B7-H3 (CD276) as a Therapeutic Target in Lethal Prostate Cancers

Advanced prostate cancer is a leading cause of death in men globally. Despite developing several new treatments, men suffering from PC have a life expectancy of 2 to 3 years. Unlike many other cancer types, the treatment of patients with advanced prostate cancer has not been improved by recent advances in drugs harnessing the immune system (also called immunotherapy) to attack cancer. This is because prostate cancers and the immune cells surrounding it have developed means to prevent tumor eradication by the body's normal, desirable immune defenses. We and others have shown that a poorly understood protein expressed on the surface of prostate cancer cells may play a role in suppressing desirable antitumor immune responses, as well as directly fueling prostate cancer growth. Emerging data from studies testing drugs targeting this protein in patients with various malignancies have shown that this approach can be safe; however, to date, little is known about the functions of this protein, how its expression evolves as tumors progress, and how it can be manipulated through novel prostate cancer drugs to improve treatment outcomes in patients with these lethal diseases.

The major objective of our research is to study how the expression of this protein varies over time and between individuals, how it is regulated, how it can be manipulated, what the functions of this protein are, and the antitumor effects of therapeutic strategies targeting this protein.

We envision that our research will directly lead to the transformation of clinical testing of novel prostate cancer treatments in the clinic within the next 2 to 3 years. This could then lead to successful large-registration Phase 3 clinical trials for prostate cancer patients of these novel treatments within 5 years, paving the way for the routine use of these agents in the clinic. These studies and novel therapies have the potential to improve life expectancy, cause tumor shrinkage, and improve quality of life in men with advanced prostate cancers. Since this treatment specifically targets a protein that is highly expressed on prostate cancer cells, but not normal healthy tissue, it is also likely to spare normal cells while killing tumor cells, arguably the 'Holy Grail' of anticancer treatment, thereby causing fewer side effects compared with less 'precise' existing treatments such as chemotherapy. Moreover, insights into the factors controlling the levels of this protein present on the cancer cell surface and the functions of this protein will facilitate the development of tools that will help to identify patients who are most likely to respond to these types of drugs, thereby reducing futile treatment of patients who will not benefit from this treatment, as well as increasing the number of prostate cancer patients who can benefit and reverse resistance to these therapeutic strategies.

Understanding how the expression of this protein evolves over time in patients with different types of prostate cancer will also allow us to develop new tools that will help separate patients with low versus high-risk disease; this information will help doctors determine the best-tailored approach to treat each patient's cancer. This part of our work will likely generate results within the next 2 years and could be used in the clinic within 3 to 4 years.

Finally, insights into the biology of how prostate cancer cells evade eradication by normal immune defenses will aid the development of other novel immunotherapeutic strategies that could improve outcomes of patients for who do not benefit from this current approach as well as enhance and improve the durability of response in patients who do benefit initially. Overall, we envision this study could deliver novel treatments and tools that could substantially improve outcomes for patients with advanced prostate cancer.