Osteosarcoma: As described above, we have written a Phase II study to test a PD L1 antibody in patients with recurrent osteosarcoma. The study will include built-in genomic and immunologic assessment of patients treated and will be performed at 4 institutions with St Jude being the lead institution. Ewings Sarcoma: Based partly on our previous finding of a study of an IGFIR antibody alone in the treatment of Ewing's sarcoma (results published several years ago), the COG has now opened a Phase III study comparing standard chemotherapy to chemotherapy plus an IGFIR Ab in high risk Ewing's sarcoma patients. 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an international consortium to study PARP inhibitors in Ewings sarcoma based on published work of others and our unpublished data suggesting that Ewings tumors may be particularly sensitive to PARP inhibition. The study has almost completed accural with the combination of the PARPi, Niraparib and temozolomide, and an additional arm combining Niraparib with irinotecan. Rhabdomyosarcoma: Based upon our published work showing synergy between Src family kinase inhibitors and IGFIR inhibitors in rhabdmyosarcomas, we now have approval to test the combination of dasatinib, a SRC family kinase inhibitor, with an IGFIR Ab. 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 around 80% of these patients harbor germline mutations in these genes. In addition, we have now shown that a number of patients with SDH deficiency but no identifiable mutation have a tumor-specific methylation of their SDHC promoter leading to silencing of SDHC expression. We have furthermore shown that all of these SDH-deficient GISTS also have global hypermethylation in the tumor genome. Based on responses of SDH mutant kidney cancers to VEGFR inhibitors such as vandetanib we opened a clinical study to test this drug in SDH mutant GIST tumors as well, but unfortunately there was no activity observed. We are currently completing a second study to test the potent DNMT inhibitor, guadecitabine in these pateints based upon the observed global hypermethylation in all SDH deficient GIST tumors and the specific SDHC promoter hypermethylation in a subset of patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC006891-29
Application #
9556767
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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
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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
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 :
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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