Effective new cancer therapies have been developed based on agents with novel mechanisms of action, and those that target the pathophysiology of malignances. Clinically active in phase I studies in relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes, Sapacitabine, the orally bioavailable form of 2'-C- cyano-2'-deoxy-1-2-D-arabino-pentofuranosylcytosine (CNDAC), acts by the unique mechanism of action of causing a single strand break in DNA. In the process, the incorporated analog is converted to a chain- terminating dideoxynucleotide, CNddC, a nucleotide that cannot be extended. Importantly, our initial results demonstrated that these nicks in DNA are relatively stable, and that they are converted to one-ended double- strand breaks when cells attempt to replicate their DNA across the nick. Further, our studies suggest that cells are mainly dependent upon homologous recombination (HR) to repair double-strand breaks that arise at collapsed replication forks. Thus, strategies that increase CNDAC incorporation into DNA, or approaches that diminish expression of HR pathway proteins would likely be synergistic with CNDAC. A corollary is that diseases with inherent deficiencies in homologous recombination repair would be selectively sensitive to the actions of CNDAC and its congeners. The overall goal of our proposal is to develop a thorough understanding of the mechanism by which CNDAC causes cell death, and to investigate strategies that will extend its toxicity to quiescent cells, overcome resistance due to highly expressed homologous recombination proteins, and provide rationale for the design combination strategies for translation to the design of clinical trials. We hypothesize that answers to questions posed in the following specific aims will clarify the mechanism of CNDAC action and indicate strategies to direct its application in the clinic. 1. What DNA damage repair mechanisms recognize and process CNDAC-induced DNA damage? By what mechanism is the CNddC lesion excised from DNA? Can mechanistic interactions be identified to provide a rationale for the design of combinations with CNDAC? By what mechanisms do histone deacetylase inhibitors (HDACi) sensitize cells to the action of CNDAC?

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This application proposes to develop a thorough understanding of the mechanism by which the small molecule CNDAC and related compounds cause cell death, and to investigate how tumors respond to avoid being killed. This information will be used to develop rationales for combinations with agents targeted at inhibiting such potential resistance mechanisms for translation to the design of clinical trials. Rationales for mechanism-based combinations with active anti-cancer drugs, and with the epigenetic regulatory pathways for DNA repair protein expression will be developed with a view to broadening the potential clinical application and impact of CNDAC (Sapacitabine).

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Arya, Suresh
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University of Texas MD Anderson Cancer Center
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Liu, Xiaojun; Jiang, Yingjun; Nowak, Billie et al. (2018) Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations. Cancer Chemother Pharmacol 81:255-267
Al Abo, Muthana; Sasanuma, Hiroyuki; Liu, Xiaojun et al. (2017) TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors. Mol Cancer Ther 16:2543-2551
Liu, Xiaojun; Jiang, Yingjun; Nowak, Billie et al. (2016) Mechanism-Based Drug Combinations with the DNA Strand-Breaking Nucleoside Analog CNDAC. Mol Cancer Ther 15:2302-2313
Lai, Tsung-Huei; Ewald, Brett; Zecevic, Alma et al. (2016) HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia. Clin Cancer Res 22:3537-49
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