The program that I established for NF1-related tumors focuses on the clinical application of new molecularly targeted anticancer drugs to these tumors based on the mechanism of action of the drug and the known pathogenesis of these tumor (e.g., the NF1 gene product, neurofibromin, regulates Ras activity through its GTPase-related domain and lack of functional neurofibromin leads to dysregulated Ras and tumorigenesis). The agents I have studied include the farnesyltransferase inhibitor, tipifarnib (I lead the first multi-institutional phase II trial of a targeted therapy for NF1 funded by a US Army Clinical Trial Award), which was designed to target Ras, the anti-fibrotic agent, pirfenidone, the immune-modulatory agent pegintron, the Raf kinase and angiogenesis inhibitor, sorafenib, and the mTOR inhibitor sirolimus. A new clinical trial with a specific MEK inhibitor for plexiform neurofibromas is now open for enrollment. For the molecularly targeted agents, such as tipifarnib and sorafenib, I perform the phase I and II clinical trials in children with cancer prior to initiating trials in NF1. As part of establishing the NF1 program, I have also focused on developing new, more sensitive clinical trial endpoints to assess the size and growth rate of NF1-related tumors, such as our automated volumetric MRI method, which has become the primary method of measuring drug effect for NF1 clinical trials. I have also developed new clinical trial designs that account for the poorly understood natural history of NF1-related tumors and their slow and unpredictable growth. The absence of an established infrastructure for the conduct of NF1 clinical trials required the development of collaborations and funding prior to the initiation of multi-institutional clinical trials. In addition to coordinating several multi-institutional clinical trials of new agents in children with plexiform neurofibromas, I have also played a leadership role in the development of a new DoD-funded national NF Clinical Trials Consortium. I am chairing the neurofibroma/plexiform neurofibroma committee and the pharmacology committee, and I am a member of the malignant peripheral nerve sheath tumor (MPNST) and biology committee. The automated volumetric MRI method of measuring PN, which is used in our multi-institutional clinical trials has not only allowed us to reproducibly and sensitively measure changes in PN size and accurately define time to disease progression as primary trial endpoint, but it has also improved our understanding of the natural history of these tumors. We demonstrated with this method that PN growth rate is highly age-dependent and that the rate of growth within patients is uniform over the 18 to 30 months required to assess the effect of a new drug treatment. In collaboration with NHGRI, I am also studying the natural history of dermal neurofibromas and developing endpoints for future clinical trials by applying digital technology to assess lesion volume. Targeted agents and angiogenesis inhibitors may predispose young children, such as children withNF1 to the development of toxicities unique to this population. For example, in preclinical models, bony toxicity (decreased growth and growth plate expansion) was observed in growing but not aged mice. We thus developed novel methods of monitoring for bony toxicity including a method of volumetric MRI analysis of the growth plates, which has been incorporated into several clinical trials. In order to allow for a more rational development of clinical trials for nF1 related pelxiform neurofibromas, we have established a collaboration with Dr. Nancy Ratner from Cincinnati Childrens hospital to evaluate novel agents in her transgenic mouse model of NF1 plexiform neurofibromas prior to the development of clinical trials. I am also conducting clinical trials, which address MPNSTs, which occur substantially more frequently in individuals with NF1 compared to the general population, and have poor outcome in NF1. These trials are discussed in project 1. Collaboratively with Dr. Katherine Warren, I will participate in the first NF Consortium trial, which addresses refractory optic pathway tumors in patients with NF1. In addition, I have developed a longitudinal NF1 natural history study. Patients enrolled on this study at the NIH undergo longitudinal evaluation for NF1 related tumor and non-tumor manifestations. They also undergo genotyping, and in collaboration with Doug Stewart (NHGRI) we are evaluating modifier genes in patients with NF1 and plexiform neurofibromas. I plan to expand this approach I have taken to other genetic tumor predisposition syndromes including neurofibromatosis type 2 related tumors, in particular vestibular schwannomas. In addition, I plan to continue the efforts in the development of effective medical treatments for patients with hereditary medullary thyroid carcinoma.
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