Abstract A024: Assessing Mitondiral Priming in Leukemia Using BH3 Complex Specific Antibodies (PRIMABS): Prediciting Patient Response to Apoptosis Inducing Drugs
Authors: Cardone Michael 
Published: November 2024

Diagnostic tools for cancer therapy that enable oncologists to inform patients about the likely benefits of their treatment versus toxicity will empower patients to make evidence-based decisions about the management of their disease, and in some cases, their last phase of life. Here we provide a novel approach that measures key drug response features of individual cancer cells with the potential for providing prognostic/predictive diagnostic utility for practicing precision medicine. Most cancer treatments work though activation of the cell suicide program of apoptosis. This process is tightly regulated by the BCL-2 family of proteins whose members either prevent or promote cell death. The relative levels of, and the specific interactions between the pro-survival and pro-apoptotic family members that dictates the fate of all cells and determines their propensity to undergo apoptosis. Cells that more readily die in response to various stimuli are referred to as “primed”. Hence, the degree of priming of a tumor sample can be predictive of responses to anti-cancer drugs and can be established using a technique called “BH3 profiling”. The relevance of this method has been demonstrated but it has had only limited application. To address this limitation a unique panel of antibody-based reagents that are mitochondrial PRIMing state detecting Antibodies (PRIMABS), have been developed by our lab, as a novel approach to implementing personalized medicine and developing predicative diagnostic tests. These antibodies enable the degree of tumor cell priming to be determined directly, unlike BH3 profiling which is an indirect measure. The key innovation lies in the approach taken to determine the presence (or absence) of the critical pro-survival : pro-apoptotic protein complexes , as these are the principal determinants of cell priming.. Such PRIMAB reagents have hitherto not been available. Here we provide data outlining the methodology development as well as evidence demonstrating feasibility of PRIMABTM Dx platform for predicting AML and CLL patient response in retrospective studies. Our platform provides a PD biomarker that will become a clinical predictor of cancer cell response to treatments tat are intended to induce apopstosis in tumor cells. The PRIMABTM -DX platform will enable heretofore hard to achieve clinical applicability of priming measurements. This will be significant due to the important prognostic implications of PRIMAB-DxTM readouts and will provide insights into drug resistance and sensitivity mechanisms and lead to new treatment options for cancer patients.

Citation Format: Michael Cardone. Assessing Mitondiral Priming in Leukemia Using BH3 Complex Specific Antibodies (PRIMABS): Prediciting Patient Response to Apoptosis Inducing Drugs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A024.