Eugenie S. Kleinerman
Division of Pediatrics,
The University of Texas
MD Anderson Cancer Center,
Dr. Kleinerman obtained her medical degree in at Duke University in 1975. She served as Chair and Division Head of UTMD Anderson for 14 years. She pioneered aerosol administration targeting sarcoma lung metastases. She identified a new immunotherapy for osteosarcoma and led clinical trials resulting in the drug?s approval by the EMA in 2009. She showed that the FAS/FasL pathway plays a critical role in osteosarcoma metastasis, that Fas expression is controlled by the mi-R-17-92 cluster, and is the first to show that EWS-FLI-1 and Notch control vasculogenesis in Ewing?s sarcoma. She has published over 195 articles
The biology and mechanisms involved in the metastasis of osteosarcoma (OS) to the lung and to the pathways that control the vascular development in Ewing?s sarcoma (ES). The goal is to develop new therapeutic approaches for the treatment of patients with OS and ES. I have a long publication record in both OS and ES research, in defining the molecular pathways that control tumor vascular expansion, and in the biologic characteristics that influence the metastatic potential of sarcoma cells to the lung. I developed a unique transplant model to identify how BM cells contribute to the vascular expansion in ES and that vasculogenesis in addition to angiogenesis was critical to the expansion of the Ewing?s tumor vasculature. I showed that EWS-FLI-1 transcriptionally down-regulated Caper-? which mediates alternative splicing of VEGF, resulting in increased production of the soluble form VEGF which is critical to the vasculogenesis process. I also showed that the Notch signaling pathway, in specific DLL4, and the SDF-1a/PDGF-B pathway, controlled the differentiation of BM cells into tumor vascular pericytes. My latest studies showed that EWS-FLI-1 upregulated REST and that in ES, REST controlled the formation of the tumor vascular pericyte layer. Down-regulating REST in 2 different Ewing?s sarcoma xenograft models resulted in the formation of non-functional vessels that lacked pericytes. I developed a nude mouse model of human OS lung metastases and demonstrated that Fas expression inversely correlates with the metastatic potential of OS cells and that the upregulation of Fas expression results in tumor regression. I have demonstrated the efficacy of aerosol gene and aerosol chemotherapy against OS lung metastases which led to the initiation of several clinical protocols in pediatrics. I pioneered the use of immunotherapy in children with OS lung metastases, demonstrating that liposomal MTP-PE activated the tumoricidal properties of macrophages and prolonged the disease free survival in relapsed patients. I led the phase II trials which demonstrated that MTP activated the patient?s immune response significantly increasing both the disease-free and overall survival of patients with relapsed osteosarcoma of the lung. Success of the phase II trials led to a national phase III trial, which demonstrated that liposomal MTP-PE plus chemotherapy treatment significantly prolonged the survival of newly diagnosed patients with OS and decreased the death rate by 30% at 8 years. This drug has now been approved by the European Medicine Agency. Thus I have a successful track record of translating preclinical laboratory investigations into clinical trials. This successful track record demonstrates my expertise, experience and productivity in clinical and translational research. Additionally, I along with Drs. Chandra and Schadler, were recently awarded a Multidisciplinary Research Grant from the institution on Energy Balance in Pediatric Oncology. I possess the expertise in sarcoma and pediatric oncology clinical trial design necessary to translate our energy balance interventions into practice.