplified regions in OvCa (TCGA) Gain-of-Function Genes that induce ovarian tumor formation Bill Hahn et al.

  13. Small-molecule probes of ID4: an ovarian cancer oncogene Loss-of-Function Genes essential for ovarian cancer proliferation Cancer GenomeAnnotation ID4 Cross reference with genes in amplified regions in OvCa (TCGA) 1536-well plate ID4 SM probe development Gain-of-Function Genes that induce ovarian tumor formation Bill Hahn et al.

  14. Cancer Target Discovery and Development (CTD2) Network probe acquired dependenciesvia RNA3-5 determine relevance (ID4; STK33; TBK1)1,4-5 probe acquired dependencies via proteins1,5 cancer genomics small-molecule probes (small-molecule probe set) small-molecule drugs1 cancer patients cancer genomics-based mouse models2,4 determinerelevance (STAT3; C/EBP in GBM)1,3 probe acquired dependencies via systems analyses3 Relate the genetic features of cancers to acquired cancer dependencies and identifysmall molecules that target the dependencies (1Broad; 2CSHL; 3Columbia; 4DFCI; 5UTSW)

  15. Small-molecule probes of STAT3 in glioblastomamultiforme G1 G2 G3 G4 G5 G6 G7 G8 G9 G10 G11 G12 GBM patient X W Y Z master regulator module(s) V STAT3 Andrea Califano et al.

  16. Small-molecule probes of STAT3 in glioblastomamultiforme G1 G2 G3 G4 G5 G6 G7 G8 G9 G10 G11 G12 GBM patient X W Y Z master regulator module(s) 1536-well plate STAT3 SM probe development V STAT3 Andrea Califano et al.

  17. CTD2 Network: challenging probe development projects

  18. Cancer Target Discovery and Development (CTD2) Network probe acquired dependenciesvia RNA3-5 determine relevance (ID4; STK33; TBK1)1,4-5 probe acquired dependencies via proteins1,5 cancer genomics small-molecule probes (small-molecule probe set) small-molecule drugs1 cancer patients cancer genomics-based mouse models2,4 determinerelevance (STAT3; C/EBP in GBM)1,3 probe acquired dependencies via systems analyses3 Relate the genetic features of cancers to acquired cancer dependencies and identifysmall molecules that target the dependencies (1Broad; 2CSHL; 3Columbia; 4DFCI; 5UTSW)

  19. Modeling human cancers: cancer genetic features in mice ORF/shRNA library of GEOI genetically defined orthotopicinjection tumorigenic phenotype context-specific target cell (e.g., pre-malignant ovarian epithelial cells) biological validation GEOI “HIT” e.g., AHNAK in ovarian cancer (CSHL) context-specific tumor cell A context-specific functional genetic screening platform: promoting cancers Scott Lowe, Scott Powers, et al.; and Ron DePinho, Linda Chin, Bill Hahn

  20. Modeling drug target inhibition: inducible RNA in vivo control shRPA shRPA • Transplantable cancer models for target identification (screens) and validation 0 • Germ-line transgenic mice for functional studies and assessment of potential drug toxicities 3 Time (days post dox addition) 6 A context-specific functional genetic screening platform: eliminating cancers 10 Scott Lowe, Scott Powers, et al.

  21. Targeting non-oncogene co-dependencies (synthetic lethality) matched to genetic signature target oncogene (e.g., BCR-ABL/imatinib, muEGFR/erlotinib) target ‘non-oncogene co-dependency’ (e.g.,for muRAS: 1) hexokinaseand 2) GSTP1/CBR1/AHNAK stress inducers (paclitaxel, irinotecan): cytotoxics broad spectrum Stockwell, Haggarty, SLS, Chem & Biol, 6, 71-83 (1999); see also: Luo, Solimini, Elledge, Cell, 136, 823-37 (2009)

  22. RAS changes cancer metabolism and small-molecule sensitivity ATP synthase inhibitor hexokinase inhibitor more tumorigenic less tumorigenic ATP synthase inhibitor hexokinase inhibitor ArvindRamanathan, SLS (2005)

  23. Drugs matched to genetic features, not cancer metabolism RAS 2-deoxyglucose Ramanathan & Schreiber PNAS, 2005 glucose transporter Yunet.al.Science 2009 aerobic glycolysis 2-deoxyglucose glutamine transporter glutaminase Fan et.alJ Biol. Chem. 2010 Wise et. al. PNAS 2008 MYC AKT W. G. Kaelin & C. B. Thompson, Nature 2010 oligomycin; glutamine depletion Fan et.al J Biol. Chem. 2010

  24. RAS changes ROS biology and small-molecule sensitivity MMTV-PyVT transgenic mouse breast cancer model BRD2293 control • Discovered in an NCI ICG probe project • Induces cell death/apoptosis in transformed but not in normal cells • Prevents tumor growth in vivo (xenograft and spontaneous cancer models) in low doses safely • Quantitative proteomics reveals a target: GSTP1/CBR1/AHNAK complex, and mechanism-of-action studies reveal a process: dissipation of ROS “Sensing the cancer genotype by targeting stress response to ROS results in selective killing of cancer cells by a small molecule”, submitted

  25. Sensitivity to BRD293 is conferred by mutant RAS hTERT + ST hTERT hTERT + ST + RAS hTERT + ST hTERT hTERT + ST + RAS BRD293: BRD293: human primary BJ fibroblasts with serial transfections + BRD2293 = Anna Mandinova, Sam Lee Mutant RAS increases levels of ROS in cells: Lee et al., J. Biol. Chem. 274, 7936-7940 (1999)

  26. CTD2probe development for additional targets in ROS biology 380 nM 1.1uM 940 nM 1.39uM Cancer drugs matched to genetic features, not ‘ROS metabolism’

  27. Cell-line models of cancer: from NCI-60 to ChemBank cell lines cancer cell lines cell measurements small molecules small molecules NCI-60: Cancer cell line/small molecule sensitivity relationships (GI50 measurements) NCI-sponsored ChemBank: Cancer cell line/small molecule sensitivity/cell measurement relationships (Paul Clemons)

  28. Next-generation cancer cell line databases: CTD2 at UTSW lung cancer genotypes (examples from 8 clades) cancer cell measurement global RNAi and 250,000 small molecules roles of quantitative variables See also studies at MGH (Settleman, Haber & collaborators)

  29. H1155 HCC44 HCC4017 H1819 HCC366 HTS identifies selective small-molecule vulnerabilities in NSCLC

  30. Cancer cell line encyclopedia: a promising public resource • copy number (Affy SNP 6.0 array) • gene expression (U133 + 2 array) • mutation profiling (OncoMap v3): Total target genes 1,645 Total exons25,261 CCLE 1,000 genomically characterized cancer cell lines: bone; osteosarcoma; leukemia T-ALL; CML; medulloblastoma neuroblastoma; fibrosarcoma NSCLC leukemia B-All lymphoma (H) lymphoma (NH_T) thyroid; CLL endometrial AML; melanoma colorectal multiple myeloma breast gastric head & neck glioma pancreas kidney bladder prostate esophageal SCLC ovarian lymphoma liver Broad/Novartis CCLE Project: JordiBarretina, Levi Garraway, Bill Sellers, and collaborators

  31. CTD2 probe kit: highly specific SM probes of new cancer targets Academic Collaborators PubMed Patents Scifinder MLPCN Publications Clinical Candidates 10,000’s of documents/compounds Bioactives • Target • MOA • Selectivity • Potency • Structure • Clinical Status Comprehensive Review/Annotation e.g., dominant rapamycin-resistant allele (mTOR S2035T) proves specificity towards mTOR ~ 1,000 Compounds CTD2 Probe Kit 225 ‘narrowly active’ probes and growing; 36% are accessed by complete synthesis Ben Munoz, AlyShamji and the CTD2 team

  32. CTD2 probe kit representative examples; a living collection reported in past several months

  33. CCLE and the CTD2 small-molecule probe kit (in progress) 1,000 CCLs (genetic features) cancer cell measurement CTD2 probe kit (high specificity) 8 (in duplicate) concentrations roles of quantitative variables

  34. CTD2 pilot of the probe set suggests new clinical directions CTNNB1 activating mutation BCL2 antagonist ABT 263 IC50 (μM) subset of 1,000 cancer cell lines

  35. CTD2 pilot of the probe set suggests new therapeutics (HDAC6) VHL loss-of-function mutation novel CTD2HDAC6 inhibitor WT161 IC50 (μM) subset of 1,000 cancer cell lines

  36. CTD2 is discovering and using small-molecule probes of cancer small-molecule probes e.g., BRD293 1536-well plate RNA LoF/GoF; systems analyses probe development projects Discover small-molecule probes that target non-traditional cancer dependencies (TFs; chromatin; etc.) Discover relationships between cancer genetic features and small-molecule efficacies

  37. CTD2 Network: an integrated approach to cancer therapeutics Chemical Biology Cancer Biology Cancer Genomics Cancer Therapeutics

  38. CTD2 pilot of the probe set suggests new therapeutics indisulam BRD-6043 20uM 150nM KRAS status wt mut 10 colon lines 3/5 wt resistant 4/5 mut sensitive % viability EC50 (uM)

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