Friday, April 4, 2025
4/4/2025
ULK Inhibition Rewires Tumor and Immune Cell Metabolism - PROJECT SUMMARY (ABSTRACT) Lung cancer is the most diagnosed cancer worldwide, and in this country, lung cancer accounts for over 20% of all cancer-related deaths annually. Approximately 25% of lung adenocarcinomas have KRAS mutations, and KRAS patients have the worst prognoses. Research has shown that autophagy, an intracellular recycling mechanism, plays a critical role in KRAS-driven cancers by supporting tumor cell metabolism during nutrient stress, thereby enabling tumor growth. Moreover, autophagy contributes to tumor immune evasion and limits response to immune checkpoint blockade (ICB). As such, autophagy inhibition represents an effective cancer treatment strategy, but unfortunately, known autophagy inhibitors lack potency, selectivity, or drug-like properties. To address this problem, our lab developed a potent and selective small molecule inhibitor, ULK-101, that targets ULK1, a protein kinase that controls the activation of autophagy. Cancer metabolism is characterized by not only the metabolic demands, nutritional status, and metabolic enzymes in tumor cells but also the immunometabolism of the tumor microenvironment (TME) and tumor- infiltrating lymphocytes (TILs). As such, we have taken a two-pronged approach investigating how metabolic perturbations impact not only tumor cell metabolism but also immune cell metabolism. Our recent work has investigated how nutrient availability impacts CD8+ T cell metabolism and function. Using 13C-based metabolite infusion and stable isotope labeling (SIL) metabolomics methods, we have established glucose, lactate, and ketone bodies as physiological fuels for CD8+ T cells. An exciting aspect of our research and an emerging aspect of cancer metabolism is the role of one-carbon methionine metabolism and DNA methylation on cells in the TME. Thus, we aim to elucidate the interconnected impact of ULK1 inhibition on tumor and immune cell metabolism. Our central hypothesis is that ULK1 inhibition rewires lung tumor and T cell metabolism, creating a distinct epigenetic landscape that is sensitive to metabolic intervention and can be exploited for a novel cancer treatment. Aim #1: Establish the role of ULK1 in lung tumor metabolism in vivo. Autophagy inhibition induces selective tumor cell killing by both tumor cell-intrinsic and extrinsic mechanisms. In this aim, we will investigate the metabolic tumor cell-intrinsic mechanisms of ULK1 inhibition in KRAS-driven lung cancer. Aim #2: Dissect the impact of ULK1 inhibition on T cell metabolism. T cells deficient in autophagy have increased levels of glucose uptake and lactate production. In this aim, we will use 13C-infusion methods to determine the metabolic impact of ULK1 inhibition on CD8+ T cell function and the epigenetic landscape. Aim #3: Investigate the mechanism of ULK1 in T cell exhaustion and rejuvenation. Exhausted T cells exhibit a distinct epigenetic profile and metabolic state, which may lead to poor response to immunotherapy. In this aim, we will examine T cell dependency on tumor burden and interrogate T cell exhaustion and rejuvenation.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).