Dissecting mechanisms of sensitivity to B7-H3 (CD276)-targeted therapeutics in prostate cancer (PC) - PROJECT SUMMARY/ABSTRACT Background. Agents that inhibit Androgen Receptor (AR) signaling are the standard-of-care treatment for prostate cancer (PC) patients. Unfortunately, essentially all patients develop resistance to AR targeting therapies (ART). We previously found robust B7-H3 (CD276) expression in metastatic PC patients resistant to ART. In our recent phase II clinical trial, we found that B7-H3 targeting agents improved clinical outcomes for 66% of PC patients for reasons unknown. We separately examined mechanistic regulators of B7-H3 expression with computational and laboratory approaches. We preliminary found that B7-H3 expression was regulated by AR and its co-regulators (FOXA1, HOXB13) at four transcription regulatory sites. Altogether, we hypothesize that AR activity regulates B7-H3 expression and thus response to B7-H3 targeted therapies. Specific Aims and Study Design. We propose to determine mechanisms of B7-H3 expression by examining the necessity of all B7-H3 transcription factors and regulator sites in PC (AIM 1). This includes the AR co- regulators HOXB13 and FOXA1, as well as the four B7-H3 enhancer sites that were hyperactivated in metastatic PC compared to primary disease. We will also determine how androgens or ARTs, which are used clinically, impact the susceptibility of ART resistant tumor cells towards B7-H3 targeted therapies (AIM 2). We will utilize single cell RNA-sequencing platforms to identify the genes and signaling programs associated with response to B7-H3 therapies in single cells. Lastly, we aim to identify the clinical and molecular characteristics of the PC patients with predicted response to B7-H3 targeted therapies (AIM 3). We will use computer- modeling tools to characterize the somatic changes and clinical features of patients that previously responded to a B7-H3 targeted therapy. We will then apply this response signature to ~7000 additional tumors to identify significant clinical and molecular features that are predictive of response. Anticipated Outcomes. We anticipate that the candidate transcription factors and regulatory sites of B7-H3 will control B7-H3 expression in PC tumors. Further, such changes in cell surface B7-H3 expression will greatly impact the tumor-forming capacity and ART resistance. We also anticipate that clinical forms of androgens or ART will alter B7-H3 expression and thus impact response to the B7-H3 targeted therapies. Lastly, we expect to identify many of the additional clinical and molecular features associated with B7-H3 expressing tumors. Future Directions and Impact. We anticipate this study will uncover mechanistic insights of B7-H3 expression and a further understanding of PC patient response to B7-H3 targeted therapies. We shall also identify the mechanisms by which B7-H3 regulates ART resistance, tumor formation, and cell signaling. Lastly, our findings will impact patient stratification methods in the upcoming B7-H3 clinical trials, which will be essential to the development and deployment of future B7-H3 therapeutics in PC patients.
