Sensitizing Prostate Cancer to Ferroptosis-Based Therapy

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 deprivation of male hormones by means of inhibiting male hormone production or inhibiting the activity of the male hormone receptor called androgen receptor. 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 are 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/therapeutic strategies that can be used to treat this deadly disease. The overall goal of this proposal is to address this urgent need, and we will use clinically relevant mouse models to validate a new therapeutic strategy for its potential in treating resistant prostate cancer. This new strategy is based on a recent discovery that a class of compounds can induce cancer cells to die via an iron- dependent form called ferroptosis. Accumulating evidence has demonstrated that these compounds can effectively kill cancer cells and are thus promising for use to treat cancer patients. However, prostate cancer cells are often resistant to the treatments with these compounds. This major challenge would significantly hinder the success of this so-called ferroptosis-based therapy in treating prostate cancer patients. In our preliminary studies, we discovered that a gene called ATF3 could increase the sensitivity of prostate cancer cells to treatments with a new-generation, orally available, ferroptosis-inducing compound called JKE-1674. We also found that a clinically used anti-cancer drug, bortezomib, can induce ATF3 expression and promote prostate cancer cells to die when they are also treated with ferroptosis-inducing compounds. Bortezomib, sold under the trade name Velcade, is approved by the FDA to treat myeloma and lymphoma. This drug has been tested in clinical trials for treating advanced prostate cancer alone or in combination with hormone-deprivation therapy. Although the trial results are discouraging, this drug has a good safety profile and thus warrants further testing of its combinations with other drugs. While we have demonstrated that inducing ATF3 expression sensitized cultured prostate cancer cells to ferroptosis, the experiments proposed in this application will validate this finding in vivo using clinically relevant mouse models and determine whether ATF3 induction is a valid strategy for improving outcomes of JKE-1674 in prostate cancer treatments. As the next step toward translating our findings into the clinic, we will also use mouse models to determine whether the FDA-approved, ATF3-inducing drug bortezomib/Velcade can be used in combination with JKE-1674 to induce ferroptosis and effectively treat advanced, lethal prostate cancer. The proposed research will also investigate the mechanism by which ATF3 increases the sensitivity of prostate cancer to ferroptosis-inducing agents in order to better understand how prostate cancer cells respond to this group of promising anti-cancer agents. An anticipated outcome of the proposed research is the demonstration of the effectiveness of a new anti- prostate cancer strategy, which is based on ATF3 induction and a new form of cell death. Our results would also lend support to further development of bortezomib for its use in sensitizing prostate cancer to the new, ferroptosis-based therap