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an international consortium to study PARP inhibitors in Ewings sarcoma based on published work of others and our unpublished data suggesting that Ewings tumors may be particularly sensitive to PARP inhibition.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.
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