Pulling the Strings: Exploiting Metabolic Dependencies in Pediatric Cancer

Abstract

Cancer is highly complex and variable, encompassing hundreds of diseases that share key features called "hallmarks,” which help explain how cancer develops, grows, and spreads. This thesis highlights one of these hallmarks, reprogrammed cancer metabolism, and explores the importance of understanding cancer metabolism and how to exploit metabolic vulnerabilities to develop targeted therapies in pediatric cancers. Pediatric cancers challenge the idea of cancer as a disease of aging. Unlike adult cancers, childhood cancers typically involve fewer mutations and are driven by specific genetic changes in driver genes. These mutations can directly alter cellular metabolism, or reprogrammed cancer metabolism itself can drive cancer through mutations in metabolic enzymes or the accumulation of harmful oncometabolites. Part of this thesis explores the relationship between cancer metabolism and epigenetics. We explored the use of novel drug, ARV-825, which targets BRD4 protein, and identified several new combination therapy strategies that effectively target T-cell acute lymphoblastic leukemia (T-ALL). We found that ARV-825 indirectly reduces MYC activity, a gene with broad functions in metabolic regulation, and that combining ARV-825 with other drugs targeting metabolism-related genes induces cell death by converging on the MYC pathway. Another focus of this thesis was on methionine metabolism. Cancer cells possess altered nutrient processing to fuel their uninhibited growth. One of the most well-known examples of this, known as the "Warburg effect," describes tumor cells’ preference for glycolysis, a less efficient but faster way to metabolize glucose. Cancer cells can also manipulate their use of certain nutrients, like amino acids, becoming more or less dependent on them as needed. In turn, these metabolic changes or dependencies create vulnerabilities that can be targeted for treatment. Methionine, an essential amino acid vital for various bodily functions, plays a crucial role in several cancers. We found in neuroblastoma, that dietary methionine restriction slowed cancer growth, and that targeting autophagy further amplified this MR-effect. Similarly, we also found that KMT2A-rearranged leukemia, an aggressive pediatric cancer, was highly sensitive to methionine restriction. These leukemia cells depend on excessive methylation, which requires methionine-derived S-adenosylmethionine, or SAM. By limiting methionine, methylation is disrupted, thereby inducing cell death and inhibiting cancer growth. We highlighted in our research several effective methods for targeting the methionine cycle, including a methionine-restricted diet, the enzyme methionine-γ-lyase (MGL), which breaks down circulating methionine, and the small molecule inhibitor FIDAS-5, which reduces SAM production. These approaches present promising new options for treating methionine-dependent cancers, and demonstrate how understanding reprogrammed metabolism can be leveraged for therapeutic advantage.