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 tumors (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. Our collaborative phase II trial of pegintron (PI Regina Jakacki) has demonstrated activity in children with progressive pexiform neurofibromas in that pegintron more than doubled the time to progression compared to the placebo arm of our NCI tipifarnib trial. A phase I clinical trial with a specific MEK inhibitor for plexiform neurofibromas is now open for enrollment, and we have observed plexiform neurofibroma shrinkage in the initial patients enrolled. 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 co-chairing the neurofibroma/plexiform neurofibroma committee and chair the malignant peripheral nerve sheath tumor (MPNST) 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 Children?s 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. We recently completed enrollment on a collaborative trial led by Dr. Jaishri Blakeley at Johns Hopkins in Baltimore directed at patient with NF2 and vestibular schwannomas. This trial evaluates the potential benefit of bevacizumab for patients with decreasing hearing as a result of their vestibular schwannomas.I plan to continue the efforts in the development of effective medical treatments for patients with rare cancers or tumor manifestations. In collaboration with Dr. Helman we are developing a trial for patients with wild-type gastrointestinal stromal tumors. In collaboration with Dr. Biesecker (PI for study)) from the NHGRI I am working on the design for a potential clinical trial targeting the clinical manifestations of Proteus syndrome.

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National Cancer Institute (NCI)
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Wiener, Lori; Battles, Haven; Bedoya, Sima Zadeh et al. (2017) Identifying Symptoms of Distress in Youth Living with Neurofibromatosis Type 1 (NF1). J Genet Couns :
Gross, Andrea; Bishop, Rachel; Widemann, Brigitte C (2017) Selumetinib in Plexiform Neurofibromas. N Engl J Med 376:1195
Avery, Robert A; Katowitz, James A; Fisher, Michael J et al. (2017) Orbital/Periorbital Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Multidisciplinary Recommendations for Care. Ophthalmology 124:123-132
Pemov, A; Li, H; Patidar, R et al. (2017) The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas. Oncogene 36:3168-3177
Dombi, Eva; Baldwin, Andrea; Marcus, Leigh J et al. (2016) Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med 375:2550-2560
Hanemann, C Oliver; Blakeley, Jaishri O; Nunes, Fabio P et al. (2016) Current status and recommendations for biomarkers and biobanking in neurofibromatosis. Neurology 87:S40-8
Stevenson, David A; Schill, Lisa; Schoyer, Lisa et al. (2016) The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway. Am J Med Genet A 170:1959-66
Blakeley, Jaishri O; Ye, Xiaobu; Duda, Dan G et al. (2016) Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2-Associated Vestibular Schwannomas. J Clin Oncol 34:1669-75
Plotkin, Scott R; Davis, Stephanie D; Robertson, Kent A et al. (2016) Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1. Neurology 87:S13-20
Scott, Jeffrey R; Courter, Joshua D; SaldaƱa, Shannon N et al. (2016) Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1-Erratum. Ther Drug Monit :

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