title: Drug discovery using clinical outcome-based Connectivity Mapping: application to ovarian cancer.
abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States (5 % of cancer deaths). The standard treatment for patients with advanced EOC is initial debulking surgery followed by carboplatin-paclitaxel combination chemotherapy. Unfortunately, with chemotherapy most patients relapse and die resulting in a five-year overall survival around 45 %. Thus, finding novel therapeutics for treating EOC is essential. Connectivity Mapping (CMAP) has been used widely in cancer drug discovery and generally has relied on cancer cell line gene expression and drug phenotype data. Therefore, we took a CMAP approach based on tumor information and clinical endpoints from high grade serous EOC patients.
  
  
  
  We determined tumor gene expression signatures (e.g., sets of genes) associated with time to recurrence (with and without adjustment for additional clinical covariates) among patients within TCGA (n = 407) and, separately, from the Mayo Clinic (n = 326). Each gene signature was inputted into CMAP software (Broad Institute) to determine a set of drugs for which our signature "matches" the "reference" signature, and drugs that overlapped between the CMAP analyses and the two studies were carried forward for validation studies involving drug screens on a set of 10 EOC cell lines.
  
  
  
  Of the 11 drugs carried forward, five (mitoxantrone, podophyllotoxin, wortmannin, doxorubicin, and 17-AAG) were known a priori to be cytotoxics and were indeed shown to effect EOC cell viability.
  
  
  
  Future research is needed to investigate the use of these CMAP and similar analyses for determining combination therapies that might work synergistically to kill cancer cells and to apply this in silico bioinformatics approach using clinical outcomes to other cancer drug screening studies.
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Raghavan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyter
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
authors.forename: Harsh B
authors.initials: HB
authors.lastname: Pathak
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Department of Medicine, Hematology & Oncology, University of California - Los Angeles, Los Angeles, CA, 90095, USA.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Konecny
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55901, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55901, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA. bfridley@kumc.edu.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016016:Proportional Hazards Models; D012008:Recurrence
chemical_list: D000970:Antineoplastic Agents
keywords: Bioinformatics; Connectivity Mapping; Drug discovery; Gene expression signature; Ovarian cancer; Time to recurrence