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 has completed enrollment, and we have observed plexiform neurofibroma shrinkage in approximately 50% of the patients enrolled. We have not observed this degree of activity in prior studies. Interestingly, in a preclinical mouse model of NF1 and neurofibromas tumor shrinkage was observed for the first time with a MEK inhibitor. We are performing volumetric MRI analysis of the neurofibroma in the mice in collaboration with Dr. Ratner (Cincinnati Children's Hospital), and will continue to evaluate novel agents in this model with the goal to more rationally select agents for clinical trials. A phase II trial of AZD6244 for children and young adults with inoperable plexiform neurofibromas is in development to more fully assess the effectiveness of the MEK inhibitor in NF1 plexiform neurofibromas. In addition to tumor shrinkage, we will evaluate changes in pain, quality of life, and function on treatment with the MEK inhibitor. In addition, we hope to develop a trial for adults with NF1 PN. 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. These efforts have become part of an international collaboration called Response Evaluation in Neurofibromatosis and Schwannomatosis, in short REiNS. Drs. Plotkin and I co-chair this working group, which has the goal of establishing consensus guidelines for clinical trials in NF. Our first set of guidelines was recently published. We hope this work will accelerate the development of effective treatments for NF related manifestations. 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. Young patients have the most rapidly growing tumors. In contrast, plexiform neurofibromas show only minimal growth in adults. Rapid growth of a neurofibroma in adults has to raise the concern for malignant degeneration. We have recently identified lesions in patients with NF1 and plexiform neurofibroma on whole body MRI, which have distinct imaging characteristics. These lesions grow more rapidly compared to the surrounding plexiform neurofibroma and show uptake on FDG glucose positron emission tomography (PET). We believe these lesions may be at greater risk of changing to malignant peripheral nerve sheath tumors, which are highly aggressive cancers. Our effort is in developing better imaging tools, which may allow detection of malignant degeneration earlier, at a time, when surgery as a treatment is still feasible. We just opened a clinical trial, which will compare the utility of FDG -PET and FLT-PET to detect malignant transformation in plexiform neurofibromas. 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. 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. This work has now become part of a new NCI initiative called the """"""""NCI rare disease initiative"""""""". The objective of this imitative is to accelerate the development of effective treatments for rare cancers by optimally utilizing the basic and clinical expertise of NCI investigators.
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