The SEMA3E-Plexin D1-NRP2 Triad in Enzalutamide Resistance and Neuroendocrine Prostate Cancer
Abstract
Prostate cancer is the second most common cause of death from cancer in men of all ages and the most common cause of death from cancer in men over age 75 in the United States. Hormone therapy, which prevents androgens such as testosterone from mediating their biological effects in the body, is the current dominant therapy. Though prostate cancer patients benefit from this type of therapy at first, prostate cancer inevitably progresses to castration resistance and is then treated with more potent hormone therapies such as enzalutamide (Xtandi). However, prostate cancer can rapidly develop enzalutamide resistance and further progress to neuroendocrine prostate cancer. This lethal type of prostate cancer reportedly constitutes up to 25% of treatment-resistant relapsed prostate cancer. Currently, there is no effective treatment for neuroendocrine prostate cancer, and the survival of patents who suffer from this deadly disease is only ~7 months. Thus, there is an urgent clinical need to develop new targeted therapies against this incurable type of prostate cancer. Recent studies, including ours, have discovered that prostate cancer cells begin to express genes normally restricted to nerve cells during their progression to neuroendocrine prostate cancer, thus acquiring transformation plasticity and surviving treatment. In line with these emerging observations, we recently found for the first time significant activation of a triad of neuronal genes, SEMA3E, PlexinD1, and NRP2, in clinical samples of neuroendocrine prostate cancer. These genes were initially identified to form a complex cooperatively modulating the migration and movement of nerve cells. Our preliminary results also show that inhibition of this triad of neuronal genes significantly slowed down neuroendocrine prostate cancer cell growth and invasion, raising the possibility that inhibiting these genes may be a novel, effective therapy for lethal neuroendocrine prostate cancer. The proposed study will further test the targeting potential of this triad of genes in neuroendocrine prostate cancer cells as well as in neuroendocrine prostate tumors grown in mice to mimic the growth and progression of prostate tumors in the human body. The proposed study will also address how this triad of genes drives neuroendocrine prostate cancer at the molecular level, such as which molecules downstream of this gene triad are induced and how these molecules promote lethal disease progression. The proposed study will address late-stage prostate cancer patients who no longer respond to even the most potent hormone therapies and develop neuroendocrine prostate cancer, which currently lacks effective interventions. The proposed study will rigidly evaluate the feasibility of targeting a triad of neuronal genes, SEMA3E, PlexinD1, and NRP2, in neuroendocrine prostate cancer in animal models. All these genes are excellent druggable targets based on their molecular structures, abundance, and locations in cancer cells. Successful execution of the proposed project will make possible the translation of research findings into novel targeted therapies for treating neuroendocrine prostate cancer, expedited by the advanced biotechnologies now available. A more immediate translation of these research findings for clinical use is to apply these genes as new biomarkers to distinguish neuroendocrine prostate cancer from other forms of prostate cancer and predict lethality as a valuable complement to the very few reliable biomarkers now available in the clinic for diagnosing neuroendocrine prostate cancer. The proposed study builds on an important new clinical discovery and addresses an incurable type of prostate cancer, one of the main objectives of current prostate cancer research. The proposed study will resolve the question of how neuroendocrine prostate cancer expresses high levels of neuronal genes by focusing on a triad of neuronal genes and reveal new molecular mechanisms tha
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910279
Entities
People
- Boyang Wu
Organizations
- United States Army
- Washington State University