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

Area of Science:

• Oncology
• Biotechnology
• Pharmacology

Background:

• Predicting patient tumor sensitivity to drugs solely via molecular markers remains challenging.
• There is a critical need for unbiased, high-throughput methods to match tumors with effective drugs without prior molecular assumptions.

Purpose of the Study:

• To present an improved high-throughput dynamic BH3 profiling (HT-DBP) method for drug screening on patient tumors.
• To demonstrate HT-DBP's utility as a companion diagnostic, therapeutic personalization, and drug discovery tool.

Main Methods:

• HT-DBP is a microscopy-based, single-cell assay for screening hundreds to thousands of drugs on fresh tumor cells.
• The assay identifies drugs that induce mitochondrial apoptotic signaling, a cell death pathway.
• It requires only 24 hours of ex vivo culture to minimize adaptive changes in tumor cells.

Main Results:

• HT-DBP identified effective compounds that induced tumor regression in breast cancer models (genetically engineered and patient-derived xenografts).
• Drug sensitivities of cancer cells were observed to change during ex vivo culture.
• Personalized pharmacotypes were generated using HT-DBP in colon cancer models and patient samples.

Conclusions:

• HT-DBP is a scalable, ex vivo functional assay for immediate drug sensitivity testing on fresh tumor cells.
• The method can simultaneously serve as a companion diagnostic, therapeutic personalization tool, and drug discovery platform.
• HT-DBP addresses the need for predictive biomarkers by directly assessing drug response in patient tumors.