American Association for Cancer Research

AACR Anna D. Barker Fellowship in Basic Cancer Research

AACR Anna D. Barker Fellowships in Basic Cancer Research foster basic research by scientists at the beginning of their careers in the cancer field. They are open to postdoctoral and clinical research fellows at an academic facility, teaching hospital or research institution who will be in the first, second or third year of their postdoctoral training at the start of the fellowship term. Fellowships support the salary and benefits of the fellow, with partial funds permitted to be designated to direct research expenses. 

2013 GRANTEE

Hugh S. Gannon, Ph.D.Hugh S. Gannon, Ph.D.
Postdoctoral Fellow, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Exploring Synthetic Lethality between Mutant p53 and Glutathione Depletion
 

TP53 is the most frequent somatically mutated gene in human cancer. This gene encodes the p53 tumor suppressor, a key transcription factor that responds to a variety of cellular stressors by activating downstream signaling pathways including apoptosis, cell cycle arrest, senescence, and redox homeostasis. These p53 functions limit the propagation of cells with acquired mutations and damaged DNA, thereby preventing cellular transformation and tumorigenesis. Therefore, a common feature of tumor cells is the bypass of p53 function, most often by direct TP53 mutations. While targeted therapies have been developed to specifically inhibit constitutively activated oncogenes, a major obstacle in cancer treatment is the loss of tumor suppressor functions as it is far more difficult to replace cellular functions that are absent. This is true of the tumor suppressor p53. Despite the prevalence of TP53 mutations across almost all cancer types, few effective therapies targeting mutant p53 in cancer patients have been developed.

Members of the Broad Institute and Dana-Farber Cancer Institute have generated large-scale datasets in hundreds of cancer cell lines and tumor samples. These datasets include gene expression profiles, genetic dependencies, and metabolite levels in cancer cell lines, and gene expression derived from RNA sequencing in human cancers analyzed by The Cancer Genome Atlas (TCGA). Gene expression results demonstrate that the gene glutathione synthetase, a key enzyme in the glutathione synthesis pathway, is expressed at a higher level in mutant TP53 cancer cell lines and tumors compared to those without TP53 mutations. In addition, reduced and oxidized glutathione levels were shown to be upregulated in TP53 mutant cells following metabolomic analyses. Importantly, genome-wide shRNA knockdown in 216 cancer cell lines reveal that glutathione synthetase is dependent for mutant TP53 cancer cell survival. Therefore, results from these existing datasets suggest that the glutathione-dependent redox homeostasis pathway is upregulated and necessary for survival in mutant TP53 cells.

"The Anna D. Barker Fellowship in Basic Cancer Research from the American Association for Cancer Research will be critical in the development and advancement of my research and I am very grateful for this award. This will allow me to fully investigate the relationship between the glutathione synthesis pathway and TP53 mutations. To do this we will use biochemical and gene expression measurements to confirm that glutathione synthesis pathway members and glutathione metabolite levels are increased in mutant TP53 cancer cell lines and tumors. We will then determine which glutathione pathway members are truly necessary for mutant TP53 cell survival using shRNAs and known inhibitors of the glutathione synthesis pathway. Finally, we will establish the mechanism of decreased cell survival in TP53 mutant cells by comparing cell cycle arrest, senescence, apoptosis, necrosis, autophagy, and the recently described ferroptosis before and after glutathione synthesis inhibition. As a glutathione pathway inhibitor has been previously developed and tested in clinical trials, understanding the synthetic lethal relationship between mutant TP53 and glutathione synthesis inhibition could immediately impact cancer patients with TP53 mutations." 

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