Clinical Development of Therapies for Neurofibromatosis Type 1-Related Tumors

1 型神经纤维瘤病相关肿瘤治疗的临床开发

• 批准号: 7592948
• 负责人: Brigitte Widemann
• 金额: $ 84.82万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592948
• 关键词: Accounting; Angiogenesis Inhibitors; Antineoplastic Agents; Award; BAY 54-9085; Benign; Child; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Development; Disease Progression; Drug effect disorder; End Point; Farnesyl Transferase Inhibitor; Funding; Future; Growth; Guanosine Triphosphate Phosphohydrolases; Hereditary Disease; Leadership; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Methods; Multi-Institutional Clinical Trial; Natural History; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; New Agents; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Pirfenidone; Play; Plexiform Neurofibroma; Rate; Research; Research Infrastructure; Role; Technology; Time; Tipifarnib; age related; base; clinical application; dermal neurofibroma; design; digital; improved; malignant neurologic neoplasms; member; programs; raf Kinases; size; therapy development; tumor; tumorigenesis

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.

我为NF1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）。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第一个多机构NF1靶向治疗II期试验），该试验旨在靶向Ras，抗纤维化药物pirfenidone和Raf激酶和血管生成抑制剂索拉非尼。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，该方法已成为测量NF1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NF1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NF1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4个多机构临床试验的新药物在儿童丛状神经纤维瘤（PN），我还发挥了领导作用，在一个新的国防部资助的国家NF 1临床试验联盟的发展。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。对于分子靶向药物，例如替吡法尼和索拉非尼，我在启动NF 1试验之前在癌症儿童中进行了I期和II期临床试验。