Friday, May 9, 2025
5/9/2025
Dormancy mimicking to inhibit prostate cancer metastasis progression and recurrence - Primary cancer cells can disseminate at early stages to distant organs and stay dormant/quiescent, enabling them to escape treatments. While these disseminated tumor cells (DTC) can reactivate, causing metastasis and recurrence, dormant cancer cells cause no symptoms in patients. Therefore, keeping the DTC dormant can be an “operational cure” for patients. In prostate cancer (PCa), disseminated tumor cells (DTC) can be detected early in patients’ bone marrow. 20-45% of these patients relapse years later despite various treatments, including primary tumor removal and enzalutamide. The mechanisms for these metastases and recurrences are overlooked, especially the treatments’ effects on PCa cell dissemination and dormancy. It’s unknown whether harnessing dormancy will inhibit bone metastatic progression and recurrence. We showed that DTC was detectable early in almost all the organs examined in a subcutaneous xenograft mouse model. Primary tumor removal, however, resulted DTC only in bones, and exclusively in the bone cortex, not the bone marrow in mice (9 out 10) that had no detectable recurrence. In vitro, we found that only osteoblasts induced PCa cells into a dormant status. Through RNA sequencing and analyzing public data sets, we revealed an inverse correlation of the enriched mitochondrial related biological processes between the osteoblasts induced dormant PCa cells and overt patient bone metastasis, suggesting dormancy impedes metastatic progression or metastasis is a result of reactivation of dormancy. Based on the dormant PCa cell signature and using a novel drug prediction algorithm, enzalutamide was predicted to reverse, but PF-562271 (PF-271), a focal adhesion kinase (FAK) inhibitor, was predicted to mimic the dormant PCa signature, and the effect was validated in vitro. Therefore, we hypothesize that dormancy-mimicking impedes PCa metastatic progression and recurrence. This proposal aims to determine how osteoblasts induce PCa dormancy, how treatments affect PCa dissemination and dormancy, how PF-271 induces dormancy-mimicking, and how PF-271 inhibits PCa bone metastatic progression and recurrence.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).