Lee J. Helman, M.D.


Portait Photo of Lee Helman
Pediatric Oncology Branch
Head, Molecular Oncology Section
Senior Investigator
National Cancer Institute
Building 31, Room 3A11
31 Center Drive MSC 2440
Bethesda, MD 20892-2440


Dr. Helman received his M.D. from the University of Maryland School of Medicine in 1980 magna cum laude, and was elected to Alpha Omega Alpha. He completed his internship and residency in Internal Medicine at Barnes Hospital Washington University, serving as the Chief Resident, Washington University VA Medical Service in 1983. He began his Fellowship training at the National Cancer Institute (NCI) in 1983, where he has remained. He became the head of the Molecular Oncology Section of the Pediatric Oncology Branch, NCI, in 1993, and Chief of the Pediatric Oncology Branch, NCI, in 1997. He was also named a Deputy Director of the Center for Cancer, National Cancer Institute, in 2001. He was named Acting Scientific Director for Clinical Research, Center for Cancer Research, National Cancer Institute, in 2005, and named as the permanent Scientific Director in 2007.

Dr. Helman's laboratory currently focuses on three major themes related to the biology and treatment of pediatric sarcomas: (1) the role of insulin-like growth factors on the biology of these tumors; (2) identification of the molecular mechanisms of metastases using animal models of spontaneously metastatic tumors; and(3) translation of these findings into treatments to improve the outcome of patients with pediatric sarcomas.


Our laboratory research focuses on three major themes related to the biology and treatment of pediatric sarcomas. The first area is the pathophysiological consequences of insulin-like growth factor (IGF) signaling in Ewing's sarcoma (ES), rhabdomyosarcoma (RMS) and osteogenic sarcoma (OS). We are currently investigating mTOR signaling, which we previously have shown to be at least in part responsible for IGF-II-mediated resistance to apoptosis, and which we now have linked to the metastasis signaling protein, ezrin. We have been studying the feedback activation of Akt upon mTOR inhibition, which is linked to IGF-I Receptor (IGF-IR) signaling. The relevance of the mTOR signaling pathway was demonstrated in our retrospective analysis of Stage III RMS patients in which we performed global proteomic analysis of primary tumors at presentation in samples obtained from the Children's Oncology Group. We determined that activation of mTOR signaling at diagnosis portended a significant poorer prognosis. Blocking these pathways in patients is a potential therapeutic strategy and for this reason, we have been testing the potential of combining mTOR inhibition with both standard cytotoxic agents as well as IGF-IR inhibitors in RMS cell lines and xenograft models.

Our second major focus is the identification of molecular mechanisms of metastasis using OS as a model system. We previously identified the cytoskeletal linker protein ezrin as a major component of metastatic behavior in a mouse model of OS. More recent collaborative studies have identified ezrin as a major contributor to metastatic behavior in a mouse genetic model of RMS, further demonstrating the importance of ezrin in multiple mouse models of metastasis. Our work has suggested a link between ezrin activity and mTOR signaling, which has created an obvious link between our studies of IGF signaling and our studies of metastasis. We also recently linked ezrin to beta4 integrin and are actively studying this relationship.

Our third major focus is on the translation of these findings into treatments to improve the outcome of patients with ES, RMS and OS. We continue to work on immunotherapy, and second-generation vaccine studies are planned. In addition, our finding of the importance of mTOR in the aggressive behavior of sarcomas contributed to the use of rapamycin in the early post-engraftment period in our allogeneic transplant studies in patients with sarcomas. We are interested in both the immunosuppressive and anti-tumor effects of rapamycin. Our laboratory interest in the role of IGF-I in sarcomas has led to collaborations with several pharmaceutical companies that have developed humanized monoclonal antibodies directed against the IGF-I receptor. In this connection, we are working to develop early therapeutic trials of these monoclonal antibodies in pediatric sarcomas, which because of their relative rarity, are not major commercial targets. As above, we aim to move quickly to test the effects of IGFIR blockade with mTOR inhibition in recurrent disease. We hope to test novel therapeutic approaches to the treatment of pulmonary metastases in patients with OS where activated pathways identified in our preclinical metastatic models can be targeted using innovative study designs. Finally, we hope to employ intensive genetic and proteomic analyses of tumor samples from as many patients as possible to better sub classify tumors in ways that support the use of individualized, targeted therapy.

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