Identification of Metabolic Targets and Vulnerabilities in Genetically-Defined Cohorts of Lung Cancer

MacMillan Family Foundation Endeavor Award (2022-Present)

The Salk Institute for Biological Studies: Reuben Shaw, PhD; Susan Kaech, PhD; Christian Metallo, PhD; and Alan Saghatelian, PhD

Reuben Shaw, PhD

Susan Kaech, PhD

Christian Metallo, PhD

Alan Saghatelian, PhD

Cancer cells adopt unique metabolic changes to sustain their biosynthetic growth demands, including the rewiring of fatty acid metabolism and glucose metabolism. Over the past few decades, it has become increasingly clear that the scope of metabolic changes in tumor cells is much more extensive than previously appreciated, and that metabolic adaptations are often critical for the pathologic behavior and immune evasion of tumors. Some changes in metabolism, like the Warburg effect, are relatively ubiquitous in cancer, but other changes only occur in tumors within specific cellular and genetic backgrounds. By dissecting the genomic context in which specific metabolic changes occur, and understanding how these changes affect various cell types in the tumor and surrounding microenvironment, new targets can be identified to advance precision medicine in cancer.

This Endeavor team, based at the Salk Institute, will examine metabolic changes in the context of specific genomic and epigenomic alterations in tumor cells. The team will focus on non-small cell lung cancer (NSCLC), one of the most common forms of cancer, and the leading cause of cancer death worldwide. Importantly, the genetic drivers behind many subtypes of NSCLC are relatively well understood, and mouse models for many of these subtypes exist and are well validated in mimicking the human disease. The team will identify metabolic changes unique to specific genetically defined subsets of NSCLC using metabolomics and lipidomic analysis. They will analyze a large panel of human lung cancer samples, coupled with systems-level metabolic flux analysis in a representative panel of NSCLC cell lines. Potentially targetable pathways identified in the experiments with human samples will inform further work in mouse models of NSCLC to demonstrate functionally conserved metabolic changes in vivo. Finally, the team will use the mouse models of NSCLC to perform preclinical testing of new metabolic therapies.

This interdisciplinary Endeavor project employs the latest advances in lipidomics and metabolic tracing in vivo and in vitro to identify novel therapeutic targets for specific defined genetic subsets of NSCLC. The team’s collective expertise in bioengineering and systems biology, the immune system, and the use of mouse models to target metabolic vulnerabilities makes them uniquely qualified to attack this ambitious goal.

This Endeavor Award is supported by a generous donation from the MacMillan Family Foundation.