Osteosarcoma: A multi-institutional study to evaluate an Astra-Zeneca src-kinase inhibitor in pulmonary metastatic osteosarcoma has continued to enroll patients and is being carried out through the SARC consortium. The study is based on preclinical testing in our osteosarcoma models and demonstrated that the drug inhibits targets of src and also showed that human osteosarcoma tumors express high levels of activated src. The study is a randomized double blind placebo controlled study. Patients who present with pulmonary metastases will receive either complete resection of pulmonary nodules plus treatment with the kinase inhibitor (orally daily) vs. placebo to determine whether DFS can be prolonged with treatment of the src kinase inhibitor. The study is double blind so we do not know at this time whether they received drug or placebo. The study is nearing its interim analysis point and we anxiously await the results. We also completed accrual to the osteosarcoma cohort in a SARC Phase II study using a human monoclonal antibody to the IGFIR in recurrent osteosarcoma. Thirty-five patients from around the U.S. were entered and a manuscript is currently being prepared to describe this cohort of patients. Ewings Sarcoma: A combination of sequential gemcitabine/docetaxel based on preliminary in vitro synergy and previous activity of the single agents was also tested through the SARC consortium. Like the osteosarcoma cohort this cohort was terminated and no significant activity was observed. We recently published these negative results. We recently completed an international study using a human monoclonal antibody directed against the IGFI receptor in Ewings rhabdomyosarcoma osteosarcoma synovial sarcoma and several other rare adult type sarcomas through the SARC clinical trials consortium. I serve as the chairman of the study committee and played a major role writing the protocol. The study opened in December 2007 and now has completed accrual in all cohorts including rhabdomyosarcoma, osteosarcoma and Ewings sarcoma. Clear objective responses have been seen in both the Ewings cohort and the rhabdomyosarcoma cohort. We amended the study to treat patients under the age of 18 on a q 3 week schedule at 27 mg/kg and the study was shut down after just 6 patients were entered due to a phase out of the drug by Roche. The overall outcome has demonstrated clear activity in Ewings sarcoma, with a relatively low objective response rate of 16.5% but several durable CRs have been observed in this refractory population of patients. The data on the Ewings sarcoma cohort was published this year. Analysis of samples to attempt to develop predictive biomarkers that might allow an enrichment strategy or at least predict success or failure at an earlier time point has almost been completed. Expression profiling suggests there is a signature in Ewings sarcomas that might provide this information and a manuscript describing this is currently in preparation. Finally, we have recently established an international consortium to study PARP inhibitors in Ewings sarcoma based on published work of others and our unpublished data suggesting that Ewings tumors may be particularly sensitivie to PARP inhibition. We are currently developing clinical studies in collaboration with several small companies who will provide support for these planned international studies. Pediatric Gastrointestinal Stromal Tumors (GIST): We have continued our program to study pediatric GIST patients, a very rare disease that is biologically distinct from adult GIST patients. Our clinics at NIH bring in patients from across the country as well as physicians with interest/expertise in this rare disease from several centers across the country including surgeons, pediatric and medical oncologists as well as pediatric endocrinologists. Following up on our initial observation of germline mutations in SDH genes in sporadic pediatric GIST patients, we have now shown that the majority of tumors studied to date harbor mutations in one of the SDH A B C or D genes and it appears that at least 50% of these patients harbor germline mutations in these genes. We have also now shown that these SDH mutant GIST tumors also have global hypermethylation in the tumor genome. Based on responses of SDH mutant kidney cancers to VEGFR inhibitors such as vandetanib we are currently developing a clinical study to test this drug in SDH mutant GIST tumors as well. We have written a pilot protocol through the SARC consortium to test the IGFIR Ab in refractory patients since others have already published that these pediatric GIST tumors express high levels of IGFI.

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Kalish, Jennifer M; Doros, Leslie; Helman, Lee J et al. (2017) Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res 23:e115-e122
Grohar, Patrick J; Glod, John; Peer, Cody J et al. (2017) A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript. Cancer Chemother Pharmacol :
Venkatramani, Rajkumar; Murray, Jeffrey; Helman, Lee et al. (2016) Risk-Based Therapy for Localized Osteosarcoma. Pediatr Blood Cancer 63:412-7
Khan, Javed; Helman, Lee J (2016) Precision Therapy for Pediatric Cancers. JAMA Oncol :
Boikos, Sosipatros A; Pappo, Alberto S; Killian, J Keith et al. (2016) Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2:922-8
Osgood, Christy L; Maloney, Nichole; Kidd, Christopher G et al. (2016) Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor. Clin Cancer Res 22:4105-18
Pappo, Alberto S; Furman, Wayne L; Schultz, Kris A et al. (2015) Rare Tumors in Children: Progress Through Collaboration. J Clin Oncol 33:3047-54
Boikos, Sosipatros A; Xekouki, Paraskevi; Fumagalli, Elena et al. (2015) Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet :
Wan, Xiaolin; Yeung, Choh; Heske, Christine et al. (2015) IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma. Neoplasia 17:358-66
Arnaldez, Fernanda I; Helman, Lee J (2014) New strategies in ewing sarcoma: lost in translation? Clin Cancer Res 20:3050-6

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