Our Science – Helman Website
Lee J. Helman, M.D.
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.
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) and pediatric GIST. 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 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’s 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 Ab 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.
A second active area of laboratory research has been focused on identifying new therapeutic targets in pediatric sarcomas. We have utilized large scale siRNA screening to 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 study 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 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 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, that 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 DCTD and generated clinical grade mithramycin and opened a Phase I/II study in Ewing’s 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’s 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’s sarcoma. Our group recently entered the first patient on this study.
Finally, we have established collaborative study group to better understand pediatric GIST tumors, that virtually never harbor KIT or PDGFRA mutations that characterize adult GIST tumors leading to 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 tumor 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 now also characterized the clinical course of these SDH deficient tumors and have developed guidelines for treatment of these patients that had not previously existed. We have 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.
This page was last updated on 6/22/2014.