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Lee J. Helman, M.D.

Portait Photo of Lee Helman
Pediatric Oncology Branch
Head, Molecular Oncology Section
Senior Investigator
Center for Cancer Research
National Cancer Institute
Building 31, Room 3A11
Bethesda, MD 20892-2440
Phone:  
301-496-4257
Fax:  
301-496-0775
E-Mail:  
helmanl@nih.gov

Biography

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, NCI, in 2001. He served as Acting Scientific Director for Clinical Research, Center for Cancer Research, NCI, 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, specifically rhabdomyosarcoma, Ewing's sarcoma and osteosarcoma: (1) determine the pathophysiologic consequences of IGF signaling; (2) identify the molecular/biochemical determinants of the biology of these sarcomas; and (3) apply preclinical laboratory findings to develop novel clinical studies for these sarcomas.

Research

Our laboratory currently focuses on three major themes related to the biology and treatment of pediatric sarcomas, specifically rhabdomyosarcoma (RMS), Ewing's sarcoma (ES) and osteosarcoma (OS). The first area is to determine the pathophysiologic consequences of IGF signaling in RMS, ES, and OS. Over the past several years, we have played a major role in running a clinical study evaluating the effect of a human IGFIR MoAb in the treatment of RMS, ES, and OS, as well as other sarcomas, through the SARC (Sarcoma Alliance for Research through Collaboration) consortium. I have chaired the Scientific Committee for this international study. We completed enrollment of all cohorts in two years, including 130 patients with recurrent Ewing's sarcoma, where the most clinical activity has been observed, and data are currently being analyzed to identify biological predictors of clinical response. We also are involved in generating a follow-up clinical study that will combine this treatment with standard salvage chemotherapy for recurrent Ewing's sarcoma patients. In addition, we continue to perform preclinical studies to better understand the mechanism of action of this therapy and have found that IGFIR receptor density is quite variable and ranging from 40,000 receptors/cell to less than 3000 receptors/cell in RMS cell lines. Furthermore, cell lines with low receptor density do not respond to MoAb to the IGFIR suggesting a potential mechanism to enrich patients more likely to respond. We have demonstrated that in our xenograft models, initial tumor response to treatment with the IGFIR Ab is always followed by re-growth of tumor, and we currently are trying to identify the mechanisms responsible for this tumor re-growth.

Our second major focus is to identify the molecular/biochemical determinants of the biology of RMS, ES and OS. This project was previously focused on identification of factors leading to metastatic behavior in these tumors, but we have expanded our focus to include identification of novel molecular pathways involved in any aspect of the biology of these tumors. We recently have published our work characterizing beta-4 integrin as a determinant of metastatic behavior in mouse models of osteosarcoma, and are currently evaluating the potential role of c-met signaling in these tumors. Our most recent work has focused on the development of inducible shRNA screening to identify molecular pathways critical for growth of RMS cells. This screen has initially focused on genes that are commonly needed by both ERMS and ARMS and identified numerous potential candidate genes. We also plan to use this model to create a regulated Pax-3-Foxo1a shRNA that will allow us to further refine the identification of critical downstream targets of this fusion transcription. We are using the initial shRNA screen to identify targets that are uniquely required for growth by ARMS and not required for growth of ERMS. Our hope is to expand this approach once we have proven its success to similar screens in Ewing's sarcoma cell lines.

Our third major focus is to apply preclinical laboratory findings to develop novel clinical studies in RMS, ES and OS. In addition to the IGFIR Ab clinical study, we opened a study testing the potential of a specific Src kinase small molecular inhibitor to alter the time to second and subsequent pulmonary recurrences in patients with osteosarcoma who undergo pulmonary metastsectomy. This study is a double-blind placebo-controlled study that also is being conducted at multiple centers through a SARC collaboration. We have developed a new program in the lab to carry out high-throughput screening for compounds that inhibit the activity of the EWS-Fli-1 fusion protein, since this fusion protein has been demonstrated repeatedly to be necessary for survival of Ewing's sarcoma cells. In collaboration with the MTP program at NCI-Frederick, MD, we have screened a natural products library using an EWS-Fli-1 target reporter luciferase vector for initial screening, followed by validation using a 15-gene EWS-Fli-1 multiplex PCR. We have identified several compounds that appear to specifically inhibit the transcriptional activity of the EWS-Fli-1 fusion using this approach and are beginning to conduct in vitro studies to validate the specificity of toxicity of these compounds. The first compound has now shown excellent in vivo activity and we are hoping to work with the NCI Experimental Therapeutics group to get support for producing GMP compound for preclinical and clinical studies. We tested the compound, ET-743, or Trabectadin, using this approach since Trabectadin was recently found to bind in the DNA minor groove at 5'CGG 3' and Ets binding sites are known to contain 5'GGAA 3'. Since the next most conserved base 5' to this site is a C, we hypothesized that this would create a 5'CGG aa 3' site that contains the CGG motif and thus might be regulated by Trabectadin. We were able to demonstrate that a significant subset of the downstream targets of EWS-Fli-1 are indeed down-regulated by Trabectadin treatment and also demonstrated that EWS-Fli-1 containing tumor cells appears to be specifically sensitive to this drug, suggesting a potential novel mechanism.

This page was last updated on 3/12/2014.