Research Projects

FAT1 protein consists an extracellular domain (ECD), a transmembrane and intracellular domain. FAT1 plays roles in cell polarity, migration, and wound healing. FAT1, drives oncogenic signaling through interactions with various pathways, a key factor in the pathogenesis of glioma, pancreatic, hepatocellular, colorectal, breast cancer, and leukemia.We have reported FAT1oncogenic role in gliomas, by promoting tumor cell migration, invasion, and inflammatory microenvironment through activation of AP1 and PDCD4 downregulation. FAT1 enhances HIF1α expression under hypoxia, critical in glioblastoma microenvironment, and plays a crucial role in driving EMT and stemness properties of glioblastoma cells. FAT1 is a target of NFkB and contributes to immunesuppression via TGF-β signaling.These findings position FAT1 as a multifaceted oncogene and potential therapeutic target.Although FAT1 oncogenic role is well-established, direct therapeutic targeting remains underexplored. Monoclonal antibody against FAT1-extracellular domain has shown antitumor effects in colorectal cancer, but no significant progress has been made in developing small-molecule inhibitors or antibodies for FAT1 in cancer. Previous studies, including our own, have used FAT1-specific siRNA/shRNA to inhibit FAT1 and its tumorigenic effects, demonstrating the therapeutic potential of FAT1 inhibition. However, limitations in siRNA-based therapies necessitate the development of small-molecule inhibitors to target FAT1-ECD.Small-molecule inhibitors, either alone or in combination with monoclonal antibodies, have significantly advanced cancer treatment. Many are in clinical use or under clinical trials, and the repurposing of FDA-approved drugs offers a cost-effective way to identify potential inhibitors. FDA-approved drugs have well-established safety profiles, facilitating smoother clinical translation. In this study, we aim to screen an FDA-approved drug library(ZINC database) for small-molecules that specifically target FAT1-ECD, inhibiting its signaling and effects on tumor growth, invasion, and migration in glioblastoma. Glioblastoma has poor prognosis, with high recurrence despite surgery/chemo-radiotherapy/immunotherapy. Hypoxia promotes EMT and stemness in glioblastoma. Our study aims to identify small-molecule inhibitors which bind to FAT1-ECD and block its oncogenic signaling. After confirming their efficacy in vitro, we will assess their synergistic effects with temozolomide, a standard chemotherapy, and evaluate their potential as adjunct therapies. We will also test their effects on tumor growth and clinical outcomes in nude mouse xenograft models. The findings could extend to other cancers where FAT1 functions as an oncogene, such as hepatocellular carcinoma and pancreatic adenocarcinoma. This approach may identify novel therapeutic agents capable of targeting FAT1-driven oncogenic pathways, which could be used in combination with conventional therapies, improving treatment outcomes