Galectin-3, a beta-galactoside-binding lectin, is involved in the progression of many cancers. In our recent publication in PNAS (PMC3612646), we have shown that in prostate cancer galectin-3 promotes tumor angiogenesis, tumor-endothelial cell adhesion, and metastasis; and also evades immune surveillance through killing of infiltrating T cells. To block galectin-3-mediated interactions, we purified a glycopeptide from cod (designated TFD100) that binds galectin-3 with picomolar affinity (PMC3612646). TFD100 blocks galectin-3- 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-3 or prostate cancer patient serum-associated galectin-3 was inhibited at nanomolar concentration of TFD100. Based on our compelling preliminary data we hypothesize that the gal3 is a master regulator of cancer cell interactions with its environment and propose that specific inhibition of galectin-3 with TFD100 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: 1) Determine TFD100's ability to block metastasis in a relevant mouse model of spontaneous aggressive, metastatic prostate cancer; and 2) Ascertain TFD100's ability to augment anti- tumor T cell responses in tumor-bearing mice.
For Aim 1, we will use a relevant mouse model of human prostate cancer, Hoxb13/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 2, we will orthotopically transplant TRAMP-C2 cells (galectin-3-containing wild type or galectin-3 knockout) in C57BL/6 mice and measure T cell antitumor activity following treatment with TFD100. Particularly, we will determine changes in tumor infiltrating T cells (a surrogate for survival) and cell fate after TFD100 administration in vivo. We will also analyze markers of T cell exhaustion including CTLA- 4, PD-1, Lag3, Tim-3 on T cells in TFD100-treated and untreated mice. We will also establish how/if TFD100 impacts different CD4 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.
Galectin-3 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-3 antagonist to prevent metastasis and elicit anti-tumor immune response.
|AlSadek, Dina M M; Badr, Haitham A; Al-Shafie, Tamer A et al. (2017) Cancer cell death induced by nanomagnetolectin. Eur J Cell Biol 96:600-611|
|Badr, Haitham A; AlSadek, Dina M M; El-Houseini, Motawa E et al. (2017) Harnessing cancer cell metabolism for theranostic applications using metabolic glycoengineering of sialic acid in breast cancer as a pioneering example. Biomaterials 116:158-173|