Abstract 2990: Individualized functional approach to tailoring acute myeloid leukemia therapy
Authors: Shruti Bhatt, Binyam Yilma, Elyse Olesinski, Holly Zhu, Mark Murakami, Vineeth Kumar Murali, Sophia Adamia, David M. Weinstock, Jacqueline S. Garcia, Anthony Letai
Journal: Cancer Research (2019)

Abstract The major focus of drug development in AML has shifted to targeted agents because, despite initial sensitivity to conventional chemotherapy, durable remissions are limited. The clinical implementation of effective targeted therapies still lags due to the lack of predictive biomarkers. To make the best use of existing therapy and to identify new targeted therapies we adopted a broadly applicable functional approach to precision medicine called “dynamic BH3 profiling” (DBP). DBP measures early death signaling induced by short-term drug exposure. Increased cell death signaling is reflected by increased mitochondrial sensitivity (priming) to standardized BH3 peptides mimicking pro-apoptotic proteins. To develop a personalized therapeutic strategy for AML using DBP, we utilized 17 patient-derived xenografts (PDX) established from de novo, primary refractory or relapsed (R/R) patients. Human myeloblasts from xenotransplanted mice were exposed to 30 targeted and 3 standard of care drugs to determine mitochondrial responses via DBP. Unsupervised clustering of ex vivo DBP responses segregated PDXs into two major clusters, where treatment naïve PDXs clustered distinctly from R/R PDXs. Most drugs induced priming in only selective PDXs, including kinase inhibitors, epigenetic modifiers, and a SMAC mimetic. In contrast, BH3 mimetics and CDK9 inhibitors showed activity across a majority of PDXs. Next, we validated the ability of DBP to predict in vivo responses of single-agent birinapant (SMAC mimetic), JQ-1 (BRD-4 inhibitor), quizartinib (FLT-3 inhibitor), and venetoclax (BCL-2 inhibitor) across 6 AML PDX models, prioritized based on their greatest range of priming responses. The models that showed increased ex vivo priming via DBP also showed greatest in vivo responses, indicating that DBP can rank PDXs according to their drug sensitivities (AUC of ROC 0.87, p&amp;lt;0.005). By comparing the predictive power of DBP to other precision medicine tools such as genomics, we found that DBP was able to accurately predict quizartinib activity in PDXs with WT FLT-3, which are categorized as unresponsive based on genomics. To test the applicability of DBP in assigning therapies in the relapsed setting, we induced resistance to PDX models to single agents via long-term in vivo selection. Myeloblasts of relapsing clone showed reduced baseline mitochondrial priming and loss of sensitivity to most of the agents. This suggested that acquired resistance to single agents selects for apoptosis-refractory clones which then drive a pan-drug resistant phenotype. Finally, we applied this approach to humans, showing that the pretreatment mitochondrial apoptotic priming determined by DBP identifies responders to lenalidomide plus MEC combination therapy in the phase 1 trial of R/R AML patients. In summary, our results suggest that mitochondria-based measurements may serve as a precision medicine tool to guide therapy for a heterogeneous population. Citation Format: Shruti Bhatt, Binyam Yilma, Elyse Olesinski, Holly Zhu, Mark Murakami, Vineeth Kumar Murali, Sophia Adamia, David M. Weinstock, Jacqueline S. Garcia, Anthony Letai. Individualized functional approach to tailoring acute myeloid leukemia therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2990.