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

我为NF1相关肿瘤建立的计划专注于基于药物的作用机制和这些肿瘤的已知发病机制的新的分子靶向抗癌药物的临床应用(例如，NF1基因产物神经纤维蛋白通过其GTPase相关区域调节RAS活性，而功能缺失的神经纤维蛋白导致RAS调节失调和肿瘤发生)。我研究的药物包括法尼基转移酶抑制剂tipifarnib(我领导了由美国陆军临床试验奖资助的针对NF1的靶向治疗的第一个多机构II期试验)，该药物旨在针对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以及mTOR抑制剂西罗莫斯。一项新的临床试验使用了一种特定的MEK抑制剂来治疗丛状神经纤维瘤，现在正在接受登记。对于分子靶向药物，如替普法尼和索拉非尼，我在NF1启动试验之前，在儿童癌症患者身上进行I期和II期临床试验。作为建立NF1计划的一部分，我还专注于开发新的、更灵敏的临床试验终点，以评估与NF1相关的肿瘤的大小和生长速度，例如我们的自动体积核磁共振方法，该方法已成为衡量NF1临床试验药物效果的主要方法。我还开发了新的临床试验设计，解释了NF1相关肿瘤的自然病史以及它们缓慢且不可预测的生长。由于缺乏进行NF1临床试验的既定基础设施，需要在启动多机构临床试验之前开展合作并提供资金。除了协调几个针对丛状神经纤维瘤儿童的新药物的多机构临床试验外，我还在国防部资助的新的国家NF临床试验联盟的发展中发挥了领导作用。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，我是恶性周围神经鞘瘤(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自动体积MRI测量PN的方法不仅使我们能够重复且灵敏地测量PN大小的变化，并准确地将疾病进展时间确定为主要试验终点，而且还提高了我们对这些肿瘤的自然病史的了解。我们用这种方法证明了PN增长率高度依赖于年龄，并且患者体内的增长率在评估新药治疗效果所需的18至30个月内是一致的。与NHGRI合作，我还在研究皮肤神经纤维瘤的自然历史，并通过应用数字技术评估病变体积，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会使年幼的儿童，如患有NF1的儿童，容易出现这一群体特有的毒性。例如，在临床前模型中，骨毒性(生长减少和生长板扩张)在生长中的小鼠中观察到，但在老年小鼠中没有观察到。因此，我们开发了监测骨骼毒性的新方法，包括生长板的体积磁共振分析方法，该方法已被纳入几项临床试验。为了更合理地开展NF1相关的盆状神经纤维瘤的临床试验，我们与辛辛那提儿童医院的Nancy Ratner博士建立了合作关系，在临床试验的发展之前，对她的NF1丛状神经纤维瘤转基因小鼠模型中的新药进行了评估。我还在进行临床试验，这些试验针对的是MPNST，与普通人群相比，MPNST在NF1患者中发生的频率要高得多，在NF1中的结果很差。这些试验在项目1中进行了讨论。我将与凯瑟琳·沃伦博士合作，参与第一个针对NF1患者难治性视路肿瘤的核因子联盟试验。此外，我还开展了一项纵向的NF1自然历史研究。在NIH登记参加这项研究的患者接受NF1相关肿瘤和非肿瘤表现的纵向评估。他们还接受基因分型，与Doug Stewart(NHGRI)合作，我们正在评估NF1和丛状神经纤维瘤患者的修饰基因。我计划将这一方法扩展到其他遗传性肿瘤易感综合征，包括神经纤维瘤病2型相关肿瘤，特别是前庭神经鞘瘤。此外，我计划继续努力，为遗传性甲状腺髓样癌患者开发有效的医疗治疗方法。

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 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.