Person:

Patel, Chirag

Computational drug repositioning methods can scalably nominate approved drugs for new diseases, with reduced risk of unforeseen side effects. The majority of methods eschew individual‐level phenotypes despite the promise of biomarker‐driven repositioning. In this study, we propose a framework for discovering serendipitous interactions between drugs and routine clinical phenotypes in cross‐sectional observational studies. Key to our strategy is the use of a healthy and nondiabetic population derived from the National Health and Nutrition Examination Survey, mitigating risk for confounding by indication. We combine complementary diagnostic phenotypes (fasting glucose and glucose response) and associate them with prescription drug usage. We then sought confirmation of phenotype‐drug associations in unidentifiable member claims data from the Aetna Insurance company using a retrospective self‐controlled case analysis approach. We identify bupropion as a plausible glucose lowering agent, suggesting that surveying otherwise healthy individuals in cross‐sectional studies can discover new drug repositioning hypotheses that have applicability to longitudinal clinical practice.

The computational repositioning of existing drugs represents an appealing avenue for identifying effective compounds to treat diseases with no FDA-approved pharmacotherapies. Here we present the largest meta-analysis to date of differential gene expression in human vestibular schwannoma (VS), a debilitating intracranial tumor, and use these data to inform the first application of algorithm-based drug repositioning for this tumor class. We apply an open-source computational drug repositioning platform to gene expression data from 80 patient tumors and identify eight promising FDA-approved drugs with potential for repurposing in VS. Of these eight, mifepristone, a progesterone and glucocorticoid receptor antagonist, consistently and adversely affects the morphology, metabolic activity, and proliferation of primary human VS cells and HEI-193 human schwannoma cells. Mifepristone treatment reduces VS cell viability more significantly than cells derived from patient meningiomas, while healthy human Schwann cells remain unaffected. Our data recommend a Phase II clinical trial of mifepristone in VS.