title: Tumor deconstruction as a tool for advanced drug screening and repositioning.
abstract: A major focus of contemporary drug screening strategies is the identification of novel anticancer compounds, which often results in underutilization of resources. Current drug evaluation involves in vivo tumor (xenograft) regression as proof-of-principle for cytotoxicity (POC). However, this end-point lacks any assessment of drug resistance of the residual tumor and its capability to establish refractory and/or recurrent disease, which would represent more appropriate indicators of therapeutic failure. We have recently developed a flow cytometry-based approach for the analyses of intra-tumor cellular heterogeneity across stem cell hierarchies, genetic instability and differential cell cycling fractions, which can potentially be predictive of refractory disease and tumor relapse. Iterating this approach after initial POC screening in the drug discovery pipeline would have a great impact in terms of precision of drug evaluation, design of optimal drug combinations and/or drug repositioning. In this perspective, we highlight how through embracing of a comprehensive, informative and analytical assessment of the cellular content of residual tumors, the fidelity and statistical robustness of preclinical drug discovery can be greatly improved.
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune 411007, India.
authors.forename: Rutika R
authors.initials: RR
authors.lastname: Naik
authors.affiliation: Department of Applied Mathematics, University of Waterloo, ON N2L 3G1, Canada.
authors.forename: Ting
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Applied Mathematics, University of Waterloo, ON N2L 3G1, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kohandel
authors.affiliation: National Centre for Cell Science, NCCS Complex, Pune 411007, India. Electronic address: sabapat@nccs.res.in.
authors.forename: Sharmila A
authors.initials: SA
authors.lastname: Bapat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D055808:Drug Discovery / Q000379:methods*; D058492:Drug Repositioning / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D057166:High-Throughput Screening Assays; D006801:Humans; D008954:Models, Biological; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents