B7-H3/PTEN: a new axis for novel anti-cancer therapies in prostate cancer

Searching for new therapies for prostate cancer. Estimations are that one out of two men will get cancer along his lifetime, the most common type of cancer in men being prostate cancer. Each year almost 5000 men in Norway get the message that they have prostate cancer, and around 1000 men die from the disease. One of the challenges we face is that many patients do not respond to the current treatments. This makes the identification of novel therapeutic targets a priority to combat prostate cancer, and the goal of this project is to search for more effective anti-cancer therapies against this tumor type. We are work with proteins which are important in prostate cancer. One of the proteins (called B7-H3) favors tumor growth, while another protein (called PTEN) limits the growth of the tumor. Our preliminary data indicates that a deficit in PTEN facilitates the expression of B7-H3 and promotes cancer. We are making characterizations of the relationship between these two proteins, and investigate closer the possibility of inhibiting the action of B7-H3 through activation of the effects mediated by PTEN. As tools for this, we are using human prostate cancer cells and mouse models of human prostate cancer. The work from the project has contributed to an increased understanding on how B7-H3 contributes to tumor growth as well as to sensitivity to targeted therapy and chemotherapy both in vitro and in vivo in prostate and other cancers (Flem-Karlsen et al., Pigment Cell Melanoma Res 2017; Flem-Karlsen et al., Trends Cancer 2018; Flem-Karlsen et al., Sci Rep 2019; and Flem-Karlsen et al., Curr Med Chem 2019), and to the precise definition of PTEN C-terminal epitopes and its implications in clinical oncology (Mingo et al., Npj Precis Oncol 2019; Pulido et al., Cold Spring Harb Perspect Med. 2019). In this regard, we have also reviewed the role of other phosphatases in prostate cancer (Nunes-Xavier et al., Biochim Biophys Acta Mol Cell Res. 2019). Our ongoing studies from Norwegian and Spanish prostate cancer cohorts suggest an important role of B7-H3 in prostate cancer progression (Nunes-Xavier et al., manuscript in preparation).

We have gained knowledge and molecular understanding on the relevance of B7-H3 and PTEN pathways in prostate cancer. We have fostered the translational value of our work by preclinical (in vitro and in vivo) validations of our findings using clinically relevant inhibitory antibodies, through external international collaborations and an international biotechnology company. This strongly strengths the interest and opportunity of our research. The results obtained will contribute to improve precision diagnostic of patients and to implement novel therapies in prostate cancer. The impact of the outcomes and results obtained was further strengthened through the expertise and cooperation of international collaborators including tumor and molecular biologists, pathologists and urologists, involving national and international partners.

B7-H3 belongs to the B7 family of immune comodulators and display coinhibitory activity in the tumor-specific T-cell-mediated immune response. B7-H3 is expressed at low levels in human tissues, and its expression is increased in human cancers, including prostate cancer (PCa). Overexpression of B7-H3 in prostate tumors correlates with poor prognosis and metastasis. However, very little is known about the oncogenic functions associated with B7-H3. PTEN is a unique tumor suppressor that counteracts the oncogenicity of the PI3K/AKT/mTOR pathway, and whose gene is frequently mutated or deleted in human cancers. A PTEN-long secreted form internalizes in acceptor cells, which has raised the interest on direct PTEN reconstitution as a novel anti-cancer therapy. Coincidentally, the expression of both PTEN and B7-H3 in exosomes from PCa cells has been associated with disease progression or response to therapy. These facts make B7-H3 and PTEN highly relevant proteins in PCa. A pathway that linkes PTEN and the B7-H3-related protein, B7-H1, through hyperactivation of the PI3K pathway, has been uncovered in several cancer types. We have identified a group of mi-RNAs that target PTEN and upregulate B7-H3 protein expression. These findings suggest the existence of a B7-H3/PTEN axis relevant in oncogenesis. In this project, we propose the oncogenicity-related validation and the mechanistic characterization of the B7-H3/PTEN axis in human prostate cancer cells and tumor samples. We will test in vitro and in vivo, using prostate cancer cell lines and a Ptenpc-/-mice model of prostate cancer, the efficacy of novel potential anti-cancer therapies, including the reconstitution of PTEN function using purified PTEN-long and the blocking of B7-H3 functions using anti-B7-H3 antibodies. Our hypothesis is that combinations of these approaches could be beneficial for the implementation of more effective anti-cancer therapies against tumors resistant to the current therapies.