Advancing targeted therapies in prostate cancer metastasis + integrin biology
The principal effort of the Mathew Laboratory at Tufts Medical Center has been to elucidate the molecular mechanisms underpinning the metastatic progression of prostate cancer in order to develop rational molecular therapeutics, recognizing the limitation of current therapeutic approaches such as hormone therapy, chemotherapy and radioisotopes. The foundational strategy of the laboratory focused on the unique and characteristic propensity of prostate cancer to colonize the bone environment with great efficiency, often to the exclusion of other organ systems. Mortality and suffering from prostate cancer is strongly linked to bone metastases, referred to as its “lethal phenotype.”
Integrins + the lethal phenotype
Our studies have led us to the identification of two integrins which cooperate with each other to facilitate and define the lethal phenotype of prostate cancer. These two integrins, referred to as alpha v and alpha 5, are receptors on prostate cancer cells that enable a connection to matrix molecules in the bone environment and other organs. This matrix connectivity confers homing, adhesion and survival properties to disseminated prostate cancer cells, while endowing them with stem-cell properties including resistance to hormone therapy as well as evasion of immune surveillance.
Development of a bispecific integrin antibody
In order to counter the lethal phenotype mediated by these integrins, we have designed and developed a novel bispecific integrin antibody that targets both integrins simultaneously. Our studies indicate that this bispecific antibody powerfully reprograms the lethal phenotype of prostate cancer cells by reversing signaling by the integrins. Specifically, the bispecific antibody controls signaling by Myc, EMT and TGF-beta signaling pathways. Myc, EMT and TGF-beta are recognized as dominant immune-suppressive mechanisms employed by a wide range of malignancies. Reversal of Myc, EMT and TGF-beta signaling is associated with activation of Type I and Type II interferon signaling with immune-mediated elimination of the prostate cancer cells by the bispecific integrin antibody in animal models of disease.
Clinical translation + future directions
Our priority is to translate these novel insights and therapeutic innovations into proof-of-concept clinical trials of the bispecific integrin antibody in men with high-risk and metastatic prostate cancer. We are also advancing our laboratory-based studies of bispecific integrin targeting in other cancers in which these integrins and the Myc, EMT and TGF-beta immunosuppressive pathways have been strongly implicated. Utilizing immune-competent models, we aim to optimize single-agent and a range of combinatorial strategies toward the goal of eliminating prostate and other cancers.
