Metabolic Targeting of Skp2 Expression as a Novel Therapy for Castration-Resistant Prostate Cancer

Prostate cancer is the most commonly diagnosed non-skin cancer and the third leading cause of cancer death in American men. While the majority of prostate cancers diagnosed in the early stage are curable, patients with cancers disseminated to other organs can die from the disease. The mainstay of therapy for the latter group of patients is based on either deprivation of male hormones by means of inhibiting male hormone production or inhibiting the activity of the male hormone receptor, called androgen receptor (AR). While these treatments are initially effective, prostate cancer cells often resume growth after an average of 18-24 months. Sadly, once prostate cancer becomes resistant to hormone therapy, treatment options are very limited and often unsuccessful. Although hormone therapy-resistant prostate cancer can be treated with new-generation drugs such as enzalutamide, 20-40% of patients are intrinsically resistant to these drugs, while almost all patients who initially show responses eventually acquire resistance. These sad facts underlie an urgent demand for novel drugs that can be used to treat this deadly disease.

The goal of this proposal is to address this urgent need and determine the in vivo anti-prostate cancer activity of nitazoxanide using clinically relevant mouse models. Sold under the trade name of Alinia® in the United States for the treatment of diarrhea caused by parasites, nitazoxanide has a very favorable safety profile and is approved by the Food and Drug Administration (FDA) for use in children down to 12 months of age. This anti-parasitic drug was recently found to have an activity that can interfere with a critical energy-generating process inside a cell. We discovered through a drug screening that chemical compounds harboring such an activity could suppress expression of a gene called Skp2 that can promote the functions of many proteins that are crucial for the growth and metastasis of prostate cancer cells. The importance of Skp2 in prostate cancer is highlighted by the facts that Skp2 is often highly expressed in prostate cancer and Skp2 expression is associated with therapy resistance and reduced patient survival. Therefore, Skp2 inhibitors like nitazoxanide hold great promises in curing prostate cancer. While we have demonstrated that nitazoxanide could inhibit the growth while inducing the death of prostate cancer cells cultured in vitro, the experiments proposed in this application will further determine whether this drug can inhibit the growth of therapy-resistant prostate cancer in animal models that are mostly relevant to the situations in patients. For a better understanding of the anti-prostate cancer activity of nitazoxanide, we will also address questions regarding how this drug can suppress Skp2 expression and how targeting this protein triggers a molecular mechanism that is detrimental to the growth and survival of prostate cancer cells.

An anticipated outcome of the proposed research is the demonstration of the in vivo anti-prostate cancer activity of nitazoxanide. As nitazoxanide is an FDA-approved anti-parasitic drug with a very favorable safety profile, the anticipated outcome would lend support to immediate clinical testing of this FDA-approved drug for the treatment of hormone therapy-resistant prostate cancer and thereby warrant rapid development of a novel therapy for castration-resistant prostate cancer patients in the near future.