High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors
- 16 June 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 13 (636)
- https://doi.org/10.1126/scisignal.aay1451
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.Keywords
Funding Information
- National Institutes of Health (R01 CA205967)
- National Institutes of Health (R35 CA242427)
- National Institutes of Health (P50 CA127003)
- National Institutes of Health (R01 CA205406)
- National Institutes of Health (R35 CA210057)
- National Institutes of Health (P50 CA168504)
- U.S. Department of Defense (DOD BC171657)
This publication has 41 references indexed in Scilit:
- Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapyNature Genetics, 2018
- Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision MedicineCancer Discovery, 2018
- Analysis of Fusobacterium persistence and antibiotic response in colorectal cancerScience, 2017
- The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in MiceCancer Cell, 2016
- Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG miceLeukemia, 2015
- Drug-Induced Death Signaling Strategy Rapidly Predicts Cancer Response to ChemotherapyCell, 2015
- Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic ChemotherapyScience, 2011
- In vitro Drug Sensitivity Predicts Response and Survival after Individualized Sensitivity-Directed Chemotherapy in Metastatic Melanoma: A Multicenter Phase II Trial of the Dermatologic Cooperative Oncology GroupClinical Cancer Research, 2006
- Design, Synthesis, and Biological Evaluation of Hydroquinone Derivatives of 17-Amino-17-demethoxygeldanamycin as Potent, Water-Soluble Inhibitors of Hsp90Journal of Medicinal Chemistry, 2006
- Biological Mechanism Profiling Using an Annotated Compound LibraryCell Chemical Biology, 2003