Author ORCID Identifier
0000-0002-4454-1496
Date of Graduation
8-2023
Document Type
Dissertation (PhD)
Program Affiliation
Medical Physics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Raghu Kalluri, M.D., Ph.D
Committee Member
Florian Muller, Ph.D.
Committee Member
Ronald DePinho, M.D.
Committee Member
Pratip Bhattacharya, Ph.D
Committee Member
John de Groot, M.D.
Committee Member
Jason Huse, M.D., Ph.D
Committee Member
Yonathan Lissanu, M.D., Ph.D
Abstract
Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is a frequent genetic alteration found in approximately 15% of all human cancers, including glioblastoma, pancreatic cancer, mesothelioma, urothelial bladder carcinoma, and lung squamous cell carcinoma. MTAP is a critical metabolic enzyme in the methionine salvage pathway responsible for the breakdown of methylthioadenosine (MTA). As a result, MTAP-deleted cells cannot metabolize MTA, leading to the accumulation of MTA. High levels of MTA in MTAP-deleted cells partially inhibit the activity of protein arginine methyltransferase 5 (PRMT5), making these cells sensitive to PRMT5 and MAT2A inhibition. Although elevated levels of MTA in vitro define a promising actionable metabolic vulnerability, the clinical relevance relies on exhibiting significant MTA accumulation in human tumors. Here, we demonstrate that, unlike cells in culture, MTA levels in MTAP-deleted primary human GBM tumors are not significantly higher compared to MTAP-intact tumors. This discrepancy is due to the secretion of MTA into the extracellular environment and its subsequent metabolism by stromal cells expressing MTAP. We also have demonstrated that the presence of MTAP-intact cells near MTAP-deleted cancer cells attenuates their sensitivity to PRMT5-MTA complex inhibitors. Moreover, we have demonstrated that putrescine, a metabolite in the polyamine biosynthesis pathway, can stimulate MTA production, and enhance the efficacy of PRMT5 inhibitor treatment in MTAP-deleted cells across multiple tumor cell lines, even in the presence of MTAP-intact cells. In summary, our findings highlight the metabolic discrepancies between in vitro models and primary human tumors, the influence of stromal infiltration on the synthetic lethal relationship between MTAP-deletion and PRMT5 inhibition, and the potential of co-treatment with putrescine and PRMT5 inhibitors to enhance this therapeutic approach.
Keywords
PRMT5, MAT2A, Synthetic lethality, MTAP-deficiency, Human GBM tumors