Session: 802. Chemical Biology and Experimental Therapeutics: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research, drug development, Therapies
METHODS: Primary T-ALL and ETP-ALL patient samples were treated with BH3 mimetics in vitro for 48 hours and sensitivity to individual BH3 mimetics was determined. Additionally, BH3 apoptotic dependency profiling was performed with both plate-based and flow cytometric-based assays to determine mitochondrial depolarization and cytochrome c release, respectively. By using peptides specific for individual anti-apoptotic proteins, the cell death dependency patterns in samples pre- and post-treatment were also determined.
RESULTS: Sensitivity of T-ALL and ETP-ALL primary patient cells to cell death following treatment with different BH3 mimetics including venetoclax, LP-118, navitoclax, and A-1155463 (BCL-XL inhibitor) was first measured (Fig. 1A). Typical pre-T-ALL samples from 20 pts showed higher sensitivity to BCL-XL targeting (LP-118, navitoclax, A-1155463) when compared to BCL-2 targeting (venetoclax). In contrast, ETP-ALL samples from 6 pts showed higher sensitivity to BCL-2 inhibition- via BCL-2 (venetoclax) or dual BCL-2/BCL-XL inhibition. Interestingly, Western blot analysis revealed no correlation between the relative ratios of BCL-2:BCL-XL protein levels and response to different BH3 mimetics. Therefore, BH3 profiling was used to identify clinically meaningful selective antiapoptotic protein dependencies in these samples. Using this method, we observed a clear increased cell death dependency on BCL-XL in pre-T-ALL samples and upon BCL-2 in ETP-ALL samples (Fig. 1B). Combining surface immunophenotyping with flow-based BH3 profiling further allowed for evaluation of apoptotic dependencies in functionally heterogenous subpopulations of cells. Our data suggest that the CD34+CD7+ compartment may be enriched with cells that are less primed to die and more resistant to BH3 peptidomimetics.
CONCLUSIONS: Our data show maturation stage-specific differences in antiapoptotic protein dependencies in ETP- vs T-ALL, that correlate with their responses to individual BH3 mimetics. Based upon this work, we believe that dual targeting of BCL-2 and BCL-XL is a promising approach for further clinical development in both types of T-lineage ALL. Additionally, the dose limiting toxicity of myelosuppression observed with navitoclax may be overcome with the novel dual inhibitor, LP-118. The ongoing phase 1 study investigating oral LP-118 in relapsed/refractory hematologic malignancies is expected to provide data on safety and clinical activity in 2023 (NCT04771572).
Disclosures: Chen: Newave Pharmaceuticals: Current Employment. Tan: Newave Pharmaceuticals: Current Employment. Anthony: Newave Pharmaceuticals: Current Employment. Chen: Newave Pharmaceuticals: Current Employment. Shen: Newave Pharmaceuticals: Current Employment. LaBelle: AbbVie: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Stock: Pfizer: Consultancy, Honoraria, Research Funding; Pluristem: Consultancy, Honoraria; Servier: Honoraria; Syndax: Consultancy, Honoraria; Newave Pharmaceuticals: Consultancy; Kura Oncology: Honoraria; Kite: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria.
See more of: Oral and Poster Abstracts