B7-H3 (CD276) as a Therapeutic Target in Lethal Prostate Cancers
Posted September 1, 2023
Johann de Bono, M.D., Ph.D., The Institute of Cancer Research, London, United Kingdom
Andrea Alimonti, MD., Ph.D., Institute of Oncology Research, Switzerland
Michael Shen, Ph.D., Columbia University Medical Center
In recent years, successful biological treatments targeting the immune system (immunotherapy) have come to the forefront of cancer care. In prostate cancer, however, immunotherapy has been largely ineffective, likely due to the
Through evaluation of B7-H3 and its receptor in biopsies from patients with lethal prostate cancer and assessing the protein’s association with immune cells in the tumor microenvironment, tumor genetics, and clinical outcomes, the team aims to determine approaches to precisely target B7-H3. To date, the team has evaluated B7-H3 expression in two data sets of gene expression in lethal prostate cancers. They found that, of all immune genes evaluated, the one coding for B7-H3 was among the most highly expressed in prostate cancer and was predominantly expressed on tumor cells, and not on normal tissue, indicating the potential to be a therapeutic target.
Assessment of biopsy samples from patients with metastatic castration-resistant prostate cancer — that is, cancer that is resistant to common hormone therapy — and
The team plans to determine the antitumor activity of targeting B7-H3 and to correlate response to tumor genetics and expression of the protein. They aim to develop biomarkers to indicate response to treatment and determine potential drug combinations. Thus far, the team has assessed a B7-H3 antibody drug conjugate (ADC). ADCs are an emerging treatment option that pair a cancer-treating drug with an antibody targeting a cancer-specific protein, in this case B7-H3. The team has treated prostate cancer cell lines, as well as tumors derived from patient biopsies grown as tiny 3D structures in the dish (also known as organoids) and implanted in mice with the B7-H3 ADC. Tumors with and without B7-H3 expression were used. The team showed that tumors expressing B7-H3 shrank in response to the B7-H3 ADC, whereas antitumor effects were not observed in tumors lacking B7-H3 expression. However, the antitumor activities varied across different tumor models indicating that B7-H3 was necessary for the antitumor effects but additional factors impacted response.
Dr. de Bono, Dr. Shen, Dr. Alimonti, and their collaborators are laying the framework for additional studies to better understand the role of B7-H3 in prostate cancer and its effect on immune cells. B7-H3 targeting drugs are currently being studied in other cancers, so the knowledge gained from this study could help other researchers understand the potential mechanisms of resistance. In addition, the team has shown the antitumor effects of B7-H3 ADCs that could be combined with other treatment options for prostate cancer and address issues of treatment resistance. Clinical trials with novel anticancer drugs targeting B7-H3 are now serving men suffering from advanced prostate cancer.
Guo C, Figueiredo I, Gurel B, et al. 2023. B7-H3 as a therapeutic target in advanced prostate cancer. European Urology 83(3):224-238
Last updated Friday, September 1, 2023