Peptoid conjugates targeting prostate cancer

PROJECT SUMMARY We propose an innovative approach to antagonize the androgen receptor (AR) by displaying AR ligands on a peptoid scaffold. This new family of molecules, called multivalent peptoid conjugates (MPCs), potently stops the growth of prostate cancer cells resistant to treatment by standard anti-androgen agents such as enzalutamide. Peptoids are small protein-like chains, but unlike polypeptides, they are protease resistant and thus exhibit improved pharmacologic stability, favorable solubility, and cell permeability characteristics, making them an attractive option for drug development. Our published and preliminary studies show that MPCs deter prostate cancer growth by antagonizing the proliferative response of AR. We propose that MPCs promote a novel AR conformation that drives a different pattern of AR-mediated gene expression compared to DHT or enzalutamide resulting in a block to cell proliferation by the gain and loss of AR occupancy at select genomic sites. We will perform ChIP-seq, RNA-seq, and ChIP-mass spec to identify MPC target genes and the coregulatory factors controlling their expression compared to enzalutamide and DHT in enzalutamide-resistant cells. In addition, MPCs can promote immune cell infiltration in treated xenograft prostate tumors, which could potentiate a cytotoxic T cell response and enhance the efficacy of immune checkpoint blockade (ICB), allowing the patient’s immune system to fight tumor growth. The inadequacy of available immune checkpoint blockade strategies is an obstacle to treating advanced prostate cancer. We will determine whether MPCs can promote anti-tumor immunity and sensitize tumors to ICB treatment. Therefore, another goal of this proposal will be to assess whether MPC309 can synergize with ICB antibodies in treating CRPC. We will also conduct X-ray crystallography studies to establish the mechanism of action of MPC309 with AR. This will provide insights into the molecular interactions between MCP309 and AR and will be used to guide the design of more potent and selective MPCs optimized for AR antagonism. Thus, MPCs can stop the growth of prostate cancer cells that have adapted to treatment by developing drug resistance and have the potential to lead to the development of novel and effective therapies for patients with advanced prostate cancer.