Pharmacology and Experimental Therapeutics Section

Anticancer drug discovery and development are moving towards a more rational and targeted approach. The Pharmacology and Experimental Therapeutics Section (PETS) focuses on the clinical development of new agents for the treatment of refractory childhood cancers and genetic tumor predisposition syndromes (GTPS) such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and hereditary medullary thyroid carcinoma (MTC). This includes preclinical and clinical studies to analyze the pharmacokinetics (PK), pharmacodynamics (PD), toxicity, and activity of novel agents in childhood tumors. By leveraging unique NIH resources, the Section has applied the principles of drug development for refractory cancers to NF1-related tumors. Simultaneous or sequential clinical development of agents with scientific rationale for both refractory cancers and GTPSs (e.g., tipifarnib or sorafenib) has provided special insights by directly comparing toxicities, PK, and PD of new agents, which have been informative for the development of these agents for both populations. Due to the distinct characteristics of GTPSs, the Section has developed new trial designs, methods of image analysis, and trial endpoints, which allow for more meaningful and safe evaluation of novel agents. The PET Section is conducting clinical trials with targeted agents as single and limited institution studies and in collaboration with consortia, for example, the Children’s Oncology Group Phase I/Pilot Consortium, the NF Clinical Trials Consortium, and the sarcoma cooperative group SARC.

The PET Section uses an integrated research program that includes preclinical models to study the pharmacology and applications of new agents in childhood tumors and an active clinical trials program to study the toxicity, activity, pharmacokinetics and pharmacodynamics of these agents in children and young adults. In collaboration with the Pediatric Neuro-Oncology Section, the central nervous system pharmacology of anticancer drugs is also studied because of the high incidence of primary and metastatic central nervous system cancers in children. Clinical trials are developed with an emphasis on new trial designs and endpoints, and are performed as single institution studies or collaboratively with other children's cancer centers or cooperative groups. 

A variety of agents are studied including cytotoxic drugs, molecularly targeted drugs, antiangiogenic agents, and drugs that modulate the therapeutic or toxic effects of anticancer drugs. The PET Section works with the Cancer Therapy Evaluation Program (CTEP) and the pharmaceutical industry to ensure that promising new drugs are studied in children.  Dr. Widemann serves as the NCI Pediatric Oncology Branch (POB) principal investigator of the Children’s Oncology Group Phase I Pilot Consortium and the Department of Defense-sponsored Neurofibromatosis Consortium. She also works with the sarcoma cooperative group SARC. Some of the clinical trials performed through these consortia are thus available to patients referred to the POB for clinical trials.

In addition to the conduct of early clinical trials for children and young adults with refractory cancers, the PET Section has established a program for NF1-related tumor and non-tumor manifestations. Phase I and II trials for NF1-related plexiform neurofibromas, which cannot be easily resected, and for patients with NF1-associated and sporadic malignant peripheral nerve sheath tumors (MPNST) are conducted.  In addition to treatment trials, a longitudinal natural history trial for children and young adults with NF1 is open for enrollment. On this study, individuals with NF1 are followed longitudinally for their tumor and non-tumor manifestations. A better understanding of the natural history of NF1 will be helpful for the development of clinical trial designs and outcome measurements to explore novel and effective treatments for the many tumor and non-tumor manifestations of NF1.

Under direction of Dr. Eva Dombi the PET Section uses novel approaches for image analysis of tumors in patients with NF1. The use of volumetric MRI analysis of plexiform neurofibromas was developed at the Branch and allows for more sensitive measurements of these complex tumors.

Multiple endocrine neoplasia (MEN) types 2A and 2B are rare genetic diseases, which lead to the development of medullary thyroid cancer and pheochromocytoma.  Surgery has been the standard treatment for these cancers and patients can be cured only by thyroidectomy when the tumor is still confined to the thyroid gland. Traditional chemotherapy is not effective.  The PET Section has an active research program in MEN-associated medullary thyroid cancer.  A clinical trial evaluating the targeted agent vandetanib in the treatment of children and young adults with medullary thyroid carcinoma was recently completed and Dr. Widemann serves as an investigator for a Children’s Oncology Group clinical trial evaluating cabozantanib in the treatment of pediatric patients with this disease.  Other efforts in this area include a clinical study following the natural history of the disease in young patients, research aimed at understanding how the cancer develops resistance to drugs like vandetanib, and the ongoing evaluation of novel therapies for medullary thyroid cancer.

Laboratory Support Staff. The PET Section is fortunate to have 3 permanent technical laboratory support staff (Ms. Diane Cole, Mr. Robert Murphy, and Ms. Nalini Jayaprakash) each of whom have provided support to the section for more than 20 years. They provide the expertise to support the quantitative analysis of pharmacokinetic and pharmacodynamic endpoints for non-human primate studies, in vitro studies, and clinical trials. Assays used include plate assays (ELISAs, RIA, functional assays), analysis of heavy metal compounds by atomic absorption spectrometry, and analysis of small molecules by HPLC with a variety of detection methods (UV, fluorescence, electrochemistry, and mass spectrometry).

Clinical Trials Support Staff. The PET Section and POB research nurses (Andrea Baldwin PNP, Joanne Derdak NP, Trish Whitcomb RN, Anne Goodwin RN, Claudia Derse Anthony RN, and Melisssa Amaya RN) have great expertise and have been highly committed to the coordination of early clinical trials for children and young adults with refractory cancers or genetic tumor predisposition syndromes.

For questions regarding PET Section clinical trials, please contact Ms. Cynthia Boyle, RN, at 301-496-0932 or by e-mail: cynthia.boyle@nih.go