The long term goal of this proposal is to identify possible new therapeutic targets for Ewing Sarcoma. Once a patient develops metastasis to distant sites, his/her 5-year survival drops to 30%. Moreover, of the 70% of patients treated with initially localized disease, 30% will relapse at metastatic sites within a few years of initial remission. As Ewing Sarcoma is such an aggressive disease with strong propensity for early spread, new therapies that could potentially prevent tumor spread are in particular need. Our laboratory has identified an epigenetic modifier, KDM3A, as a positive regulator of Ewing Sarcoma migration and in vivo metastasis. Further analysis has shown that KDM3A holds regulatory power over a number of genes which promote metastasis, including Melanoma Cell Adhesion Molecule (MCAM). MCAM is overexpressed in several other types of cancers, and we have shown it to promote tumor cell migration. Importantly, MCAM has recently been identified as overexpressed in many different kinds of pediatric tumors, including Ewing Sarcoma. Our own preliminary data in conjunction with published work from other models lead to our hypothesis that KDM3A promotes Ewing sarcoma growth and dissemination through upregulation of MCAM. The following specific aims will test this hypothesis.
Specific aim 1. Determine the role and mechanism of MCAM in KDM3A- induced metastatic phenotypes in Ewing Sarcoma in vitro.
Specific aim 2. Determine the relative effects of KDM3A, MCAM and FAK inhibition on Ewing sarcoma metastasis in vivo. Understanding how KDM3A and its downstream target MCAM function to promote metastasis, may help us identify new therapeutic approaches for Ewing Sarcoma.
Ewing Sarcoma is the 2nd most common sarcoma (cancer of bone and soft tissues) in children. While people with early stage disease can benefit from chemotherapy, they often relapse later in life, and those with cancer that has already spread to distant sites only have a 5-year survival of 30%. We have identified cellular factor KDM3A as a regulator of tumor metastasis genes. It is our hope to develop KDM3A, and one of its downstream targets, MCAM, as possible therapeutic targets for the inhibition of metastatic spread of Ewing Sarcoma.
| Parrish, Janet K; McCann, Tyler S; Sechler, Marybeth et al. (2018) The Jumonji-domain histone demethylase inhibitor JIB-04 deregulates oncogenic programs and increases DNA damage in Ewing Sarcoma, resulting in impaired cell proliferation and survival, and reduced tumor growth. Oncotarget 9:33110-33123 |
| Sechler, M; Parrish, J K; Birks, D K et al. (2017) The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis. Oncogene 36:4150-4160 |
