Abstract 4824: Synergistic interaction of PIM kinase inhibitor, JP_11646, and cytotoxic or targeted therapies in acute leukemia models

Abstract

Abstract Standard therapy for acute myeloid leukemia (AML) results in significant mortality and morbidity with an overall cure rate of only 25%. Implementation of novel therapeutic options is needed in order to significantly improve patient survival and outcome. PIM serine/threonine kinases are overexpressed in hematological malignancies and regulate cell cycle, survival and drug resistance pathways—thus providing viable therapeutic targets. We hypothesized that targeted or cytotoxic therapy will enhance anti-tumor activity in combination with JP-11646, a novel PIM2 inhibitor, in preclinical AML models. Preclinical data has shown JP-11646 exerted potent inhibition of AML cells in vitro and in vivo in subcutaneous AML xenograft models. An in vitro MTT assay was used to determine the overall anti-proliferative effects of single and combination therapies with respect to the downstream effects of PIM kinase and mechanism of action of JP-11646 in leukemia. First, the single agent efficacy in human AML (HEL, and MV(4;11)) cell lines were examined after 72 hours of exposure to JP-11646, rapamycin, daunorubicin and cytarabine. Overall potency, IC50, (0.17 μM (0.15-0.19), 0.003 μM (0.002-0.004), 0.067 μM(0.065-0.0699) and 0.31 μM (0.294-0.345), respectively) and maximal inhibition, Imax, of the various therapies was determined. Potential synergistic effects were first tested by treating AML cell lines with JP-11646 and daunorubicin, cytarabine, or rapamycin (an inhibitor of a pathway that regulates downstream molecules of the PIM kinase pathway). To quantify the synergy or interaction of JP-11646 in combination, a simple inhibitory non-competitive interaction model with an interaction parameter (Ø) as well as a three dimensional interaction surface was employed (Ø<1 synergism, Ø>1 antagonism). The intensity of the interaction (Ø) of JP-11646 with rapamycin (0.819 (0.395-0.543)), daunorubicin (0.469 (0.665-0.975)) or cytarabine (0.173 (0.118-0.229)) demonstrated synergistic effects across all combinations. Here, we demonstrate that novel drug targets and drugs for AML treatment alone, and in combination with pre-existing therapies, may lead to improved strategies for AML treatment and these findings support future development of JP-11646 in novel combinatorial regimens for AML therapy. Citation Format: Krista Pundt, Camern Baldino, Justin Caserta, Alex Adjei, Kelvin Lee, Xu Zhu, Alissa Verone-Boyle, Frank Engler, Laura Pitzonka, Gerald Fetterly. Synergistic interaction of PIM kinase inhibitor, JP_11646, and cytotoxic or targeted therapies in acute leukemia models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4824.