Redirecting the Immune Response to Prostate Cancer Using Synthetic Constructs.

摘要

Prostate cancer is the second leading cause of cancer related deaths in the United States, and it is predicted that one in six American men will develop prostate cancer in his lifetime. This thesis discusses the design, synthesis, and biological evaluation of synthetic constructs capable of redirecting the immune response to prostate cancer cells expressing the prostate specific membrane antigen (PSMA). The first class of synthetic constructs discussed is a class of antibody-recruiting small molecules targeting prostate cancer (ARM-P). ARM-Ps function by redirecting anti-dinitrophenyl (DNP) antibodies found in the human bloodstream and immune effector cells to PSMA-expressing prostate cancer cells, resulting in immune mediated cytotoxicity. We have further demonstrated that in the presence of anti-DNP antibodies, ARM-P functions in vivo by inhibiting the growth of PSMA-expressing prostate tumor xenografts and enhancing the median survival of their hosts. Additionally, during the course of characterizing ARM-Ps, we found that ARM-Ps were able to inhibit the enzymatic activity of PSMA with potencies rivaling some of the most potent PSMA inhibitors known to date. With in depth biochemical, crystallographic, and computational studies, we made a serendipitous discovery of an arene-binding site on PSMA accessible by electron poor aromatic rings. Such a discovery gives hope to developing more potent ARM-P analogues for in vivo characterization.;The success of the ARM-P project gave rise to two new projects that seek to broaden the scope of using the immune system to target prostate cancer. The first project involves a class of synthetic antibody mimics targeting prostate cancer (SAM-P), which functions by simultaneously binding to PSMA and the FcγRI expressed on a wide variety of immune effector cells. Such a construct mimics the function of an antibody by redirecting immune effector cells to a target cell of interest, but unlike the ARM-P system, it bypasses the requirement for an endogenous antibody. The second project involves using a pH-low insertion peptide (pHLIP) to selectively target anti-DNP antibodies to cancer cells based on their hypoxic nature and the acidic tumor microenvironment. This construct is capable of redirecting antibodies not based on the cell surface expression profile of a cancer cell, but based on characteristics that are common to most solid tumors. Taken together, the projects discussed in this thesis have broadened our understanding of prostate cancer therapy and provides approaches that complement the already diverse repertoire of cancer therapeutics.