Clinical Development of Novel Drugs for Children with Ca

作为P&ET部门的一员，我的研究项目一直专注于儿童癌症分子靶向药物的开发，以及与遗传性疾病--神经纤维瘤病1型(NF1)相关的神经系统良恶性肿瘤靶向药物的新合作临床试验计划的开发。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)。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以及Raf激酶和血管生成抑制剂索拉非尼。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4项新药物治疗丛状神经纤维瘤(PN)儿童的多机构临床试验外，我还在国防部资助的新的NF1临床试验联合体的开发中发挥了领导作用。在我们的多机构临床试验中使用的自动化容量MRI测量PN的方法，不仅使我们能够重复性和敏感性地测量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历史的了解。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。对于分子靶向药物，如替普法尼和索拉非尼，我在启动NF1试验之前，在儿童癌症患者身上进行I期和II期临床试验。对于替法尼布，我领导了实体肿瘤(包括患有PNS的NF1患者)和白血病的单独I期试验，我正在COG内开发替法尼布治疗急性髓细胞白血病的II期试验。我一直在继续我的临床和临床前研究，研究MTX救援剂羧基肽酶-G2，这将导致NDA；在完成了依西比隆类似物的I期试验后，我正在领导COG范围的实体肿瘤II期试验。通过另一项美国陆军临床试验奖，我开发了一项II期试验，评估新辅助化疗对恶性周围神经鞘瘤(MPNST)的益处，这种肿瘤在NF1中的终生发病率为8-13%，与散发性肿瘤相比，NF1的预后更差。这项试验将为更有针对性的治疗方法提供平台，并将NF1和肉瘤中心联系起来，以便及时完成。

As a member of the P&ET Section, my research program has focused on the development of molecularly targeted drugs for childhood cancers and the development of a new collaborative clinical trials program of targeted agents for benign and malignant tumors of the nervous system associated with the genetic disorder, neurofibromatosis type 1 (NF1). 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. With tipifarnib, I have led separate phase I trials in solid tumors (including NF1 patients with PNs) and leukemias, and I am developing the phase II trial of tipifarnib in AML within the COG. I have continued my clinical and preclinical studies of the MTX rescue agent, carboxypeptidase-G2, which will lead to an NDA; and, after completing a phase I trial of the epothilone analog, ixabepilone, I am leading the COG-wide solid tumor phase II trial. Through another US Army Clinical Trial Award, I developed a phase II trial, which assesses the benefit of neoadjuvant chemotherapy for malignant peripheral nerve sheath tumors (MPNST), which have a life time incidence of 8-13% in NF1 and worse outcome in NF1 compared to sporadic tumors. This trial will provide the platform for more targeted treatment approaches and links NF1 and sarcoma centers to allow timely completion.