226-LB: Repurposing a Cancer Drug, AZD6738 (ATRi), for the Prevention of Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is a chronic, incurable autoimmune disorder caused by the destruction of pancreatic β cells by diabetogenic T cells, leading to insulin deficiency and hyperglycemia. It affects 3 million Americans and 80 new people are diagnosed daily. Despite treatment with insulin, patients have a significantly reduced life expectancy. This study proposes a new approach to prevent T1D by specifically targeting diabetogenic T cells undergoing the Warburg effect, a metabolic process similar to cancer cells, with a cancer drug approved by the FDA. The use of FDA-approved drugs accelerates the development of new therapies as these agents have already undergone initial efficacy and toxicity tests in humans. One promising drug for this purpose is AZD6738 (ATRi), a cancer drug that is currently in clinical trials. ATRi is a small molecule inhibitor that targets ATR, a central DNA damage response kinase, whose inhibition blocks DNA replication. We demonstrate that ATRi treatment significantly delays T1D onset in an adoptive transfer mouse model by reducing the survival of diabetogenic CD4+ T cells by inhibiting their proliferation. Furthermore, an FDA-approved glycolysis inhibitor PFK158 potentiates inhibition of diabetogenic CD4+ T cells by ATRi. These agents target different properties of the Warburg effect. While ATRi inhibits rapid proliferation, PFK158 blocks glycolysis. Combination therapy allows for increased efficacy while reducing potential toxicity by allowing the use of lower doses of each agent. These data show promise in the rapid establishment of novel T1D prevention methods by repurposing FDA-approved cancer drugs. Disclosure N. Sugitani: None. H. R. Mason: None. S. Roy: None. J. D. Piganelli: None. Funding National Institutes of Health (R01DK132583); JDRF (2-SRA2020-910-S-B)