A Novel Class Of Chemicals That React With Damaged Dna And Specifically Kill B-Cell Cancers

Majority of B-cell malignancies arise in germinal center, where the processes of somatic hypermuation (SHM) and class switch recombination (CSR) for antibody maturation are initiated by activation-induced demainase (AID). AID belongs to the AID/APOBEC family and deaminates cytosine in DNA creating uracil. We have previously shown that B-cell lymphoma cell lines and patient tumors express AID at high levels and contain high levels of uracils in their genome. These cells also contain uracil-DNA glycosylase that removes uracils generating high levels of abasic (AP) sites. AP sites exist in equilibrium with the open form of deoxyribose sugar that reacts with alkoxyamines forming a stable oxime. This principle was used to block the repair of excess AP sites in B cell cancers using an alkoxyamine, AA3. We found that AA3 effectively kills B-cell lymphoma cell lines which have high levels of endogenous AP sites. In contrast, AA3 is not toxic to normal human B cells and mouse splenocytes, as well as non-hematological cancers. To elucidate the molecular mechanism of selective cell killing by AA3, we compared the number of AP sites in B cell cancers and non-hematological cancers and confirmed that B cell cancer cells contained many more AP sites in their genome. Additionally, we found that AA3 was covalently linked to B cell cancer genome and AA3-DNA adducts caused cell death by blocking DNA replication and elevating DNA strand breaks. To determine which functionality of AA3 is responsible for its cytotoxicity and to discover better candidates for killing B cell cancers, we designed and synthesized a series of AA3 analogues. Using this approach, we have defined the functional groups required for AA3 toxicity. Overall, we have discovered that AA3 is selectively toxic to B cell cancers. This new family of chemicals could be developed further as novel and unique anti-cancer drugs. Citation Format: Shanqiao Wei, Madusha Watuthanthrige, Sophia Shalhout, Ashok S. Bhagwat. A novel class of chemicals that react with damaged DNA and specifically kill B-cell cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3757.