Targeting the androgen receptor (AR) has been the cornerstone of treatment for men suffering from prostate cancer, essentially starving tumors of the fuel they need to grow and survive. However, these therapies have been a double-edged sword; undoubtedly they have benefited survival, but in nearly 25% of patients the tumors eventually come back even stronger and more aggressive than before. For these men who progress to this deadly form of prostate cancer, called neuroendocrine prostate cancer (NEPC), the only treatment option is a highly toxic chemotherapy; however, the survival is only measured in months.

Our research is focused on deciphering how prostate tumors treated with AR-directed therapy evolve into NEPC. Toward this end, we discovered a protein called BRN2 that is essential for the growth and survival of NEPC. Moreover, we have developed drugs that can inhibit BRN2 and display a potential to inhibit NEPC progression. The current proposal outlines the following strategies:

1. Understand BRN2’s role in structural changes in the genome and how that causes treatment resistance, as well as this transformation to NEPC.

2. Test our first-in-field BRN2 inhibitors on human patient NEPC tumors that are grown in mice.

3. Test the efficacy of the BRN2 inhibitors in combination with current AR inhibitors. Measure the effects on tumor growth, as well as transformation to NEPC.

4. Using these NEPC tumors, we will also validate the relationship between BRN2 and another protein, IGFBP5, which can be measured in the blood, to develop a companion diagnostic to identify patients who should get BRN2 inhibitors. Also, we will test whether blood levels of IGFBP5 can be used as a surrogate to measure the transformation to NEPC.

At the successful completion of this research, we will have tested a BRN2 inhibitor and confirmed its ability to inhibit growth of NEPC tumors from human patients that are being grown in mice. This scenario should provide the most accurate representation of what can be expected in humans with NEPC who are treated with a BRN2 inhibitor. We expect to be ready for an immediate integration into a clinical trial, along with a companion diagnostic tool that will help select patients. The 3-year term of this grant provides the proper timeframe needed for us to develop and test these technologies, and by the end of this grant term, we will be ready to begin clinical trials, with the ultimate goal of changing the way NEPC is treated.