Clinical Development of Therapies for Neurofibromatosis Type 1-Related Tumors

我针对NF1相关肿瘤建立的项目，主要是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。正在研究的药物包括法尼基转移酶抑制剂tipifarnib（我正在领导由美国陆军临床试验奖资助的NF1靶向治疗的第一个多机构II期试验），该药物旨在靶向Ras，抗纤维化剂吡非尼酮，Raf激酶和血管生成抑制剂sorafenib。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4项针对儿童丛状神经纤维瘤（PN）新药的多机构临床试验外，我还在美国国防部资助的一个新的国家NF1临床试验联盟的发展中发挥了领导作用。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。对于分子靶向药物，如蒂法尼和索拉非尼，在开始NF1试验之前，我在患有癌症的儿童中进行了I期和II期临床试验。

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 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 being studied include the farnesyltransferase inhibitor, tipifarnib (I am leading 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, and the Raf kinase and angiogenesis inhibitor, sorafenib. 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 4 multi-institutional clinical trials of new agents in children with plexiform neurofibromas (PN), I have also played a leadership role in the development of a new DoD-funded national NF1 Clinical Trials Consortium. 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. 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 the NF1 trials.