Development of Therapies for Neurofibromatosis Type 1 Related Tumors and other G

我为NF 1相关肿瘤建立的项目侧重于基于药物的作用机制和这些肿瘤的已知发病机制（例如，NF 1基因产物神经纤维蛋白通过其GTP酶相关结构域调节Ras活性，功能性神经纤维蛋白的缺乏导致Ras失调和肿瘤发生）。我研究过的药物包括法尼基转移酶抑制剂替吡法尼（tipifarnib）（我领导了第一个由美国陆军临床试验奖资助的NF 1靶向治疗的多机构II期试验），该试验旨在靶向Ras，抗纤维化药物吡非尼酮，免疫调节剂pegintron，Raf激酶和血管生成抑制剂索拉非尼和mTOR抑制剂西罗莫司。一种新的特异性MEK抑制剂的临床试验正在开发中。对于分子靶向药物，如tipifarnib和索拉非尼，我在NF 1试验开始之前在癌症儿童中进行I期和II期临床试验。作为建立NF 1项目的一部分，我还专注于开发新的、更敏感的临床试验终点，以评估NF 1相关肿瘤的大小和生长速度，例如我们的自动体积MRI方法，该方法已成为测量NF 1临床试验药物效应的主要方法。我还开发了新的临床试验设计，解释了对NF 1相关肿瘤的自然史知之甚少及其缓慢和不可预测的生长。由于缺乏开展NF 1临床试验的既定基础设施，因此需要在启动多机构临床试验之前开展合作并提供资金。除了协调几个多机构临床试验的新药物在儿童丛状神经纤维瘤，我还发挥了领导作用，在一个新的国防部资助的国家NF临床试验联盟的发展。我是神经纤维瘤/丛状神经纤维瘤委员会和药理学委员会的主席，我是恶性外周神经鞘瘤（MPNST）和生物学委员会的成员。 在我们的多机构临床试验中使用的测量PN的自动体积MRI方法不仅使我们能够重复和灵敏地测量PN大小的变化，并准确地将疾病进展时间定义为主要试验终点，而且还提高了我们对这些肿瘤自然史的理解。我们用这种方法证明了PN生长率具有高度的年龄依赖性，并且在评估新药治疗效果所需的18至30个月内，患者体内的生长率是均匀的。与NHGRI合作，我还研究了皮肤神经纤维瘤的自然史，并通过应用数字技术评估病变体积来为未来的临床试验开发终点。靶向药物和血管生成抑制剂可能使幼儿（如NF 1患儿）易发生该人群特有的毒性。例如，在临床前模型中，在生长但非老龄小鼠中观察到骨毒性（生长和生长板扩张减少）。因此，我们开发了监测骨毒性的新方法，包括生长板的体积MRI分析方法，该方法已被纳入几项临床试验。为了使nF 1相关的盆状神经纤维瘤的临床试验更合理地发展，我们与辛辛那提儿童医院的Nancy Ratner博士建立了合作关系，在临床试验发展之前，在她的NF 1丛状神经纤维瘤转基因小鼠模型中评估新药物。我还在进行临床试验，这些试验涉及MPNST，与普通人群相比，MPNST在NF 1患者中发生的频率更高，并且在NF 1中的结果很差。这些试验在项目1中讨论。与凯瑟琳沃伦博士合作，我将参加第一个NF联盟试验，该试验涉及NF 1患者的难治性视路肿瘤。此外，我还开发了一个纵向NF 1自然史研究。在NIH参加这项研究的患者接受了NF 1相关肿瘤和非肿瘤表现的纵向评价。他们也进行基因分型，并与道格斯图尔特（NHGRI）合作，我们正在评估NF 1和丛状神经纤维瘤患者的修饰基因。我计划将这种方法扩展到其他遗传性肿瘤易感综合征，包括2型神经纤维瘤病相关肿瘤，特别是前庭神经鞘瘤。此外，我计划继续Balis博士和合作者的努力，为遗传性甲状腺髓样癌患者开发有效的医学治疗方法。

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 is in development. 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 of Dr. Balis and collaborators in the development of effective medical treatments for patients with hereditary medullary thyroid carcinoma.