Osteosarcoma: A multi-institutional study to evaluate an Astra-Zeneca src-kinase inhibitor in pulmonary metastatic osteosarcoma has now enrolled 13 patients to date, 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. Two patients entered at the NCI have completed 1 year of treatment and are now on observation, continuing in CR more than 1 year after last recurrence. The study is double blind so we do not know at this time whether they received drug or placebo. 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 data are currently being prepared to submit a manusript. 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. A manuscript has been submitted to report this negative study. 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 data has now been analyzed and a manuscript on the Ewing's cohort has been accepted for publication. 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. We are currently also analyzing 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. Samples are currently being genetically analyzed for specific copy number alterations, and mutations. Unfortunately, as mentioned above, Roche has now abandoned development of this antibody for business reasons, and we are currently attempting to develop a partnership with another company to pursue a registration study in Ewings sarcoma using combination Ab plus salvage chemotherapy in first recurrence patients. We continue to accrue patients to a study evaluating treatment of MPNST patients, in both the sporadic and NF-1 associated setting. This study under the leadership of Dr. Brigitte Widemann. We will evaluate the objective response rate of alternating Ifos/etoposide with Adria/Ifos in these patients, followed by surgical resection after 4 cycles of therapy. We have now entered 28 patients to date, and this study is now accruing patients across the SARC Consortium. Finally, in collaboration with Dr. Su Young Kim, we have developed a program to study pediatric GIST patients, a very rare disease that is biologically distinct from adult GIST patients. We have held several clinics where we 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. We have already identified specific novel germline mutations in SDH genes in patients with non-syndromic, apparently sporadic GIST tumors. We have now also demonstrated that essentially all patients with wild-type pediatric GIST have absent SDH protein expression, and this segregates with a unique methylation pattern in these patients that is clearly distinct from mutant and wild-type adult GIST. We believe these data are clearly leading to a better classification and understanding of these rare tumors. We have written a pilot protocol to test the IGFIR Ab in refractory patients since others have already published that these pediatric GIST tumors express high levels of IGFIR. Based upon the SDH loss, we are also writing a study to use a VEGFR inhibitor in these patients since activity with this approach has been described in kidney cancer patients with lack of SDH activity. A paper describing the SDH alterations has been published, and several other manuscipts are in preparation at this time.

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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 :
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
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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