Pediatric Oncology Branch Clinical Care and Education

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

While dramatic improvements in the care of children with cancer have been realized over the past five decades, many rare cancers have had limited development of new effective therapies. A major focus of the POB Clinical Core is to use the resources and expertise of the POB in collaboration with extramural and intramural investigators to more rapidly advance promising therapies for children with cancer. In addition to rapidly translating findings from basic and translational researcher within the Branch, the POB utilizes a number of additional strategies to accomplish this goal including: (1) collaboration with medical oncology investigators to extend the age of eligibility into the pediatric age range (2) participation in industry sponsored muti-institution studies to help extend development of promising agents into the pediatric space and (3) collaboration with extramural investigators. The main research focus of the POB Clinical Core is to develop and implement clinical trials based on the work of translational researchers within the Branch. Additionally, the POB Clinical Core (CC) worked with other intramural and extramural groups to develop new therapies for children with cancer. We collaborated on a multi-center phase II study of the anti-programmed death ligand 1 (PD-L1) antibody, atezolizumab for patients with alveolar soft part sarcoma (ASPS). The study led to the recent approval by the US Food and Drug Administration for atezolizumab for adult and pediatric patients greater that 2 years of age with unresectable or metastatic alveolar soft part sarcoma. The CC played a lead role in a recently completed multi-institution study exploring the safety and efficacy of trabectedin given over one hour in combination with Irinotecan for patients with relapsed or refractory Ewing sarcoma. The CC also has a robust research program in rare inherited tumor predisposition syndromes. These syndromes have a significant impact on the lives of affected individuals and their families and present unique challenges in the development of improved therapies and cancer prevention strategies. In addition to cancer, other manifestations of these diseases may not be fully appreciated and may cause morbidity. Individual centers typically follow no more than a few patients with a specific rare disease making deep expertise and clinical research challenging. The NIH intramural program is in a unique position to improve the understanding of the natural history, identify under-appreciated aspects of the disease phenotype, and ultimately develop, test, and implement novel therapies for these patients. Multiple Endocrine Neoplasia Type 2B (MEN2B) is a rare autosomal dominant inherited tumor predisposition syndrome affecting less than 1 in one million live births. The disease is almost always caused by a single p.Met918Thr germline activating point mutation of the REarranged during Transfection (RET) receptor tyrosine kinase. Patients have a nearly 100% risk of developing medullary thyroid carcinoma (MTC) as well as an approximately 50% lifetime risk of pheochromocytoma (PCC). In addition to the neoplastic manifestations of the disease, non-neoplastic aspects of the phenotype include mucosal neuromas, intestinal ganglioneuromas, marfanoid body habitus, and skeletal abnormalities. We are working to develop a detailed understanding of the natural history and clinical characteristics of patients with MEN2B that will facilitate improvements in care and advances in the treatment of MTC. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the GI tract. While approximately 85% of GIST in adult patients are driven by activating mutations in KIT or PDGFRA, the majority of GIST in children are due to germline inactivating mutations in one of the subunits of the Krebs cycle enzyme, succinate dehydrogenase. Patients with dSDH-GIST are most commonly children and young adults and respond poorly to KIT or PDGFRa targeted therapy. To better understand the pathogenesis of GIST tumors without mutations in KIT or PDGFRa and develop effective therapies for these patients, the NIH Pediatric and Wild type-GIST Clinic was founded in 2008. This collaborative intramural-extramural effort has greatly increased the understanding of the underlying biology and natural history of dSDH-GIST. The initial report on 34 patients identified that all patients with wt-GIST lacked expression of the B subunit of succinate dehydrogenase (SDH; mitochondrial complex II) by immuno-histochemistry. Through following a large cohort of patients with this disease we have developed a better understanding of the natural history of SDH-deficient GIST that forms the basis for ongoing studies to develop new therapies for this rare tumor as well as minimally invasive tests used for tumor screening for for GIST in this patient population. Another critical focus of the CC is the training of pediatric hematology/oncology fellows. As part of a joint fellowship with Johns Hopkins University we provide extensive clinical training as well as a unique training experience in basic scientific discovery, translational research, and the development and implementation of early phase clinical trials in pediatric oncology. Our goal is to train a group of dedicated and talented pediatricians who will become the next generation of leaders in the field.