Drug discovery using clinical outcome-based Connectivity Mapping: application to ovarian cancer

BMC Genomics

Research Article

Brooke L. Fridley¹  Rama Raghavan¹  Ellen L. Goode²  Chen Wang²  Gottfried Konecny³  Andrew K. Godwin⁴  Harsh B. Pathak⁴  Stephen Hyter⁴ 

[1] Department of Biostatistics, University of Kansas Medical Center, 3901 Rainbow Blvd, 66160, Kansas City, KS, USA;Department of Health Sciences Research, Mayo Clinic, 55901, Rochester, MN, USA;Department of Medicine, Hematology & Oncology, University of California – Los Angeles, 90095, Los Angeles, CA, USA;Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 66160, Kansas City, KS, USA;

关键词: Gene expression signature;    Time to recurrence;    Bioinformatics;    Connectivity Mapping;    Drug discovery;    Ovarian cancer;   

DOI  :  10.1186/s12864-016-3149-5

 received in 2016-03-03, accepted in 2016-10-07,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundEpithelial 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.MethodsWe 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.ResultsOf 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.ConclusionsFuture 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.

【 授权许可】

CC BY   
© The Author(s). 2016