Abstract 3893: Novel synergistic targets for combination therapy in Philadelphia chromosome-like acute lymphoblastic leukemia
Authors: Ding Yang Y. , Madden Kellyn , Loftus Joseph P. , Kim Hannah , Chen Chia-hui , Tasian Sarah K. , Tan Kai 
Published: September 2020

Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like ALL) is a common leukemia subtype associated with high relapse rates and poor overall survival. Ph-like ALL has a kinase-activated gene expression signature similar to that of BCR-ABL1-rearranged ALL, but is driven by alternative mutations in JAK or ABL kinase signaling pathway genes. Preclinical studies using tyrosine kinase inhibitor (TKI) monotherapy in Ph-like ALL models demonstrate incomplete efficacy, emphasizing the need for combination therapy to improve cure rates. In these studies, we use a novel patient ‘omics data-driven approach to nominate pathways for optimal synergistic targeting in Ph-like ALL. We utilized our OptiCon algorithm (Hu et al. Nat. Comm. 2019) to analyze publicly-available genomic and transcriptomic data from patient leukemia samples. We identified synergistic gene pairs that control a maximal number of deregulated genes (for optimal efficacy) and a minimal number of unperturbed genes (to minimize toxicity) in Ph-like ALL, including a top-ranked synergistic control pair STAT5B and BAG1. STAT5B is hyperactive in different subclasses of Ph-like ALL and BAG1 (BCL2-associated athanogene1) enhances the anti-apoptotic effect of BCL-2 likely via degradation prevention. We then validated the anti-leukemic efficacy of co-targeting this pairing in Ph-like ALL cell lines and patient-derived xenograft (PDX) models. We assessed the in vitro and in vivo effects of combining the BCL-2 inhibitor venetoclax with the JAKi ruxolitinib or ABL1i dasatinib in 3 Ph-like ALL cell lines (CRLF2-rearranged/JAK-mutant MUTZ5 and MHH-cALL-4, immortalized ABL1-rearranged TVA-1) and 3 Ph-like ALL PDX models (CRLF2-rearranged/JAK-mutant ALL4364 and UP_ALL4988, ABL1-rearranged TVA-1). Co-treatment of the 3 cell lines with venetoclax and ruxolitinib or dasatinib showed synergy at all dose combinations tested, versus monotherapy (CI &lt;1.0). Venetoclax and ruxolitinib co-treatment of UP_ALL4988 and ALL4364 PDX mice significantly inhibited leukemia proliferation in vivo when compared to vehicle or single-agent inhibitors. Similar findings were observed in TVA-1 PDX mice treated with venetoclax and dasatinib. These preclinical results provide compelling rationale for potential combination therapy using BCL-2 inhibitor with TKIs in treatment of patients with Ph-like ALL, and represent an unbiased approach to the identification and testing of synergistic targets as candidates for multi-agent precision medicine therapy.

Citation Format: Yang Y. Ding, Kellyn Madden, Joseph P. Loftus, Hannah Kim, Chia-hui Chen, Sarah K. Tasian, Kai Tan. Novel synergistic targets for combination therapy in Philadelphia chromosome-like acute lymphoblastic leukemia [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 3893.