The primary objective of this project is to develop new agents for the treatment of cancers in children and young adults with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. In addition, novel cytotoxic agents are undergoing clinical evaluation. Clinical trials are conducted as single site and multi-site trials. In addition, we are collaborating with the Children's Oncology Group (COG), the sarcoma cooperative group SARC, and the NF Clinical Trials Consortium in the development and conduct of trials. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, and tumors with no known effective medical therapy such as alveolar soft part sarcoma or malignant peripheral nerve sheath tumors (MPNST). This work is performed through the Pharmacology and Experimental Therapeutics (P&ET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) Example of collaboration with the Children's Oncology Group (COG): Phase I trial of cabozantinib (XL184) for refractory solid tumors: Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK) including primarily MET, VEGFR2 and RET and to a lesser extent KIT and TIE-2. RET inhibition provided the rationale for our development of cabozantinib for pediatric medullary thyroid carcinoma (MTC) (see project 2). However, cabozantinib also targets RTKs that are overexpressed in a variety of pediatric cancers including, VEGFR2 in pediatric sarcomas, MET in osteosarcoma, glioma, and papillary thyroid carcinoma. We thus collaborated with the COG Phase I/Pilot Consortium in the development of cabozantinib in a phase I trial with an arm specifically for MTC (see project 1), and an arm for refractory solid tumors including brain tumors. This trial has completed enrollment and has achieved the primary objectives. In collaboration with the COG, a phase II trial of cabozantinib for several solid tumor strata is in development. 2) Example of collaboration with the sarcoma cooperative group SARC and with the DoD sponsored NF Clinical trials Consortium: The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors are ongoing for both patient populations. For example, I directed a multi-institutional clinical trial for patients with refractory sporadic or NF1 related malignant peripheral nerve sheath tumors (MPNST) with the mTOR inhibitor RAD001 in combination with the angiogenesis inhibitor bevacizumab. This trial is receiving funding through a Department of Defense Clinical Trial Award. Based on preclinical work from Dr. Karen Cichowski's laboratory, we also developed a phase I/II clinical trial of the mTOR inhibitor sirolimus in combination with the HSP90 inhibitor ganetespib for adults with refractory sarcomas and MPNST. This trial completed enrollment, and additional trials targeting MPNST and other sarcomas are in development. 3) Example of clinical trial development translating CCR laboratory findings to the clinic: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, with an annual incidence of 4-7 cases per million children under 15 years in the US. Patients with metastatic and recurrent disease are essentially incurable with a 5-year overall survival of less than 20%, and outcomes have only minimally improved over the past several decades. Targeting of the type-1 insulin-like growth factor receptor (IGF-1R) has shown promise in the treatment of pediatric sarcomas, with clinically meaningful responses in about 10% of patients in early phase trials. In RMS models,preclinical work at the CCR (Dr. Helman) has demonstrated that blockade of IGF-1R results in YES activation and that YES activation is associated with resistance to IGF-1R blockade. In addition, combination treatment blocking both IGF-1R and YES results in enhanced growth inhibition of RMS in vitro and in vivo. In collaboration with Drs. Helman and Heske, we are therefore developing a phase I/II clinical trial of a monoclonal antibody against IGF-1R combined with an agent targeting YES for patients with RMS.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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Chuk, Meredith K; Widemann, Brigitte C; Minard, Charles G et al. (2018) A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group. Pediatr Blood Cancer 65:e27077
Huang, Victoria; Bergner, Amanda L; Halpin, Chris et al. (2018) Improvement in Patient-reported Hearing After Treatment With Bevacizumab in People With Neurofibromatosis Type 2. Otol Neurotol 39:632-638
Ramsey, Laura B; Balis, Frank M; O'Brien, Maureen M et al. (2018) Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance. Oncologist 23:52-61
Lagmay, Joanne P; Krailo, Mark D; Dang, Ha et al. (2016) Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward. J Clin Oncol 34:3031-8
Shah, Nirali N; Merchant, Melinda S; Cole, Diane E et al. (2016) Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®): Results From a Phase I Study in Children, Adolescents, and Young Adults With Refractory Solid Tumors or Leukemias. Pediatr Blood Cancer 63:997-1005
Widemann, Brigitte C (2016) Reply to: Glucarpidase for the Treatment of Methotrexate-Induced Renal Dysfunction and Delayed Methotrexate Excretion. Pediatr Blood Cancer 63:366
Stieglitz, Elliot; Ward, Ashley F; Gerbing, Robert B et al. (2015) Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 62:629-36
Lodish, Maya; Gkourogianni, Alexandra; Bornstein, Ethan et al. (2015) Patterns of thyroid hormone levels in pediatric medullary thyroid carcinoma patients on vandetanib therapy. Int J Pediatr Endocrinol 2015:3
Widemann, Brigitte C (2015) Practical considerations for the administration of glucarpidase in high-dose methotrexate (HDMTX) induced renal dysfunction. Pediatr Blood Cancer 62:1512-3
Fox, Elizabeth; Widemann, Brigitte C; Pastakia, Devang et al. (2015) Pharmacokinetic and pharmacodynamic study of tariquidar (XR9576), a P-glycoprotein inhibitor, in combination with doxorubicin, vinorelbine, or docetaxel in children and adolescents with refractory solid tumors. Cancer Chemother Pharmacol 76:1273-83

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