Cochaperone Unc45A: A Novel Immunotherapeutic Target to Eradicate Breast Cancer

Breast cancer is the second-leading cause of cancer death among women in the US. Although hormone and targeted therapies have significantly improved the outcomes for patients with steroid receptor and HER2+ breast cancer subtypes, resistance to therapies or relapse remains a major obstacle to beating this disease. Therefore, there is an urgent need for improved therapeutic strategies. For cancers in general, immune therapy is widely becoming an exciting new approach, using methods that allow the patient's own immune system to attack the tumor. Recent discoveries in our laboratory suggest a novel way of activating the immune system to eradicate breast cancer. We found that a protein called Unc45A is essential for growth of cell lines representing various breast cancer subtypes. In contrast, Unc45A was not needed for normal cell proliferation. Therefore, we have shown that inhibiting Unc45A is a way to target the proliferation of breast cancer cells – regardless of subtype. The true novelty of our research strategy comes from our subsequent discovery that Unc45A links to the immune system. Based on our preliminary data, we are proposing that silencing Unc45A causes cells to die through a type of cell death that activates the immune system. We have demonstrated that reducing the level of Unc45A in tumor cells implanted in the mammary gland of mice of the same genetic background triggers an immune response that destroys the established breast tumors – and vaccinates mice against cancer recurrence. This discovery qualifies Unc45A as a novel immunotherapeutic target, such that Unc45A inhibition may provide a novel therapeutic strategy to engage the immune system to end breast cancer. We propose to introduce siRNA, a molecular construct designed to specifically reduce the level of Unc45A into cancer cells. The goal of the proposed studies is to generate proof-of-principle that loss of Unc45A releases the immune system to recognize and fight tumors. To this end, we have identified a highly efficacious siRNA that will be tested in vivo using a delivery system that is already in clinical trials. An advantage of our strategy is that, as opposed to typical inhibition strategies, not all cancer cells need to be treated, just enough to activate the patient's immune system, which will then recognize and kill tumor cells. If the experiments go as planned, this research is positioned to advance to the clinic within the 3-year timeframe of this award, bringing a radical breakthrough for breast cancer treatment by engaging the immune system and bypassing therapeutic resistance and disease recurrence.