Abstract 2848: Combination of DNA methyltransferase and PARP inhibitors as a novel therapy strategy for poor prognosis acute myeloid leukemia

Abstract

Abstract We present here strong preclinical data for a novel, mechanistically based, combinatorial approach to using DNA methyltransferase inhibitors (DNMTi’s), such as decitabine (DAC) and 5-Azacytidine (AzaC), with PARP inhibitors (PARPi’s) as a treatment strategy for acute myelogenous leukemias (AML). AzaC and DAC alone show efficacy in AML but combinatorial approaches will be required to maximize therapeutic responses. PARPi's have not been well studied as agents for these diseases. The mechanistic rationale for our approach is based upon: 1) data from our group and others showing DNMT's and PARP co-reside in DNA damage induced protein complexes; 2) the fact that AzaC and DAC trap DNMT's into DNA via their mechanism of action, led us to hypothesize that these drugs might also increase PARP trapping at DNA damage sites 3) the cytotoxicity of clinically available PARPi’s, and especially the most potent ones, appears to correlate with degree of trapping of PARP1 at DNA damage sites in chromatin. We first find that, indeed, in cultured human AML cells, the DNMTi's (10 to 20 nM DAC) and PARPi's (1 to 10 nM BMN 673) alone trap PARP into chromatin and this effect is enhanced when the drugs are combined. Concomitant with this, the combined doses, especially, strongly reduce double strand break (DSB) repair thereby increasing cytotoxic DNA damage. In association with these findings, in methylcellulose cloning assays of both cultured (N = 4) and primary AML cells (N = 9), a combination of the DNMTi's and PARPi's strongly decreased colony survival compared to each of the agents alone. Interestingly those cell lines and primary samples expressing poor prognostic FLT3/ITD (Fms-like tyrosine kinase 3 internal tandem duplication) mutations, were particularly sensitive to the combination treatment. Based on all the above results, we developed an in-vivo treatment model, using human FLT3/ITD-positive, MV411-luc xenografts in immunocompromised mice. As opposed to mock treatment, and treatment with AzaC or BMN673, alone, the combined drug treatment, over a 40 day treatment course, starkly and significantly decreases leukemia burden, as measured by luciferase imaging, peripheral blood blast counts and spleen weights. Our data suggest a novel use of both DNMTi's and PARPi's in a compelling therapeutic strategy for poor prognosis AML, that will be funded by Van Andel-SU2C for a clinical trial to be based at the University of Maryland. Citation Format: Nidal E. Muvarak, Carine Robert, Pratik K. Nagaria, Khadiza Chowdhury, Eun Yong Choi, Vu Duong, Ashkan Emadi, Maria R. Baer, Rena Lapidus, Stephen Baylin, Feyruz Rassool. Combination of DNA methyltransferase and PARP inhibitors as a novel therapy strategy for poor prognosis acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2848. doi:10.1158/1538-7445.AM2015-2848