Microfluidic-based dynamic BH3 profiling predicts anticancer treatment efficacy

Abstract

Precision medicine is starting to incorporate functional assays to evaluate anticancer agents on patient-isolated tissues or cells to select for the most effective. Among these new technologies, dynamic BH3 profiling (DBP) has emerged and extensively been used to predict treatment efficacy in different types of cancer. DBP uses synthetic BH3 peptides to measure early apoptotic events (‘priming’) and anticipate therapy-induced cell death leading to tumor elimination. This predictive functional assay presents multiple advantages but a critical limitation: the cell number requirement, that limits drug screening on patient samples, especially in solid tumors. To solve this problem, we developed an innovative microfluidic-based DBP (µDBP) device that overcomes tissue limitations on primary samples. We used microfluidic chips to generate a gradient of BIM BH3 peptide, compared it with the standard flow cytometry based DBP, and tested different anticancer treatments. We first examined this new technology’s predictive capacity using gastrointestinal stromal tumor (GIST) cell lines, by comparing imatinib sensitive and resistant cells, and we could detect differences in apoptotic priming and anticipate cytotoxicity. We then validated µDBP on a refractory GIST patient sample and identified that the combination of dactolisib and venetoclax increased apoptotic priming. In summary, this new technology could represent an important advance for precision medicine by providing a fast, easy-to-use and scalable microfluidic device to perform DBP in situ as a routine assay to identify the best treatment for cancer patients.

Dinaciclib synergizes with BH3 mimetics targeting BCL‐2 and BCL‐XL in multiple myeloma cell lines partially dependent on MCL‐1 and in plasma cells from patients

“…The future of MM treatment relies on precision medicine, with decision making based on the ex vivo analysis of particular characteristics of malignant plasma cells. In this sense, dynamic BH3 profiling (DBP) has emerged as a useful tool to identify cellular dependence on individual antiapoptotic proteins with a simple FACS analysis or a microfluidic-based DBP device [74,75]. As an alternative, standardized titration of cancer cells sensitivity to BH3 mimetics may be addressed.…”

Patient-Derived Ex Vivo Cultures and Endpoint Assays with Surrogate Biomarkers in Functional Testing for Prediction of Therapeutic Response

“…Because DBP detects very early changes in the apoptotic response, it can be performed rapidly (typically < 24 h), allowing its application to early ex vivo cultures from patients. Although specialized materials, equipment, and techniques are required, this method has been validated by other groups [ 89 , 90 ] as well as the original inventor [ 91 ]. Since induction of apoptosis is especially important for the efficacy of anti-cancer drugs in hematological cancers, DBP is particularly useful for this type of cancer.…”