Dr. Helman's laboratory currently focuses on three major themes related to the biology and treatment of pediatric sarcomas, specifically rhabdomyosarcoma, Ewing's sarcoma osteosarcoma, and pediatric gastrointestinal stromal tumors (GIST): (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.
Phase 1 Study of a Combination of the PARP inhibitor, Niraparib and Temozolomide in Patients with Previously Treated, incurable Ewingamp;#39s SarcomaReferral Contacts
Contact Name Phone Number Melissa Amaya 301.451.9036
Molecular Oncology Section
The Molecular Oncology Section currently focuses on three major themes related to the biology and treatment of pediatric sarcomas, specifically rhabdomyosarcoma (RMS), Ewing's sarcoma (ES), osteosarcoma (OS) and pediatric gastrointestinal stromal tumor (GIST).
Determining the Pathophysiologic Consequences of IGF Signaling. The first area is to determine the pathophysiologic consequences of insulin-like growth factor (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 monoclonal antibody (moAb) in the treatment of RMS, ES, and OS, as well as other sarcomas, through the SARC (Sarcoma Alliance for Research through Collaboration) consortium. Dr. Helman 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. The overall response rate of this study in Ewing sarcoma was 13%. However, most responses were transient indicating rapid development of resistance. We have demonstrated that in our xenograft models, initial tumor response to treatment with the IGFIR moAb is always followed by re-growth of tumor, predicting what was seen in the clinic. Our current focus is to identify mechanisms of resistance and we have identified several mechanisms to date, that we hope will lead to combinations involving IGFIR inhibition with additional kinase inhibitors targeting pathways we have identified as activated in by-pass resistance pathways.
Identifying New Therapeutic Targets. A second active area of laboratory research has been focused on identifying new therapeutic targets in pediatric sarcomas. We used large-scale siRNA screening against several ES cell lines, and identified several signaling pathways that appear to be critical for ES growth. These hits have been confirmed and independently identified in a large-scale kinase inhibitor screen against human sarcoma cell lines by a collaborator. Based upon these screens, we are now working to identify the mechanism of action of these kinase inhibitors against ES xenografts and cell lines with the ultimate goal of testing these inhibitors in the clinic. We have also using shRNAi screening against RMS cells and previously reported that CRKL-YES is a critical signaling pathway in these cells. Since YES is a member of the SRC-Family Kinases (SFK), we have been targeting this pathway with currently available SFK inhibitors including dasatinib. Based on the studies above and other studies of SFK signaling in OS, 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 is a double-blind placebo-controlled study that also is being conducted at multiple centers through a SARC collaboration. The study is almost complete, and data will be analyzed this year for recurrence-free survival.
Our laboratory also recently carried out a high-throughput screen 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 Molecular Targets Laboratory at NCI's Frederick campus, 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 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. One compound validated in these studies was the drug mithramycin, which demonstrated activity against several human cancers in the early 1960s and was subsequently used for a number of years to treat malignant hypercalcemia. Since this drug has been given to thousands of patients over the years, we quickly collaborated with the NCI Division of Cancer Treatment and Diagnosis and generated clinical-grade mithramycin and opened a Phase I/II study in Ewing sarcoma that is currently ongoing. We also identified trabectedin, or ET-743, as an inhibitor of EWS-FLI-1 activity. This compound is commercially available in Europe to treat sarcomas, and we are working on developing a Phase II study to test the combination of this drug with irinotecan that showed marked synergy in our preclinical testing.
This work also led us to test PARP inhibitors in Ewing tumors, since other groups identified cells harboring EWS-FLI-1 fusion proteins as uniquely sensitive to these compounds. We conducted a series of studies both confirming these studies but also demonstrating that several PARP inhibitors were much more potent growth inhibitors of ES growth compared to others and that combination treatment with temozolomide was much more potent against human tumor xenografts. These observations contributed to a recently opened international study conducted by the SARC consortium testing the PARPi, niraparib in combination with temozolomide in recurrent Ewing sarcoma. Our group recently entered the first patient on this study.
Understanding Pediatric GIST. Finally, we have established a collaborative study group to better understand pediatric GIST tumors, which virtually never harbor the KIT or PDGFRA mutations that characterize adult GIST tumors leading to a response to imatinib and other TKIs targeting KIT and PDGFR. We have now established that the overwhelming majority of these GIST tumors are SDH deficient, with most patients harboring germline SDH A, B, C, or D (SDHx) mutations. However, about 25% of the SDH-deficient tumors have no identifiable SDH mutations and work is ongoing to identify the mechanism of loss of SDH protein in these tumors. We have also shown that all the SDH-deficient tumors are globally hypermethylated, presumably due to succinate excess that inhibits the TET2 demethylase. We have also now characterized the clinical course of these SDH-deficient tumors and have developed guidelines for treatment of these patients that had not previously existed. We also just opened a clinical trial testing vandetanib in patients with progressive tumors based upon its activity in SDH-deficient renal cancer cell lines and the lack of any SDH-deficient GIST models to date, despite numerous efforts to establish cell lines and PDX models.
Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors.Cell Growth Differ. 1: 325-31, 1990. [ Journal Article ]
- J Biol Chem. 270: 27983-6, 1995. [ Journal Article ]
- J Biol Chem. 272: 30822-7, 1997. [ Journal Article ]
R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study.J. Clin. Oncol. 29: 4541-7, 2011. [ Journal Article ]
Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.Cancer Discov. 3: 648-57, 2013. [ Journal Article ]
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 osteosarcoma, and pediatric GIST tumors: (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.
|Joshua Baumgart||Postbaccalaureate Fellow (IRTA/CRTA)|
|Sosipatros Boikos||Special Volunteer|
|Christine Heske M.D.||Clinical Fellow|
|Sameer Issaq Ph.D.||Postdoctoral Fellow (CRTA)|
|Michael Lizardo Ph.D.||Postdoctoral Fellow (Visiting)|
|Amy McCalla Ph.D.||Postdoctoral Fellow (CRTA)|
|Arnulfo Mendoza Ph.D.||Research Biologist|
|James Morrow||Special Volunteer|
|Xiaolin Wan M.D., Ph.D.||Research Biologist|
|Choh Yeung B.S.||Research Biologist|