2022 Grantee: G. Aaron Hobbs, PhD
Medical University of South Carolina Hollings Cancer Center
Research Project: KRAS G12R Metabolic Reprogramming Alters Therapeutic Sensitivity
Award: 2022 Pancreatic Cancer Action Network Career Development Award in memory of Skip Viragh
Award Period: July 1, 2022 – June 30, 2024
Dr. G. Aaron Hobbs, PhD, is currently an assistant professor at the Medical University of South Carolina (MUSC), a position he began in August of 2020. While born in Indiana, Aaron was raised in Des Moines, Iowa and attended the University of Iowa, where he received a BS with honors in Biochemistry. He completed his PhD studies in Biochemistry and Biophysics under the mentorship of Dr. Sharon Campbell at UNC Chapel Hill, where he studied the role of oxidation and post-translational modifications on RAS family GTPases. Aaron then completed a post-doctoral fellowship with Dr. Channing Der, also of UNC Chapel Hill, where he determined that specific KRAS mutations found in pancreatic cancer drive differential tumor development and inhibitor sensitivity. Dr. Der is also a PanCAN research grant recipient and member of the organization’s Scientific & Medical Advisory Board.
At MUSC, Dr. Hobbs is continuing his research on developing KRAS-mutation specific therapies for pancreatic cancer, building on the promise of precision medicine. When not in the lab, Aaron spends his free time with his wife and two children, coaching youth sports, and enjoying the city of Charleston.
Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, is characterized by activating mutations in the KRAS oncogene, a well-validated driver of pancreatic cancer. The majority of KRAS mutations comprise missense mutations at codon 12; G12D mutations are the most frequent, followed by G12V and G12R, while G12C mutations are rare. Missense mutations refer to changes in the genetic code that lead to different amino acids, the building blocks of proteins, to be inserted.
While recent progress targeting KRAS G12C has been achieved in lung cancer, these inhibitors will be ineffective for 98% of pancreatic cancer patients. Nevertheless, the development of G12C-selective inhibitors has established a new paradigm for anti-KRAS drug discovery, the development of KRAS mutation-selective therapies. Dr. Hobbs and his team are interested in another mutation, known as KRAS G12R, which accounts for approximately 20% of all KRAS mutations in pancreatic cancer. KRAS G12R is found essentially only in pancreatic cancer. They found that the KRAS protein with the G12R mutation is unable to bind to a protein called PIK3CA, which is essential for KRAS-driven tumor formation. Another recent study showed that KRAS G12R failed to promote precancerous pancreatic intraepithelial neoplasm (PanIN) lesions in mouse models. Finally, unique to the KRAS G12R subtype, restriction of nutrients had no effect on the cancer cells’ growth yet dramatically reduced sensitivity to targeted therapies known as MEK1/2 MAPK inhibitors in cells grown in the lab. These results clearly demonstrate that the KRAS G12R mutation is unique among KRAS-mutant pancreatic cancer.
Dr. Hobbs hypothesizes that KRAS G12R-mutant pancreatic cancer will exhibit additional therapeutic vulnerabilities. To identify a therapeutic approach specific for this subset of KRAS-mutant pancreatic cancer, they are utilizing a multi-faceted approach. First, they previously applied a 525-oncology drug screen and identified KRAS G12R-distinct therapeutic sensitivities. To extend these analyses, Dr. Hobbs and his team propose analyzing the up- or down-regulation of 2,500 genes to identify additional therapeutic vulnerabilities that distinguish KRAS G12R vs. G12D pancreatic cancer. They will perform this search under nutrient restriction conditions that better mimic the nutrient availability in pancreatic tumors, to determine how nutrient restriction alters therapeutic sensitivity.
While KRAS G12R cannot interact with the PIK3CA lipid kinase, these tumors overcome this limitation by upregulating a related isoform, PIK3CG. The expression of PIK3CG was thought to be limited to immune cells. They will next determine the role of PIK3CG in supporting KRAS G12R-mediated tumor formation in mice with pancreatic tumors implanted into their pancreas. Finally, the Hobbs lab has established an independently generated KRAS G12R mouse model of pancreatic cancer, which will be used to validate the therapeutic targeted identified in their previous experiments. The goals of this project are to identify the function of PIK3CG overexpression in human pancreatic cancer while developing new models and therapies specific for studying KRAS G12R pancreatic cancer.