# Exploitation of Intrinsic DNA Repair Defects with DNA Damaging Agents in Cancer > **NIH NIH F30** · YALE UNIVERSITY · 2020 · $50,520 ## Abstract Project Summary: Exploitation of Intrinsic DNA Repair Defects with DNA Damaging Agents in Cancer The lifetime risk of cancer in the U.S. is 1 in 3 and the financial burden of cancer exceeds 100 billion dollars annually. These figures are predicted to continue increasing as populations continue to age. Alkylating agents were the first chemotherapies used to treat cancer with the application of nitrogen mustard gas to treat lymphoma in the 1940s at Yale. Over the last 80 years, many different classes of alkylating agents have been developed and they remain an integral component of cancer treatment today. Despite their long history and prevalent clinical usage, knowledge of how alkylating agents damage DNA is still poorly understood due to the reactive nature of these species. Additionally, cancers often develop exploitable therapeutic vulnerabilities in DNA repair pathways that enable them to accumulate more mutations and become more aggressive. This incomplete understanding of alkylators results in the empirical selection of alkylating agents in cancer treatment regimens rather than selection based on mechanism and underlying cancer biology. MGMT and ALKBH2/3 are two key direct DNA alkyl damage reversal enzymes responsible for repairing a variety of alkyl adducts. These enzymes are also commonly deficient in isocitrate dehydrogenase1/2 (IDH1/2) mutant cancers such as gliomas, colorectal cancers, and hematological malignancies. Understanding how alkylators damage DNA in the absence of any repair enzymes and how repair enzymes contribute to alkylator resistance is crucial for the therapeutic advancement of alkylating chemotherapies including a better understanding of alkylating agents, the development of novel alkylators, and personalized alkylator selection based on patient tumor DNA repair status. I will test the hypothesis that targeting cancer cells deficient in either MGMT and/or ALKBH2/3 with the appropriate alkylator will result in enhanced sensitivity because deficiency in the corresponding DNA repair pathway will lead to unrepairable damage. I plan to test this hypothesis through two aims. My first aim is to develop a LCMS-based assay to profile the spectrum of alkylation damage in cell free plasmid DNA and CRISPR/Cas9 generated glioma models. This aim will answer the question of how alkylators damage DNA by identifying both the species and quantities of DNA alkylation adducts that form when cell free plasmid DNA and various glioma model cell lines are treated with a panel of clinically used alkylators. My second aim is to conduct a high-throughput differential screen for alkylator sensitivity based on DNA repair pathway status. This aim will elucidate the relationship between known DNA repair pathways and alkylator sensitivity. Ultimately, this work could contribute to the therapeutic advancement of alkylating chemotherapies including the development of novel alkylators and personalized alkylator selection based on patient tumor DNA rep... ## Key facts - **NIH application ID:** 10066154 - **Project number:** 1F30CA254158-01 - **Recipient organization:** YALE UNIVERSITY - **Principal Investigator:** Kingson Lin - **Activity code:** F30 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $50,520 - **Award type:** 1 - **Project period:** 2020-07-16 → 2023-07-15 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10066154 ## Citation > US National Institutes of Health, RePORTER application 10066154, Exploitation of Intrinsic DNA Repair Defects with DNA Damaging Agents in Cancer (1F30CA254158-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066154. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*