Abstract B12: Co-inhibition of PI3K and Myc pathways is synthetic lethal to PTEN null T-ALL leukemia-initiating cells
Authors: Schubbert Suzanne , Cardenas Anjelica , Wei Christopher , Ma Lingda , Garcia Consuelo , Guo Wei , Wu Hong 
Published: August 2014

T-cell acute lymphoblastic leukemia (T-ALL) is a common hematological malignancy associated with poor prognosis and significant risk of relapse. Loss of PTEN function due to mutations or deletions is common in primary T-ALL samples and is associated with resistance to therapeutic agents. We previously developed a VEC-Cre+;Ptenloxp/loxp (Pten null) T-ALL model to investigate the molecular and cellular mechanisms underlying T-ALL pathogenesis and resistance to therapy. Pten-null T-ALL develops after acquisition of a T cell receptor α/δ-c-myc translocation that causes c-Myc over-expression, and the leukemia-initiating cells, or leukemia stem cells (LSCs), are enriched in a c-kitmidCD3+ subpopulation. The goal of our current study is to develop improved therapeutic approaches to target LSCs and eliminate T-ALL. We hypothesize that small molecule inhibitors that target molecular lesions and pathways required for the development and survival of Pten null LSCs and T-ALL may be potent in eliminating LSCs and abolishing T-ALL. Rapamycin, an inhibitor of the PI3K downstream kinase mTOR, can suppress leukemia development in Pten null pre-leukemic mice, but is insufficient to eliminate LSCs and T-ALL. Therefore, we are investigating the therapeutic utility of combinational therapies that co-target multiple deregulated pathways that are critical for LSC formation and T-ALL survival. We found that combination treatment of Pten null T-ALL mice with rapamycin and VX-680, an Aurora kinase inhibitor shown to have synthetic lethality with Myc over-expression, causes robust elimination of leukemia blasts and significantly diminishes the LSC population. Functional studies for leukemia-initiating-cell activity using transplantation of treated bone marrow into NOD-SCID-IL2rγ-/-(NSG) recipients showed that dual treatment reduced leukemia-initiating-cell activity in bone marrow by at least 100-fold in comparison to single agent alone. Importantly, a large portion of Pten null T-ALL LSCs are actively cycling (~50% in S-phase), which may contribute to the mechanism underlying the efficacy of VX-680. We have developed a T-ALL in vitro culture system derived from primary Pten null T-ALL mice to conduct more detailed evaluation of the cellular and biochemical effects of rapamycin and VX-680, perform mechanistic analysis, and screen additional cell cycle-directed and Myc-targeted agents. We found that Pten null T-ALL is highly sensitive to killing by the CDK1 inhibitor purvalanol and JQ1, a bromodomain inhibitor reported to down-regulate c-myc expression that is suitable for use in vivo. Rapamycin and JQ1 combination treatment of Pten null T-ALL mice causes a significant reduction in both the leukemia blast and LSC populations, similar to the effects of rapamycin and VX-680 combination therapy. Our results highlight the importance of understanding the mechanisms underlying T-ALL development and survival and show potent synthetic lethality of PI3K and Myc pathway co-inhibition in PTEN null T-ALL LSCs. Importantly, such targeted combination therapy may offer an improved therapeutic approach to treat human T-ALL.

Citation Format: Suzanne Schubbert, Anjelica Cardenas, Christopher Wei, Lingda Ma, Consuelo Garcia, Wei Guo, Hong Wu. Co-inhibition of PI3K and Myc pathways is synthetic lethal to PTEN null T-ALL leukemia-initiating cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B12.