Cancer is a major health problem worldwide and new therapies are critically needed, especially for glioblastoma, the most fatal brain tumor. Unpublished studies in our lab have revealed a new bystander effect for tumor suppressor p53. Upon activation by chemo- or radiation therapies p53 induces the death of adjacent tumor cells, while sparing normal cells. We discovered that the effecter mechanism relies upon the secretion of galectin-3, a galactose-recognizing lectin, which induces apoptosis. We also found that secreted galectin-3 reduced tumor formation in vivo. In this study we are extending these initial findings by dissecting the underlying mechanisms and determine whether Gal3 has clinical potential. We determine the type of apoptotic signaling pathways activated in tumor cells by extracellular galectin-3 (Aim 1), whether secreted galectin-3 selectively binds to a specific cell surface receptor, with tumor-specific characteristics (Aim 2), and whether Gal-3 delivery can be used as a viable therapeutic for cancer using an in vivo mouse glioma model (Aim 3).
Our working hypothesis is that p53 exerts a tumor suppressive bystander effect by stimulating exosomal secretion of Gal3, which in turn binds in a tumor-selective fashion to 1-integrin complexes due to unique N-glycanation in cancer, and induces a therapeutic effect by activating apoptosis. These studies are important because we identified a new p53-induced tumor suppressive mechanism mediated by soluble Gal3, which has therapeutic implications. Examining the role of extracellular Gal3 in glioma apoptosis and tumor growth in vivo is novel. These studies will provide proof-of-principle data for targeting cancer with Gal3 (or agonists such as peptidomimetics or small molecules). Successful outcome of this project will support the clinical translation of Gal3 for the treatment of malignant glioma and possibly other cancers.
There is an urgent need to develop novel therapies for patients with highly malignant uveal melanomas in the eye. Patients with uveal melanoma die within one-two years of diagnosis despite current conventional therapies, including eye enucleation, brachotherapy and chemotherapy. Hypoxia drives tumor progression by activating angiogenesis, cell motility and metastasis, as well as metabolic adaptation to growth under a hypoxic environment, and is a major factor in the resistance of cancer cells to radio- and chemotherapies. Hypoxia activates transcription factors of the Hypoxia-Inducible Factor (HIF) family that induce the expression of genes that encode pro-angiogenic factors and glycolytic enzymes essential for tumor growth and favor tumor invasion.
Based on these findings, we formulated the central hypothesis that development of hypoxia and activation of the HIF pathway play a critical role in ocular cancer growth and spread, and that therapeutic targeting of this pathway using small molecule inhibitors will inhibit ocular tumor growth and metastasis. We have generated substantial preliminary data validating this concept. We show that our lead probe (KCN1) is a potent inhibitor of the in vivo growth of uveal melanoma in the eye (70% tumor size reduction) and its metastasis to the liver (50% reduction in number of metastases), while being extremely well tolerated. The overall goals of this study are to refine the structur of the novel HIF pathway inhibitor (HPI) chemical probes we developed, optimize their potency and pharmacological properties, leading to the identification of one-two clinical lead probes that will be ready to undergo IND-directed pharmacology and toxicology towards phase one clinical testing in patients with malignant uveal melanoma through the NCI NExT program.
Our multi-disciplinary team has expertise in major aspects of chemical probe development and will divide the project tasks into the following aims:
- Aim 1: screening analogs of the parent compound in primary and secondary assays to identify and confirm chemical probes with improved potency and solubility
- Aim 2: screening analogs of the optimized probes for improved pharmacology and formulation development
- Aim 3: determine the anti-tumor efficacy of the optimized lead probe(s) in orthotopic uveal melanoma models in mice
There is an urgent need to develop novel therapies for patients with medulloblastoma (MB), the most common malignant central nervous system (CNS) tumor in children. Current treatments include surgery, radiotherapy, and chemotherapy and result in 5-year survival rates of 40-90% depending on subtype. Moreover, children suffer important morbidity secondary to treatment, including neurological, intellectual and physical disabilities. The overall purpose of the present project is to investigate the role of the Brain-specific Angiogenesis Inhibitor 1 (BAI1) in cerebellar development and susceptibility to transformation, and explore new therapies for MB based on the related mechanisms. BAI1 is an orphan seven transmembrane G protein-coupled receptor (GPCR) specifically expressed in the brain, and belonging to the adhesion-type sub-family. Our new preliminary data show that BAI1 expression is significantly reduced in patients with MBs, and the promoter is epigenetically silenced, suggesting that BAI1 loss may facilitate MB formation. To test this in the physiological setting, we generated Bai1 knockout (KO) mice and found haploinsufficiency of Bai1 dramatically accelerates MB tumorigenesis in Ptch1+/- transgenic mouse models of MB, the first demonstration that a reduction in Bai1 dosage can promote MB formation in vivo. Interestingly, we detected enhanced Gli1/2 expression and a thicker external granule layer (EGL) during early postnatal cerebellum development in the Bai1 KO mice. Therefore, our preliminary studies link BAI1 with cerebellar development and neoplastic transformation. Based on these results, we hypothesize that BAI1 is a tumor suppressor in the cerebellum and that restoration of its expression with epigenetic therapy may represent a novel therapeutic intervention for MB. To test our hypothesis, we propose the following aims: (i) determine whether Bai1 loss accelerates MB formation in mice through abnormal activation of a growth-signaling pathway in the developing cerebellum, (ii) determine how BAI1 restoration in human MB cells can inhibit their growth, and alter their tumorigenic properties, and (iii) define the mechanisms of BAI1 inactivation in MB, and determine whether epigenetic reactivation of BAI1 expression has therapeutic effects in vivo. These studies are important as they increase our knowledge about developmental neurobiology in the CNS, and may lead to the development of novel therapeutic approaches for patients with medulloblastoma.
Public Health Relevance Statement
We want to study the tumor suppressor function of the Brain-specific Angiogenesis Inhibitor (BAI1) in brain development. We found that loss of Bai1 expression in mice is associated with abnormal development in the cerebellum and medulloblastoma formation, a highly malignant brain tumor in children. The knowledge derived from these studies may lead to the development of novel therapeutics for brain cancer through the restoration of the BAI1 tumor suppressor pathway function.