Sir Peter MacCallum Department of Oncology - Theses
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ItemNovel combination therapies targeting Pol I and Pol II transcription to treat AML( 2017)Our laboratory has demonstrated that a small molecule (CX-5461, Senhwa Biosciences; currently in phase I clinical trial for haematological malignancies) that inhibits ribosomal RNA gene (rDNA) transcription by RNA Polymerase I (Pol I), is highly efficacious in various cancer types in preclinical studies. Although CX-5461 has entered the clinic and its therapeutic effects in preclinical study are promising, it is still unclear: 1) what mechanisms confer sensitivity or resistance to Pol I therapy, 2) which patients will benefit the most from CX-5461 and 3) what combination therapies will improve the response rates and survival. The goal of my thesis is to begin to address these questions, by focusing on an aggressive acute myeloid leukaemia (AML), a refractory disease associated with low survival rates and high risk of relapse. We have demonstrated that in AML, CX-5461 acts in part to elicit a nucleolar specific DNA damage response (DDR) via ATM and ATR signaling, resulting in the arrest of leukemia cells in S and G2/M phases (Hein et al, 2017). Importantly, pharmacologic inhibitors targeting DDR were shown to sensitise cancer cells to CX-5461 treatment (Quin et al, 2017). It has been demonstrated that mechanistic interactions underlying the DDR rely on context-specific chromatin structure, including chromatin’s structural rearrangement by histone chaperones and the bromodomain and extra-terminal (BET) proteins. Due to the specialised transcriptional context of rDNA, we hypothesise that targeting epigenetic and transcriptional regulators (eg., bromodomain inhibitors) in combination with CX-5461 may render cancer cells highly sensitive to ATM/ATR activation and result in enhanced anti-tumour activity. Here we used IBET-151 (GSK) to block BET protein binding to acetylated chromatin marks in combination with CX-5461 in a disease model of AML. We observed strong synergy between CX-5461 and IBET-151 across a human AML cell line panel. Importantly, co-treatment with CX-5461 and IBET-151 significantly improved survival over single agents in a preclinical model of aggressive MLL-AF9; NrasG12D as well as AML1-ETO9a; NrasG12D -driven AML. Treatment of AML cell lines with IBET-151 or the knockdown of its target, BRD4, resulted in increased rDNA accessibility to micrococcal nuclease (MNase). We propose that inhibition of BRD4 by IBET-151 increases the ‘open’ state frequency of rDNA chromatin, leading to an enhanced CX-5461-mediated DDR. This model is supported by synergistic checkpoint activation, including a heightened γH2AX response following combined CX-5461 and IBET-151 treatment. Together, our studies highlight the potential therapeutic value of targeting multiple rDNA transcriptional mechanisms for treating patients with AML.