Targeting galectin-3 for prostate cancer therapy

DESCRIPTION provided by applicant Galectin a beta galactoside binding lectin is involved in the progression of many cancers In our recent publication in PNAS PMC we have shown that in prostate cancer galectin promotes tumor angiogenesis tumor endothelial cell adhesion and metastasis and also evades immune surveillance through killing of infiltrating T cells To block galectin mediated interactions we purified a glycopeptide from cod designated TFD that binds galectin with picomolar affinity PMC TFD blocks galectin mediated angiogenesis tumor endothelial cells interactions and seeding of lungs by prostate cancer cells in mice Moreover apoptosis of activated T cells induced by either recombinant galectin or prostate cancer patient serum associated galectin was inhibited at nanomolar concentration of TFD Based on our compelling preliminary data we hypothesize that the gal is a master regulator of cancer cell interactions with its environment and propose that specific inhibition of galectin with TFD will suppress prostate tumor growth and progression by impeding tumor neo angiogenesis and tumor cell extravasation and by promoting anti tumor immune response To test this hypothesis we propose the following specific aims Determine TFD andapos s ability to block metastasis in a relevant mouse model of spontaneous aggressive metastatic prostate cancer and Ascertain TFD andapos s ability to augment anti tumor T cell responses in tumor bearing mice For Aim we will use a relevant mouse model of human prostate cancer Hoxb MYC Phenol lox BMPC transgenic mice that develop spontaneous aggressive metastatic prostate cancer Following drug treatment we will perform detailed quantitative histopathological analyses of the prostate For Aim we will orthotopically transplant TRAMP C cells galectin containing wild type or galectin knockout in C BL mice and measure T cell antitumor activity following treatment with TFD Particularly we will determine changes in tumor infiltrating T cells a surrogate for survival and cell fate after TFD administration in vivo We will also analyze markers of T cell exhaustion including CTLA PD Lag Tim on T cells in TFD treated and untreated mice We will also establish how if TFD impacts different CD T cell subsets This study for the first time will explore the therapeutic utility of a natural carbohydrate compound to enhance anti tumor immune response and to suppress tumor growth PUBLIC HEALTH RELEVANCE Galectin is involved in prostate cancer progression and metastasis by promoting angiogenesis tumor cell adhesion and immune suppression The objective of this project is to use a galectin antagonist to prevent metastasis and elicit anti tumor immune response