Research ArticleCancer therapy

High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors

See allHide authors and affiliations

Science Signaling  16 Jun 2020:
Vol. 13, Issue 636, eaay1451
DOI: 10.1126/scisignal.aay1451

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Speedy screen for tumor therapies

Although cell death screens using patient biopsies could be used to identify effective, personalized treatments, it takes several days to obtain results, meaning that the cells ultimately guiding treatment decisions may become molecularly different than those in the patient. Bhola et al. developed a high-throughput method (called HT-DBP) that identifies, within 24 hours, drugs that initiate cell death programs in tumor cells from freshly isolated patient biopsies. HT-DBP identified single agents and combinations that shrunk breast and colon tumors in mice but that would not have seemed as promising when screened after the usual multiday period of culture outgrowth. The findings may enable a fast and broadly applicable tumor screening technique to guide effective treatment decisions for patients.

Abstract

Despite decades of effort, the sensitivity of patient tumors to individual drugs is often not predictable on the basis of molecular markers alone. Therefore, unbiased, high-throughput approaches to match patient tumors to effective drugs, without requiring a priori molecular hypotheses, are critically needed. Here, we improved upon a method that we previously reported and developed called high-throughput dynamic BH3 profiling (HT-DBP). HT-DBP is a microscopy-based, single-cell resolution assay that enables chemical screens of hundreds to thousands of candidate drugs on freshly isolated tumor cells. The method identifies chemical inducers of mitochondrial apoptotic signaling, a mechanism of cell death. HT-DBP requires only 24 hours of ex vivo culture, which enables a more immediate study of fresh primary tumor cells and minimizes adaptive changes that occur with prolonged ex vivo culture. Effective compounds identified by HT-DBP induced tumor regression in genetically engineered and patient-derived xenograft (PDX) models of breast cancer. We additionally found that chemical vulnerabilities changed as cancer cells expanded ex vivo. Furthermore, using PDX models of colon cancer and resected tumors from colon cancer patients, our data demonstrated that HT-DBP could be used to generate personalized pharmacotypes. Thus, HT-DBP appears to be an ex vivo functional method with sufficient scale to simultaneously function as a companion diagnostic, therapeutic personalization, and discovery tool.

View Full Text

Stay Connected to Science Signaling