Targeting PLK1 in RAS mutant chronic myelomonocytic leukemia

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PROJECT SUMMARY Chronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with dismal outcomes. There is an unmet need for CMML focused rationally derived therapies. CMML can be divided into “proliferative” (pCMML) and “dysplastic” subtypes, with pCMML having a high frequency of RAS pathway mutations and being associated with a median survival of <18 months. We have shown that in pCMML, mutant NRAS is a bona fide oncogenic driver and that RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic check point kinases such as PLK1. PLK1 was among the top protein coding genes upregulated in RAS mutant CMML and given that prior RNAi studies had shown increased sensitivity of RAS mutant cells to PLK1 inhibition and the fact that PLK1 physically interacts with RAF1 at the mitotic spindles, as well as the ongoing use of clinical grade PLK1 inhibitors in AML trials, we selected PLK1 as a therapeutic target in RAS mutant pCMML. We showed differential sensitivity of RAS mutant pCMML cells to PLK1 inhibition using in vitro (progenitor colony assays) and in vivo models (patient- derived xenografts) and demonstrated potential synergy with hypomethylating agents (HMA). We now propose a seminal Phase 1 clinical trial testing the safety and preliminary efficacy of Onvansertib, a novel, oral, PLK1 inhibitor in patients with relapsed/refractory pCMML, using an innovative BOIN (Bayesian Optimal Interval) design. Samples from trial patients will be used to assess pharmacokinetics, targeting efficacy and response correlations with PLK1 and KMT2A (regulator of RAS PLK1 axis) expression levels. We will also use our large CMML biorepository (n=177 RAS mutant samples) to develop in vitro and in vivo models to assess mutational, transcriptomic and epigenetic predictors of response and resistance; specifically the impact of individual RAS pathway mutations and cooccurring TET2 and ASXL1 mutations, the two most common response defining mutations in CMML, on Onvansertib responses. Based on our preliminary data, it is our central hypothesis that PLK1 inhibition is an effective treatment strategy in RAS mutant pCMML, with responses being influenced by defined mutational profiles and epigenetic features. We will address this hypothesis by first performing a Phase 1 clinical trial testing the safety and targeting efficacy of Onvansertib, an oral selective PLK1 inhibitor, in pCMML (AIM 1). Second, we will determine the in vitro impact of individual RAS pathway mutations and associated CMML transcriptomic and epigenetic profiles on Onvansertib responses (AIM 2). Finally, we will assess the impact of ASXL1/TET2 mutations on response to Onvansertib and Onvansertib plus HMA in RAS- pathway mutant CMML xenografts (AIM 3). If successful, this research will provide the first targeted therapy for RAS mutant myeloid neoplasms, setting the stage for personalized therapeutics in hematological malignancies.