Abstract 347: Targeting the AICDA/RAD51 axis: A novel gain-of-function synthetic lethal therapy for the treatment of AICDA-expressing cancers

Abstract

Abstract A key characteristic of many cancers is genomic instability, and is often associated with poor prognosis. While genomic instability can promote tumorigenesis, it also provides a therapeutic opportunity for synthetic lethality. The induction of DNA damage creates stress that necessitates highly active DNA repair as a critical survival system for many transformed cells. Recently, therapeutics that target PARP1 have been approved by the FDA as synthetic lethal therapeutics for cancers with deficiencies in BRCA1/2 and associated pathways. Here we present the early development of a new synthetic lethal therapy that leverages gain-of-function abnormalities to selectively target cancer cells. Activation Induced Cytidine Deaminase (AICDA or AID) is a DNA-directed cytidine deaminase that is normally expressed exclusively and transiently in activated B-lymphocytes, where it plays critical roles in somatic hypermutation and immunoglobulin class switching. AICDA is a DNA damaging enzyme, producing DNA base pair mismatches which can subsequently be converted into mutations, DNA single strand breaks (SSB), or DNA double strand breaks (DSB). Numerous cancers show constitutive overexpression of AICDA, leading to hypermutation, genomic instability, and tumor evolution. We have previously demonstrated that cells expressing AICDA are critically dependent upon the DNA repair factor RAD51. Here we present data illustrating the effectiveness of a novel small molecule, CYT02A, in targeting the AICDA/RAD51 axis. Cell culture assays showed CYT02A to be a potent DNA repair inhibitor that targets RAD51 subcellular localization and filament formation. Although CYT02A was stable when incubated with liver microsomes. Although CYT-02A showed limited oral bioavailability, it was stable in liver microsome assyas assays and the pharmacokinetic profile following intravenous injection revealed dose proportionality and acceptable in vivo exposures. CYT02A was efficacious in a human-to-mouse xenograft model of chronic lymphocytic leukemia (CLL). CYT02A was administered intravenously at a concentration of 50 mg/kg to AID+ CLL xenograft mice daily for up to 9 days. Treated mice showed a significant reduction in CLL burden in the bone marrow compared to vehicle control animals. CYT02A was well tolerated by the animals, with no observable change in behavior or complete blood counts (CBC). Taken together, these data validate a novel gain of function synthetic lethal approach targeting the RAD51/AICDA axis. Preclinical efficacy data support this strategy for the treatment of AICDA-expressing cancers. We continue to build upon this foundation to produce a new therapeutic paradigm that may be effective in a wide range of both hematologic malignancies and solid tumors. Citation Format: Muneer Hasham, Kin-hoe Chow, Tyler Maclay, Amber Cyr, Darryl Patrick, Melinda Day, Kevin D. Mills. Targeting the AICDA/RAD51 axis: A novel gain-of-function synthetic lethal therapy for the treatment of AICDA-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 347.