Antagonizing Glutamine Bioavailability Promotes Radiation Sensitization in Prostate Cancer
Abstract
Background and Research Goals: Prostate cancer is the most commonly diagnosed cancer in men in the western world. The standard treatments for localized prostate cancer are surgery and radiation, usually in combination with androgen targeted therapy. Our research group has demonstrated that androgen targeted therapy can cause stromal near epithelial cells to secrete nutrients in the form of the amino acid glutamine, which allows cancer cells to not only survive, but eventually develop into drug resistant prostate cancer. This advanced form of disease requires treatment with toxic chemotherapy drugs and usually leads to death of the patient within 2 years. Unfortunately, there has not been advent of any new drugs that is able to completely overcome or reverse this type of drug resistance of prostate cancer. So far, glutamine has only been studied in regards to androgen targeted therapy in prostate cancer, and we do not know how it contributes to resistance to radiation therapy. Further, even less is understood about how radiation affects the stromal cells. We hypothesized that depriving prostate cancer cells alone with their stroma will increase their sensitivity to radiation therapy. Preliminary data obtained in our laboratory suggests that taking away glutamine from prostate cells in culture drastically reduces their ability to survive radiation. This may be because glutamine, in addition to being a nutrient, is a key signaling molecule in a cellular process called O-glycosylation, a type of protein modification that is carried out by the enzyme OGT. We believe glutamine through this way is able to alter the function of hundreds of proteins within the cell, some of which may be a key in radiation resistance. Thus, we believe limiting glutamine will impact both metabolic and DNA repair capabilities of cancer cells by altering protein O- glycosylation, leading to radiation sensitization. In this proposal, we first want to identify how glutamine supports the acquisition of radio-resistant features in prostate cancer progression. First, we will test whether removing OGT via gene editing as well as stopping its function with a clinically viable small molecule antagonist in PC epithelia in response to radiation and androgen therapy. In parallel, we will employ the use of sodium phenylbutyrate, an FDA-approved drug, to deplete glutamine supply in the blood. We will use mouse models with orthotopic grafts of prostate cancer cells to validate this hypothesis. Next, we want to determine how glutamine metabolism regulates the stromal cell activation in the support of PC radiation resistance. As mentioned before, stromal cells release glutamine in response to androgen therapy. We believe that O-glycosylation may also be involved in this process, especially in the context of radiation. Once again, we will remove OGT via gene editing and deplete glutamine with sodium phenylbutyrate in stromal cells and graft them orthotopically alongside cancer cells in mice. Next, we will check to see if these tumors are able to leave the initial graft site and travel to other sites in the body as metastasis is often a key factor in patient survival. We expect that the interruption of the glutamine metabolism will greatly diminish PC radio-resistance, tumor progression and eventual metastasis. Impact: Our main objective with this study is to better define the biology of lethal prostate cancer to reduce death and develop treatments that improve outcomes for men with lethal prostate cancer. This proposal aims to target glutamine metabolism and identify if this is viable strategy to improve disease free survival in both local and advanced patients. There are two novel aspects of this study; first, we will determine how radiation influences stromal cells in the tumor to supporting epithelial cells in surviving radiation therapy, and second, we will repurpose sodium phenylbutyrate, a well-tolerated FDA drug, for use in lethal prost
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310145
Entities
People
- Manish Thiruvalluvan
Organizations
- Cedars-Sinai Medical Center
- United States Army