As part of the Lombardi Comprehensive Cancer Center's Pediatric Research Program at Georgetown University, we focus our research on childhood cancers. Our primary goal is to develop small molecules that will become the next generation of medicines for Ewing Sarcoma and Osteosarcoma. As we develop small molecules targeting fusion protein products of tumor specific chromosomal translocations, we expand our research program to Rhabdomyosarcoma, Synovial sarcoma and prostate cancer.
Development of a first-in-class small molecule inhibitor for ETS transcription factors in prostate cancer.
Our lab focuses on developing small molecule inhibitors for undruggable target proteins in different cancers. Our generic approach has been to screen small molecules that can directly bind to target proteins in surface plasmon resonance instruments (Biacore). Compounds that can directly bind to target proteins then evaluated in functional assays to eliminate nonspecific binders and binders with no functional significance. This approached provided us YK-4-279 in a Ewing Sarcoma project. We demonstrated that YK-4-279 can directly bind to ERG and ETV1 proteins in prostate cancer cells. We established that YK-4-279 effectively inhibits ERG and ETV1 functions in prostate cancer cells both in vitro and in vivo.
Development of first-in-class small molecule inhibitors of ezrin to prevent metastasis in osteosarcoma.
Our lab studies the molecular mechanism of tumor metastasis in osteosarcoma (OS). Most tumors are found in extremities, which can be effectively treated by surgical resection or amputation if necessary. All OS patients die because of pulmonary failure due to tumor metastasis. Ezrin is a key regulator of metastasis in OS and other tumors. We discovered two lead compounds that can directly bind to ezrin protein and prevent metastatic phenotype. These compounds inhibited protein-protein interactions involving ezrin and blocked OS metastasis to lungs in mouse models.
Identification of a key signaling pathway in Ewing Sarcoma and discovery of a novel therapeutic approach.
Our laboratory investigates signal transduction pathways in pediatric sarcomas. We established the role of Wnt/beta-catenin and Hedgehog/GLI pathways in Ewing Sarcoma pathogenesis. We discovered that GLI expression was directly regulated by the Ewing Sarcoma specific EWS-FLI1 oncoprotein. We demonstrated that an FDA approved agent, arsenic trioxide (ATO), can directly bind to GLI1 transcription factor and inhibit its function. ATO inhibited growth of Ewing Sarcoma and medulloblastoma growth in mouse models. Many of the current agents in clinical trials targeting Hedgehog pathway are acting on the plasma membrane by inhibiting the receptor (smoothened). In medulloblastomas and basal cell carcinomas, patients are developing resistance to these agents by mutation in smoothened protein. Our discovery of ATO’s effect on GLI1 provides and alternative downstream mechanism that can be used even in patients with mutant smoothened.
Development of targeted therapies for Ewing Sarcoma.
Ewing Sarcoma contains a tumor specific chromosomal translocation that is present in 95% of cases. The protein product of this fusion gene, EWS-FLI1, is required for cancer cell survival. Since EWS-FLI1 chimeric protein is absent in any of the normal cells, it represents the perfect molecular target. We were able to purify high quality EWS-FLI1 recombinant protein. This accomplishment led to discovery of novel EWS-FLI1 binding protein partners and screening studies, where identified small molecules that can directly bind to EWS-FLI1. YK-4-279 was developed as the EWS-FLI1 specific small molecule inhibitor. All preclinical work is completed and an IND application has been approved. Phase I clinical trials in children with Ewing sarcoma has begun in 2016.
Development of a novel mouse model for HPV-induced cervical cancer.
All cervical cancer patients carry Human Papilloma Virus DNA in their genome. The role of the virus in initiating the neoplasm was clearly established. However, HPV infections are very common with millions of women being infected every year. Even though every cervical cancer had HPV, every patient with HPV infection did not develop cervical cancer. It was not known who among HPV infected population would develop cervical cancer. We discovered that activation of Wnt/beta-catenin pathway in HPV positive cervical epithelium was enough to cause malignant transformation. We demonstrated this finding in cell culture and developed a transgenic mouse model to confirm our hypothesis.
We would also like to thank those who have supported us in the past: Department of Defense (DOD) National Institutes of Health (NIH) National Cancer Institute (NCI) Translational Science Awards Program (CTSA) Georgetown-Howard Universities Center for Clinical and Translational Science National Center for Advancing Translational Sciences (NCATS) Dani’s Foundation Wendy Will Case Cancer Fund Sarcoma Foundation of America The Brandon Carrington Lee Foundation Alex’s Lemonade Stand Foundation Alan B. Slifka Foundation