Roles of Lin28b in Neuroendocrine Prostate Cancer

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death in North American males. One out of every nine men will be diagnosed with prostate cancer in his lifetime. The incidence of this disease will only grow with increases in life expectancy, creating a perpetual burden on healthcare systems. While most of the tumors can be treated with surgery and or radiation therapy to effectively control the disease, approximately 20% of the patients will have the tumors come back, at which stage there is no cure for the disease. The recurrent tumor cells grow by mainly relying on the male hormones (androgens) to activate a receptor protein in the cells called the androgen receptor. The androgen receptor promotes tumor recurrence by increasing the expression (increasing the volume of protein produced) of many tumor-promoting genes. Therefore, patients with these recurrent tumors are typically given hormonal therapies that either block human cells from synthesizing androgens or suppressing androgens from binding to the androgen receptor. In these ways, the androgen receptor's capability to induce tumor-promoting genes will be abolished. Although initially effective, hormonal therapies will eventually fail to control the recurrent tumors. Even with the most potent androgen receptor inhibitors, such as Enzalutamide and Abiraterone, patient survival can only be prolonged for 4 to 5 months.

Researchers have found that, in many cases, the failure of hormonal therapies is due to the classic prostate tumor cells being changed into a different type of cells with neural or neuronal features. The resultant tumors are called neuroendocrine prostate cancer (NEPC). Tumor cells in NEPC either produce no androgen receptor protein or produce androgen receptor without any activity. These findings explain why hormonal therapies cannot inhibit NEPC growth. Furthermore, new research had also found that it is the hormonal therapies that stimulate classic prostate cancer to be changed into NEPC so that tumors can no longer be attacked by the hormonal therapies and continue to grow. Therefore, it is a dilemma that the hormonal therapies are helpful overall to improve prostate cancer patient survival in the short term, but eventually promote formation of a more aggressive type of hormone therapy-resistant NEPC tumor that kills patients. It is therefore important to find how classic prostate cancer can be transformed into NEPC, which gene/genes are responsible for this transformation, and whether therapies can be developed to block the activity of the NEPC promoting genes to improve patient outcome.

Our laboratory has found that a gene called Lin28b can be responsible for transforming classic prostate cancer into NEPC. We found that, not only is the amount of Lin28b protein in NEPC significantly higher than that in classic prostate cancer, but also removal of the Lin28b gene from NEPC tumor cells will slow or fully stop them from forming NEPC. These exciting findings indicate that Lin28b may be responsible for classic prostate cancer to be transformed into NEPC. They also indicate that any drug that can inhibit Lin28b activity can be used as a therapy to treat NEPC patients.

In this project, we will use multiple NEPC cell and tumor model systems (cells and tumors grow in the laboratory but show similar behavior to cells and tumors from patients) and complicated molecular techniques to (1) confirm that the Lin28b is a drug target to be used to treat NEPC patients; (2) figure out how the Lin28b transforms classic prostate cancer cells into NEPC tumors; and (3) develop Lin28b inhibitors by designing complex software and assembling multiple computers together to screen a chemical bank containing ~400 million chemicals for Lin28b inhibitors. We will then test these identified chemicals for their inhibitory effects to NEPC growth.

At the conclusion of this project, we will collect enough knowledge on how classic prostate cancer is transformed to NEPC by Lin28b and find Lin28b inhibitors that can be used to be tested for NEPC in clinical trials, and if successful, be applied in clinics to treat NEPC patients.