Clinical Development of Novel Drugs for Children with Refractory Cancers

该项目的主要目标是开发治疗儿童和年轻人癌症的新药物，重点是基于目前对人类癌症分子发病机制的理解，开发更合理、更有针对性的药物开发方法。基于药物的作用机制和靶点在儿童癌症中的重要性，正在进行成人癌症临床开发的新型分子靶向药物将应用于儿童癌症。此外，新的细胞毒性药物正在进行临床评估。临床试验分为单点试验和多点试验。此外，我们正在与儿童肿瘤小组（COG）、肉瘤合作小组SARC和NF临床试验联盟合作开展试验。临床试验的目标是顽固性实体肿瘤，如尤文氏肉瘤或横纹肌肉瘤，以及没有已知有效药物治疗的肿瘤，如肺泡软组织肉瘤或恶性周围神经鞘肿瘤（MPNST）。这项工作通过NCI POB的药理学和实验治疗学（P&ET）部分完成。正在进行和正在开发的临床试验的例子包括：1)与儿童肿瘤组（COG）合作的例子：cabozantinib （XL184）治疗难治性实体肿瘤的I期试验：cabozantinib是一种多受体酪氨酸激酶（RTK）的小分子抑制剂，主要包括MET、VEGFR2和RET，以及较小程度的KIT和TIE-2。RET抑制为我们开发卡博赞替尼治疗小儿甲状腺髓样癌（MTC）提供了基本原理（见项目2）。然而，cabozantinib也靶向多种儿科癌症中过表达的rtk，包括儿童肉瘤中的VEGFR2，骨肉瘤、胶质瘤和甲状腺乳头状癌中的MET。因此，我们与COG I期/试点联盟合作，在一期试验中开发cabozantinib，专门用于MTC（见项目1），以及用于包括脑肿瘤在内的难治性实体肿瘤。本试验已完成入组，达到主要目的。与COG合作，cabozantinib用于几种实体肿瘤层的II期试验正在开发中。2)与SARC肉瘤合作小组和国防部赞助的NF临床试验联盟合作的例子：mTOR途径参与人类癌症和1型神经纤维瘤病（NF1）相关肿瘤的进展，mTOR抑制剂的临床试验正在进行中。例如，我指导了一项针对难治性散在或NF1相关恶性周围神经鞘肿瘤（MPNST）患者的多机构临床试验，该试验使用mTOR抑制剂RAD001联合血管生成抑制剂贝伐单抗。这项试验正在接受国防部临床试验奖的资助。基于Dr. Karen Cichowski实验室的临床前工作，我们还开发了mTOR抑制剂西罗莫司与HSP90抑制剂ganetespib联合用于成人难治性肉瘤和MPNST的I/II期临床试验。该试验完成了入组，针对MPNST和其他肉瘤的其他试验正在进行中。3)临床试验发展将CCR实验室发现转化为临床的例子：横纹肌肉瘤（Rhabdomyosarcoma， RMS）是儿童最常见的软组织肉瘤，在美国15岁以下儿童的年发病率为每百万4-7例。转移性和复发性疾病的患者基本上是无法治愈的，5年总生存率低于20%，并且在过去的几十年里，预后只有很小的改善。靶向1型胰岛素样生长因子受体（IGF-1R）在儿童肉瘤的治疗中显示出希望，在早期试验中约10%的患者有临床意义的反应。在RMS模型中，CCR的临床前工作（Helman博士）已经证明，阻断IGF-1R导致YES激活，并且YES激活与对IGF-1R阻断的抗性有关。此外，同时阻断IGF-1R和YES的联合治疗可增强体外和体内对RMS的生长抑制。在与博士合作。因此，我们正在开发针对IGF-1R的单克隆抗体与针对RMS患者的YES药物联合的I/II期临床试验。

The primary objective of this project is to develop new agents for the treatment of cancers in children and young adults with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. In addition, novel cytotoxic agents are undergoing clinical evaluation. Clinical trials are conducted as single site and multi-site trials. In addition, we are collaborating with the Children's Oncology Group (COG), the sarcoma cooperative group SARC, and the NF Clinical Trials Consortium in the development and conduct of trials. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, and tumors with no known effective medical therapy such as alveolar soft part sarcoma or malignant peripheral nerve sheath tumors (MPNST). This work is performed through the Pharmacology and Experimental Therapeutics (P&ET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) Example of collaboration with the Children's Oncology Group (COG): Phase I trial of cabozantinib (XL184) for refractory solid tumors: Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK) including primarily MET, VEGFR2 and RET and to a lesser extent KIT and TIE-2. RET inhibition provided the rationale for our development of cabozantinib for pediatric medullary thyroid carcinoma (MTC) (see project 2). However, cabozantinib also targets RTKs that are overexpressed in a variety of pediatric cancers including, VEGFR2 in pediatric sarcomas, MET in osteosarcoma, glioma, and papillary thyroid carcinoma. We thus collaborated with the COG Phase I/Pilot Consortium in the development of cabozantinib in a phase I trial with an arm specifically for MTC (see project 1), and an arm for refractory solid tumors including brain tumors. This trial has completed enrollment and has achieved the primary objectives. In collaboration with the COG, a phase II trial of cabozantinib for several solid tumor strata is in development. 2) Example of collaboration with the sarcoma cooperative group SARC and with the DoD sponsored NF Clinical trials Consortium: The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors are ongoing for both patient populations. For example, I directed a multi-institutional clinical trial for patients with refractory sporadic or NF1 related malignant peripheral nerve sheath tumors (MPNST) with the mTOR inhibitor RAD001 in combination with the angiogenesis inhibitor bevacizumab. This trial is receiving funding through a Department of Defense Clinical Trial Award. Based on preclinical work from Dr. Karen Cichowski's laboratory, we also developed a phase I/II clinical trial of the mTOR inhibitor sirolimus in combination with the HSP90 inhibitor ganetespib for adults with refractory sarcomas and MPNST. This trial completed enrollment, and additional trials targeting MPNST and other sarcomas are in development. 3) Example of clinical trial development translating CCR laboratory findings to the clinic: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, with an annual incidence of 4-7 cases per million children under 15 years in the US. Patients with metastatic and recurrent disease are essentially incurable with a 5-year overall survival of less than 20%, and outcomes have only minimally improved over the past several decades. Targeting of the type-1 insulin-like growth factor receptor (IGF-1R) has shown promise in the treatment of pediatric sarcomas, with clinically meaningful responses in about 10% of patients in early phase trials. In RMS models,preclinical work at the CCR (Dr. Helman) has demonstrated that blockade of IGF-1R results in YES activation and that YES activation is associated with resistance to IGF-1R blockade. In addition, combination treatment blocking both IGF-1R and YES results in enhanced growth inhibition of RMS in vitro and in vivo. In collaboration with Drs. Helman and Heske, we are therefore developing a phase I/II clinical trial of a monoclonal antibody against IGF-1R combined with an agent targeting YES for patients with RMS.