PB1779: DEVELOPING NOVEL SYNERGISTIC DRUG COMBINATIONS WITH VENETOCLAX IN ACUTE MYELOID LEUKAEMIA

Abstract

Background: The treatment of AML remains a challenge due to complex genomic heterogeneity. In recent years, advancements in genomic technologies and the development of targeted therapies have changed the treatment paradigm, offering targeted treatments for patients with specific genomic vulnerabilities (1). The orally available BCL-2 inhibitor venetoclax is well tolerated and has recently received FDA approval in combination with hypomethylating agents (HMAs) for the treatment of newly diagnosed AML patients unfit for standard induction chemotherapy. Recent clinical trials have shown complete remission in around 70% of newly diagnosed AML cases with venetoclax and HMA regimens (2,3). However, relapses are common and there is still an unmet need for effective therapies with long-lasting remissions. The development of novel combinations allows for dual targeting of molecular drivers in AML. Recent studies have investigated novel venetoclax-based combination regimens to further improve anti-leukemia efficacy, evade drug resistance, reduce toxicities, and promote deep durable remissions. Venetoclax in combination with IDH1/2 inhibitors, FLT3 inhibitors, CDK inhibitors, and MEK inhibitors are among the most promising novel combination regimens currently being investigated (4–7). Aims: This investigation aims to develop novel synergistic drug combinations with venetoclax via high throughput screening of >2000 compounds to improve venetoclax safety, efficacy and overcome resistance. Methods: Venetoclax dose response experiments, Western blot analyses of BCL-2 protein expression and qPCR analyses of BCL2 gene expression were performe in a panel of 8 AML cell lines. A drug library comprised of 1,971 FDA approved compounds and 755 clinical compounds will be screened for anti-leukemia efficacy at 3 concentrations, in 3 AML cell lines at 3 timepoints. A secondary screen will combine successful candidate compounds with venetoclax and assess synergistic anti-leukaemic effect and ability to overcome resistance. Results: Venetoclax IC50 values in the 8 AML cell lines range from <0.01µM to >5µM highlighting differential response among the panel. Western blot and qPCR analyses showed diverse BCL-2 protein and BCL2 gene expression in the 8 cell lines which may account for variation in response. Summary/Conclusion: Further experiments will be performed to characterize mechanisms of induced cell death including target engagement analysis, Annexin V/ Propidium iodide staining. Candidate venetoclax-based combinations will be assessed for efficacy in a larger panel of cell lines and patient samples.