Androgen-dependent mTORC1 activation in advanced androgen receptor (AR) independent prostate cancer
Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Androgens (e.g., testosterone) are key factors that control the initiation and progression of PCa. Androgens accomplish this by binding to a protein known as the androgen receptor (AR), which turns on genes involved in tumor growth. Androgen deprivation therapy (ADT) is the first-line treatment strategy for advanced PCa, which uses drugs to inhibit gonadal androgen synthesis. Although ADT is effective initially, within 12 to 24 months after therapy, most patients experience tumor recurrence. Recurrent tumors usually no longer respond to ADT. This condition is called castration-resistant PCa (CRPC). To overcome this resistance, there are drugs that directly target the AR, such as enzalutamide. However, resistance to this line of attack also develops; moreover, there is a subset of CRPC tumors that no longer requires the AR at all to grow. The need to find new genetic targets is imperative, and new potential targets have arisen. One of these genes is known as phosphatase and tensin homolog (PTEN), and it is deleted in 43% of all CRPC cases. When present, PTEN inhibits cancer cell growth by blocking a tumor growth pathway called the PI3K/Akt pathway. One of the ways PI3K/Akt promotes tumor growth is through a protein complex called mTORC1 (mechanistic target of rapamycin complex 1). mTORC1 controls cell growth and protein production; because PTEN blocks PI3K/Akt, it tightly regulates mTORC1. mTORC1 can directly sense levels of nutrients, like amino acids and cholesterol, and activate pathways involved in cell growth and protein production. Currently, there are multiple clinical trials of mTORC1 inhibitors, and some results suggest therapeutic potential. Recent evidence indicates that amino acid stimulation of mTORC1 can bypass tumor suppression independently of PTEN. My preliminary research suggests that not only do androgens also stimulate mTORC1 and so can potentially promote tumor growth, but also this stimulation is independent of PI3K/Akt and PTEN. Therefore, this is a possible route that tumors lacking AR can use to grow. How androgens in AR-negative prostate cancer stimulate mTORC1 is unknown. I identified a novel mTORC1 binding partner, progesterone receptor membrane component 1 (PGRMC1), which stimulates mTORC1 activity in the presence of androgens and promotes tumor growth in multiple cancers. Therefore, I hypothesize that androgens directly stimulate mTORC1 in AR-negative prostate cancer and this activation depends on PGRMC1. If my hypothesis is correct, this investigation will lay the foundation for future studies of the clinical significance of the mTORC1/PGRMC1 interface in AR-negative CRPC. This pathway represents a potential novel treatment target for the development of new drugs for men with lethal CRPC, which could be a plausible therapy for these patients within the next 10 years. My professional goal is to lead an academic research laboratory that focuses on high-impact translational investigations of mechanism of metabolic resistance in CRPC and other cancers. During my Ph.D. research, I studied the orphan nuclear receptor, NR4A1, (nuclear receptors are found in the cell’s nucleus) and a group of tumorigenic factors known as specificity (Sp) genes. This experience gave me expertise in nuclear receptor biology and elucidating mechanisms of metabolic resistance, which are essential for this project. I joined Dr. Nima Sharifi’s research team at the Cleveland Clinic as a postdoctoral fellow, which includes both Ph.D. scientists as well as clinical urology and oncology trainees. Dr. Sharifi is a urological medical oncologist whose clinic is dedicated solely to treating patients with prostate cancer, most of whom have advanced CRPC. He also conducts clinical trials for experimental hormonal therapies. Therefore, his combination of clinical insight and extensive basic science knowled
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010090
Entities
People
- Erik Hedrick
Organizations
- Cleveland Clinic
- United States Army