Abstract
Despite significant advances in the treatment of acute myeloid leukemia (AML) the long-term prognosis remains relatively poor and there is an urgent need for improved therapies with increased potency and tumor selectivity. Mylotarg is the first AML-targeting drug from a new generation of antibody drug conjugate (ADC) therapies aiming at the acute leukemia cell compartment with increased specificity. This agent targets leukemia cells for apoptosis with a cytotoxic payload, calicheamicin, carried by a CD33-specific antibody. Calicheamicin induces DNA double strand breaks (DSB) which, if left unrepaired, lead to cell cycle arrest and apoptosis in cancer cells. However, repair of DSB by the non-homologous end joining pathway driven by DNA-dependent protein kinase (DNA-PK) can reduce the efficacy of calicheamicin. M3814 is a novel, potent and selective inhibitor of DNA-PK. This compound effectively blocks DSB repair, strongly potentiates the antitumor activity of ionizing radiation and DSB-inducing chemotherapeutics and is currently under clinical investigation. Suppressing DSB repair with M3814 synergistically enhanced the apoptotic activity of calicheamicin in cultured AML cells. Combination of M3814 with Mylotarg in two AML xenograft models, MV4-11 and HL-60, demonstrated increased efficacy and significantly improved survival benefit without elevated body weight loss. Our results support a new application for pharmacological DNA-PK inhibitors as enhancers of Mylotarg and a potential new combination treatment option for AML patients.
Highlights
It is estimated that over 20,000 people in the U.S will be diagnosed with acute myeloid leukemia (AML) in 2019 [1]
We have previously shown that the DNA-PK inhibitor M3814 can effectively enhance the antitumor effect of ionizing radiation (IR) by inhibiting non-homologous end joining (NHEJ) repair of IR-induced double strand breaks (DSB) in solid tumor cells [15, 16]
In cancer cells expressing wild-type p53, this effect is largely due to overactivation of the ataxia telangiectasia mutated (ATM)/p53 signaling axis boosting p53 to levels much higher than the levels induced by radiation alone
Summary
It is estimated that over 20,000 people in the U.S will be diagnosed with AML in 2019 [1]. Despite established standards of induction and consolidation therapies, the overall 5 years survival rate is ∼30%, and U.S statistics show few changes in per capita AML deaths in the last two decades [1]. Strong chemotherapeutic regimens remain the standard approaches to AML treatment, and patient mortality is often linked to treatment-related toxicities or ablated normal hematopoiesis [2]. Death rates from AML are higher in patients over 65 years of age [1]. There is a clear need for novel, M3814 and Mylotarg for AML Therapy targeted therapeutic strategies for AML. Such therapies would ideally display high potency toward the leukemic burden and improved tolerability in normal tissues
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