Conformation-Based Targeting of AR Transcriptional Complexes to Overcome Prostate Cancer Treatment Resistance
Each year, more than 34,000 American men die from prostate cancer. Patients who present with prostate cancer that has not spread beyond the prostate are treated using surgery or radiation. Some men present with metastatic prostate cancer that cannot be cured by such treatments, and in others prostate cancer recurs after operation or radiation. For those men, hormone therapy is the standard of care. Hormone therapy prevents the growth of prostate cancer cells that is induced by male hormones. At first, hormone therapy induces remissions, but it does not cure prostate cancer. There is an urgent need to develop new therapies for advanced prostate cancer that overcome the resistance to hormone therapy. We propose to overcome this resistance by targeting the molecular mechanisms that cause sustained growth of cancer cells when hormone therapy has failed. Our laboratory has discovered protein-protein interactions that can be targeted for this. But, in order for this strategy to be successful, we need to gain more insights in the 3D conformations and interactions of these proteins. Our proposal is designed to use a new technology known as cross-linking mass spectrometry to obtain this information. We propose also to use these insights to develop new molecular tools to disrupt these protein-protein interactions and to test in prostate cancer cells and patient-derived cancer tissue models if these tools prevent further prostate cancer growth. If our studies are successful, our results may lead to a new class of prostate cancer drugs that can overcome resistance to hormone therapy.
We are learning about prostate cancer that has become resistant to hormonal therapies. We plan to target the molecular mechanisms that cause sustained growth of cancer cells when hormone therapy has failed. We plan to use technology to obtain this information and use these insights to develop new molecular tools to disrupt prostate cancer growth.