Advanced prostate cancer is initially treated with androgen deprivation therapy, which blocks a key pathway for prostate cancer survival. Eventually, most patient tumors will progress to castration-resistant prostate cancer, the lethal form of the disease. Approximately 26,000 men will succumb to castration-resistant prostate cancer this year. In the Grabowska laboratory, we are working to improve prostate cancer patient outcomes through understanding the “who”, “what”, and “how” of prostate cancer progression. We are exploring how prostate cancer progresses to castration-resistant. We are also exploring who will fail androgen deprivation therapy and what new drugs and therapies we can develop or repurpose to help these patients. Our studies utilize human derived prostate cancer cell lines, pre-clinical models, and human prostate cancer specimens.
Nuclear factor I (NFI) family members in prostate cancer: Our studies focus on transcription factors, which are proteins that bind to DNA and determine what genes are turned on or off. We are interested in how a specific transcription factor family, the nuclear factor I (NFI) family, interacts with androgen receptor. Androgen receptor is the target of androgen deprivation therapy and the major therapeutic target in prostate cancer. Therefore, understanding how androgen receptor activity is regulated is critical for determining how patients fail androgen deprivation therapy. Our previous studies have demonstrated that the NFI family can control androgen receptor activity, and our current work focuses on determining how this control changes during therapeutic failure in prostate cancer.
Drivers of enzalutamide resistance in castration-resistant prostate cancer: A second line of investigation in the laboratory focuses on identifying genes that contribute to enzalutamide resistance in castration-resistant prostate cancer. Using a knockdown screen, we identified 11 genes that support enzalutamide resistance in castration-resistant prostate cancer. Ongoing studies are working to determine how two of these gene products support enzalutamide resistance and whether blocking their activity can sensitize enzalutamide-resistant cells and xenografts to therapy.
Benign prostatic hyperplasia (BPH)
Benign prostatic hyperplasia (BPH) is a benign urologic condition in men, largely characterized by lower urinary tract symptoms (LUTS), such as difficulty voiding. These symptoms can be due to overgrowth of the prostate gland stromal and/or epithelial components (benign prostatic enlargement [BPE]) resulting in bladder outlet obstruction (BOO), as well as dysfunction of the bladder and urethra. Our previous studies discovered NFIB is lost in the luminal cells of BPH patients and knockout of Nfib in the mouse prostates results in changes similar to those observed in BPH patients (increased stromal and epithelial proliferation, immune recruitment, and fibrosis). Our current studies are evaluating how NFIB loss in the normal prostate supports these changes.