Grants and Contracts per year
Grants and Contracts Details
Advanced prostate tumors that often metastasize to the lung, bone, and other vital tissues, are resistant to conventional therapy. Prostate apoptosis response-4 (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells. Although baseline levels of Par-4 secreted by cells are inadequate to induce apoptosis, normal cells can be induced to produce robust secretion of Par-4 protein that targets cancer cells in a paracrine manner. Accordingly, secreted Par-4 is systemically available in vivo and binds to its cell surface receptor GRP78 in cancer cells to trigger apoptosis in primary and metastatic tumors. Importantly, secreted Par-4 induces cancer-specific apoptosis, but it does not induce apoptosis in normal cells as GRP78 is expressed only on the surface of cancer cells, not on normal cells. “Small-molecule” drugs that efficiently and selectively induce Par-4 secretion without killing the normal cells would, therefore, represent an important therapeutic advance. In preliminary studies, we synthesized and screened newly developed 3-arylquinolines as well as related quinolones and quinothiolones for the secretion of Par-4 protein from normal mouse and human fibroblast and epithelial cells. This screening led to the identification of 2-amino-7-(N,N-dimethylamino)-3-(2’-fluorophenyl)quinoline (called “Arylquin-1”) as a member of a new class of agents that trigger robust secretion of Par-4 from normal cells at nanomolar, non-toxic concentrations. As expected, Par-4 secreted from these normal cells induced paracrine apoptosis in diverse prostate and lung cancer cell cultures, but not in normal cell cultures. Using a biotinylated, biologically active version of Arylquin-1, we identified vimentin, a protein linked to motility, invasion, EMT and metastasis, as the molecular target of Arylquin-1 that in turn produces Par-4 secretion. In this study, we will determine the effect of Arylquin-1 on Par-4 secretion from normal cells and apoptosis in prostate cancer cell culture and in vivo, on tumor growth in prostate cancer models. Computational dynamics revealed that Arylquin-1 forms a stable interaction with a hydrophobic pocket on vimentin. We will, therefore, determine the domains of Par-4 and vimentin that bind to each other to elucidate the mechanism underlying inhibition of Par-4 secretion by vimentin and its release by Arylquin-1. Consistent with the interaction of Arylquin-1 with vimentin, our preliminary studies also indicated that Arylquin-1 inhibits motility and invasion in prostate cancer cells by an apoptosis-independent mechanism. We will, therefore, study whether Arylquin-1 inhibits motility, invasion and EMT in cell culture and metastasis in mouse models of prostate cancer via vimentin-dependent mechanisms. Developing agents that selectively promote Par-4 secretion from normal cells, induce apoptosis in cancer cells and halt metastatic processes in prostate cancer would be of extraordinary academic and therapeutic value.
|Effective start/end date||7/1/15 → 6/30/21|
- National Cancer Institute: $1,711,016.00
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