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

我针对NF1相关肿瘤建立的项目，主要根据药物的作用机制和已知的肿瘤发病机制（如NF1基因产物神经纤维蛋白通过其gtpase相关结构域调节Ras活性，缺乏功能性神经纤维蛋白导致Ras失调和肿瘤发生），重点研究新型分子靶向抗癌药物在这些肿瘤中的临床应用。我研究过的药物包括法尼基转移酶抑制剂，替法尼布（我领导了第一个由美国陆军临床试验奖资助的NF1靶向治疗的多机构II期试验），它被设计用于靶向Ras，抗纤维化剂，吡非尼酮，免疫调节剂培金tron， Raf激酶和血管生成抑制剂，索拉非尼布，以及mTOR抑制剂西罗莫司。我们的合作II期试验pegintron （PI Regina Jakacki）已经证明，与我们的NCI替法尼试验的安慰剂组相比，pegintron在进展性针状神经纤维瘤儿童中的活性增加了一倍以上。一项针对丛状神经纤维瘤的特异性MEK抑制剂的I期临床试验现已开放招募，我们已经观察到初始入组患者的丛状神经纤维瘤萎缩。作为建立NF1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NF1相关肿瘤的大小和生长速度，例如我们的自动体积MRI方法，它已成为NF1临床试验中测量药物效果的主要方法。我还开发了新的临床试验设计，以解释人们对nf1相关肿瘤的自然历史知之甚少，以及它们缓慢而不可预测的生长。由于缺乏开展NF1临床试验的既定基础设施，需要在开展多机构临床试验之前开展合作并提供资金。除了协调几项针对丛状神经纤维瘤儿童新药的多机构临床试验外，我还在美国国防部资助的国家神经纤维瘤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恶性周围神经鞘肿瘤（MPNST）委员会的联合主席。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和敏感地测量PN大小的变化，并准确地定义疾病进展的时间作为主要试验终点，而且还提高了我们对这些肿瘤自然历史的理解。我们用这种方法证明了PN生长速率高度依赖于年龄，并且在评估新药治疗效果所需的18至30个月期间，患者体内的生长速率是一致的。与NHGRI合作，我也在研究真皮神经纤维瘤的自然史，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使患有nf1的儿童易患该人群特有的毒性。例如，在临床前模型中，在生长而不是衰老的小鼠中观察到骨毒性（生长减少和生长板扩张）。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nF1相关球状神经纤维瘤的临床试验更加合理，我们与辛辛那提儿童基金会的Nancy Ratner博士建立了合作关系。在开展临床试验之前，在她的NF1丛状神经纤维瘤转基因小鼠模型中评估新型药物。我也在进行针对MPNSTs的临床试验，与一般人群相比，MPNSTs在NF1患者中发生的频率更高，并且NF1的预后较差。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，该试验旨在解决NF1患者的难治性视神经通路肿瘤。此外，我还开展了一项纵向NF1自然历史研究。在NIH入组的患者接受NF1相关肿瘤和非肿瘤表现的纵向评估。他们也接受基因分型，并与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。我计划将我所采取的这种方法扩展到其他遗传肿瘤易感综合征，包括2型神经纤维瘤病相关肿瘤，特别是前庭神经鞘瘤。我们最近完成了一项由巴尔的摩约翰霍普金斯大学的Jaishri Blakeley博士领导的针对NF2和前庭神经鞘瘤患者的合作试验的招募。该试验评估了贝伐单抗治疗因前庭神经鞘瘤导致听力下降的患者的潜在益处。我计划继续努力，为罕见癌症或肿瘤表现的患者开发有效的药物治疗方法。与赫尔曼博士合作我们正在研究一项针对野生型胃肠道间质瘤患者的试验。与NHGRI的Biesecker博士（研究PI）合作，我正在设计一项针对Proteus综合征临床表现的潜在临床试验。

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.