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• W3081908256 abstract "Acute myelogenous leukemia (AML) is the most common acute leukemia in adults. Despite advances in treatment, long-term survival for AML remains poor and development of novel treatments is an unmet need. Due to highly divergent subtypes and mutation profiles in AML, use of patient-derived models may improve drug discovery and development. To address this, we have established a short-term culture system that supports growth of primary AML cells ex vivo to permit evaluation and/or screening of candidate therapeutic agents. Our AML bank is comprised of patient-derived specimens across a range of subtypes (which includes M1, M2, M4, M5, NOS and others), and includes models with common mutations in FLT3 (ITD), IDH1/IDH2 and NPM. Primary AML specimens were characterized for common mutations by TruSight sequencing and for surface marker expression by flow cytometry. The ex vivo assay system was evaluated for the ability to support survival and expansion of primary AML specimens. Among these, majority of the models showed evidence of proliferation, a few models had no net expansion, and some failed to survive. Extension of culture period for up to 14 days was feasible, with most models having equal or increased cell numbers by end of the culture period. All models stably expressed CD33 throughout the assay. To verify the applicability of this system for drug testing, a standard of care agent cytarabine (Ara-C) was assessed. A small cohort of models with distinct mutations were tested for sensitivity towards small molecule inhibitors venetoclax, gilteritnib, glasdegib, panobinostat and Ibrutinib. Cell growth/viability was assessed using Cell titer-Glo assay. Concentration-dependent responses to Ara-C were observed across multiple models (IC50 10 nM to 150 nM), indicating a range of relatively sensitive to resistant AML models. Heterogeneous concentration-dependent responses were observed across multiple patient-derived ex vivo models when treated with venetoclax, glasdegib, gilteritnib, ibrutinib and panobinostat, with both sensitive and resistant models identified. A cohort of models were evaluated in vivo for sensitivity to Ara-C. Systemic engraftment of the patient-derived xenograft AML models (into NOG or NOG-EXL mice) was evaluated by flow cytometry. When engrafted, AML-bearing mice were randomized into Ara-C or vehicle control groups. Two weeks later, mice were evaluated for the presence of human CD45+CD33+AML cells. Models that were relatively sensitive to Ara C ex vivo (IC50 100 nM that had no response to Ara C in vivo. The diversity in these AML models is reflective of patient diversity, enhancing their utility in the evaluation of novel therapeutic candidates. These data indicate the feasibility of utilization of these primary models, ex vivo as well as in vivo, for drug discovery for AML, from screening to preclinical efficacy modeling. Citation Format: Bhavna Verma, Nikolett Biel, Amy Wesa. 2D ex vivo patient derived acute myeloid leukemia platform for evaluation of novel molecular targeted therapeutic agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6298." @default.
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• W3081908256 date "2020-08-13" @default.
• W3081908256 modified "2023-10-17" @default.
• W3081908256 title "Abstract 6298: 2D ex vivo patient derived acute myeloid leukemia platform for evaluation of novel molecular targeted therapeutic agents" @default.
• W3081908256 doi "https://doi.org/10.1158/1538-7445.am2020-6298" @default.
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