Many known chemotherapeutic drugs kill abnormal cells through a process called apoptosis. Bcl-2 proteins are negative regulators of apoptosis that control cell survival and death. Increased expression of anti-apoptotic Bcl-2 proteins commonly occurs in up to 30% of all cancers, providing cancer cells a pro-survival advantage to evade cell death, grow, and proliferate. Drugs targeting these specific anti-apoptotic proteins are potential anti-cancer therapeutics. A need exists for improved methods to select patients that may benefit from drugs targeting apoptotic pathway, such as Bcl-2 homology domain-3 (BH3) mimetics.
Researchers at the NCI developed a multiplex assay to determine the efficacy of apoptosis-related drugs targeting the Bcl2 family of proteins or aid in the selection of cancer patients likely to respond. The immunoassay quantitatively measures heterodimer protein complexes of specific Bcl-2 family proteins. Traditional assays performed in needle biopsies only measure individual Bcl-2 family proteins and do not capture the protein-protein interactions.
The assay was confirmed using tumor tissue biopsy samples and has the potential to predict drug efficacy. The assay may be useful as a companion diagnostic in conjunction with apoptosis-inducing agents. The assay also has the potential to aid in the selection of cancer patients likely to respond to drugs targeting the apoptosis pathway.
- Companion diagnostic to determine efficacy of anti-apoptotic therapies such as BH3 mimetics
- Diagnostic for the selection of appropriate drug therapy for cancer patients
- Novel assay to simultaneously measure multiple indicators of apoptosis in a single sample compared to traditional assays
- Quantitative measurement of pro-apoptotic drug efficacy
Apurva K Srivastava Ph.D. (NCI/Leidos), Dominic Esposito Ph.D. (NCI/Leidos), Jeevan Prasaad Govindharaju Ph.D. (NCI/Leidos), Ralph E Parchment Ph.D. (NCI/Leidos), James H Doroshaw MD (NCI)
Srivastava AK, et al. Effect of a Smac Mimetic (TL32711, Birinapant) on the Apoptotic Program and Apoptosis Biomarkers Examined with Validated Multiplex Immunoassays Fit for Clinical Use. [PMID 26446940]
- U.S. Provisional: U.S. Provisional Patent Application Number 62/798,615 , Filed 30 Jan 2019
- PCT: PCT Application Number US 2020/015694, Filed 06 Aug 2020