Role of Androgen Deprivation-Induced Glutamine in Prostate Cancer Metastatic Progression
Abstract
Men with prostate cancer who have disease relapse following surgery or irradiation require hormone therapy, given the dependence of this cancer on male hormones (androgens). We found that inhibitions of androgens cause changes in cancer-supporting cells (fibroblasts) that initiate a cascade of tumor-host interactions to facilitate resistance to hormone therapy. The activation of oncogenes (in the absence of mutations) in the fibroblasts seem to drive a metabolic signaling pathway involving the most abundant amino acid in the body, glutamine. Inhibiting the uptake or the metabolism of glutamine restored hormone therapy sensitivity in mouse models. In validating these findings, we reported that PCa patients that show resistance to hormone therapy had elevated blood glutamine levels compared to those with therapeutically responsive disease. But all the men on hormone therapy, regardless of their responsivity, had elevated circulating glutamine levels compared to prior to being on therapy. Further, we found that bone marrow fibroblasts also generated glutamine in response to hormone therapy. Based on these novel findings, we hypothesize that hormone therapy directly, and indirectly by glutamine signaling, can support metastatic progression at bone metastatic sites. As we defined how glutamine affects PCa growth, here we aim to (1) determine the role of glutamine in signaling and metabolic driver of prostate cancer progression; (2) define the role of glutamine in hormone therapy resistance: and (3) reveal the role glutamine plays in prostate cancer bone metastasis. The output of this project will provide greater understanding of the bone metastatic microenvironments in response to hormone therapy and determination of whether glutaminase inhibition is a clinically viable therapeutic target to extend the hormone therapy sensitivity in the context of companion biomarkers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910388
Entities
People
- Neil Bhowmick
Organizations
- Cedars-Sinai Medical Center
- United States Army