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Imaging MS : Therapeutic Targets
Speaker: Katy Margulis
Metabolic Profiling of MYC-induced Tumors by DESI-MSI to Identify Possible Druggable Targets

Cancers have altered metabolism, and its investigation may uncover unique therapeutic vulnerabilities. The MYC proto-oncogene is frequently mutated and overexpressed in human cancers, but its role in metabolic changes involved in initiation, maintenance, and progression of tumors remains vague. Experimentally, MYC inactivation regresses tumors however, therapies that target MYC directly have yet to be identified.

In collaboration with the Oncology Department, Stanford School of Medicine, we monitored MYC-induced tumorigenesis in four conditional transgenic mouse models: kidney, liver, lung and leukaemia tumors. In these models MYC overexpression could be activated on demand to induce tumorigenesis, and later could be blocked fully regressing the tumors. These models present excellent systems to study metabolic hallmarks of tumor generation, maintenance and regression. We employed Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI-MSI) to reveal their unique metabolic derangements and to identify and validate possible druggable targets. We also examined MYC-driven cell-lines and human xenograft models.

We have uncovered a mutual signature for all studied MYC-driven cancers and possible druggable targets in their metabolism. Thus, we have determined that MYC closely cooperates with the transcription factor Sterol Regulated Element-Binding Protein (SREBP1) and together they activate fatty acid (FA) synthesis, and drive FA chain elongation. We identified acetyl-CoA carboxylase A (ACACA) as one of the enzymes overactivated by this cooperation, which also presents a potential druggable target. We specifically inhibited this enzyme and monitored the therapeutic efficacy of this inhibition by DESI-MSI. This inhibition diminished MYC induced tumorigenesis, elicited the regression of established tumors, and prevented tumor formation....

Aug 11, 2020 10:00 AM in Pacific Time (US and Canada)

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