Targeting Neuromimicry in Prostate Cancer Metastasis
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. The main cause of death in nearly all prostate cancer patients is that cancer will metastasize (spread) from the prostate to other parts of the body. Current treatments of prostate cancer that include hormone therapy, radiation therapy, and surgery, though effective for patients during the early stages of the disease, fail to respond to patients with the advanced-stage metastatic prostate cancer. A more comprehensive understanding of how prostate cancer spreads will speed up the search for novel and effective therapeutic targets and strategies for the treatment of advanced and metastatic prostate cancer. The prostate is rich in nerve supply and provides a favorable environment for nerves to communicate with other types of surrounding cells, including cancer cells. The invasion of cancer cells in, around, and through the nerves has long been observed in prostate cancer and considered as an important route for the spread of prostate cancer cells. In some cases with the absence of cancer cell invasion through the lymphatic or vascular channels, the nerves become the sole route of prostate cancer spread. The clinical phenomenon of prostate cancer invasion facilitated by nerves has been correlated with worse clinical outcomes and decreased survival in prostate cancer patients. Recently, this phenomenon has been further correlated with the recurrence of local castration-resistant prostate cancer. However, there has been no targeted treatment for this area developed to date. This represents a new opportunity for developing novel therapeutics for prostate cancer metastasis. We recently discovered that prostate cancer cells begin to express genes normally restricted to nerve cells. We found that the expression of monoamine oxidase A (MAOA), a key brain enzyme that controls brain function, mood, and behavior, is increased in high-grade and metastatic prostate cancer patient samples. In particular, the expression of this enzyme is increased more significantly in patient samples where the invasion of nerves by prostate cancer cells occurs. In addition, MAOA also activates a number of genes responsible for the growth of nerve cells, the amplification/extension of nerve fibers, and the movement of nerve cells in a series of prostate cancer cell models. By expressing these genes and exhibiting acquired nerve-like behavior, prostate cancer cells are able to mimic and reciprocally communicate with nerves to promote prostate cancer spread in and along nerves to initiate metastasis. The proposed project is aimed to fill the critical unmet needs for more effective mechanism-based therapies for metastatic prostate cancer by (1) understanding how MAOA and its downstream target genes mediates the interactions between prostate cancer cells and nerves and (2) evaluating the effectiveness of MAOA inhibitors on treating prostate cancer metastasis in animal models. This proposed study will benefit prostate cancer patients at most stages, with a special attention for late-stage patients who develop recurrent and metastatic spread of prostate cancer currently without effective therapy. The proposed treatment strategies will benefit recurrent prostate cancer patients by preventing the metastatic disease progression by blocking the spread of cancer cells through the route of nerves. The proposed strategies will also offer hope for prostate cancer patients who already develop metastasis by (1) relieving cancer pain, such as bone pain, by eliminating the injury of sensory nerves caused by cancer cell invasion and (2) eradicating pre-existed metastatic deposits by cutting off the growth factor supply to cancer cells as provided by nerves. In view of the fact that MAOA inhibitors are currently used as anti-depressants in the clinic, this study will promote t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510493
Entities
People
- Boyang Wu
Organizations
- Cedars-Sinai Medical Center
- United States Army