Preliminary Evaluation of FDG-PET with anti-IGF-1R Targeted Therapy in GISTs

描述（由申请人提供）：评价反应是至关重要的，早期的获益信号对于开发新药治疗是迫切的。FDG-PET用于伊马替尼（IM）的早期试验，IM是一种口服酪氨酸激酶抑制剂，对KIT和PDGFRA具有活性，用于晚期胃肠道间质瘤（GIST）患者。IM治疗导致显著的代谢反应，这被证明是长期疾病控制的预测。缺乏c-KIT或PDGFRA突变的GIST（GIST的常见肿瘤学驱动因素）对IM治疗的反应较低。我们的研究小组已经证明，胰岛素样生长因子1受体（IGF-1 R）在GIST中过度表达和组成性激活，特别是那些缺乏c-KIT和PDGFRA突变的GIST。IGF 1 R和IGF信号通路已被证明在恶性细胞生长、转移和对化疗药物的抗性中起作用。主要关注胰岛素生长因子-1和-2（IGF-1和IGF-2）和IGF-1 R的许多研究已经证明，与正常组织相比，这些基因在许多癌症中表达或过表达。我们在GIST细胞系中的临床前研究已经证明，单独使用IGF-1 R抑制剂或与IM组合使用可降低细胞增殖。因此，在晚期GIST患者中测试抗IGF-1 R抗体单独和与IM组合的功效是合理的。本提案旨在初步评价FDG-PET在评价抗IGF-1 R抗体BIIB 022单独治疗和与IM联合治疗晚期GIST患者中的作用。抗IGF 1 R抗体治疗的主要毒性是高血糖症，表明存在正常胰岛素稳态的扰动。关于FDG-PET成像评估IGF-1 R抑制剂治疗反应的可靠性，有限的已发表数据不存在，也没有关于IGF-1 R抗体对胰岛素家族配体循环水平影响的信息。循环IGF家族成员水平的扰动可能会影响FDG-PET成像的可靠性。我们将进行一项I/II期研究，将FDG-PET沿着常规成像和血清葡萄糖、胰岛素和IGF-1 R配体IGF-1和IGF-2及其抑制剂IGF结合蛋白（IGFBPs）的循环水平的测量。我们将在接受抗IGF 1 R抑制剂BIIB 022单药治疗或与IM联合治疗的晚期GIST患者中探索FDG-PET肿瘤代谢活性变化与肿瘤大小、血糖、胰岛素、IGF-1 R配体或IGFBPs血清水平之间的相关性。 公共卫生相关性：在临床试验中纳入功能成像正在成为一个重要的工具，以尽量减少药物开发的时间。该提案旨在评估FDG-PET扫描在晚期GIST患者中单独或联合IM靶向IGF-1 R抗体的I/II期临床试验中测量生物学效应和预测临床获益的有效性。该提案的结果将适用于所有癌症类型，并扩展了我们对FDG-PET在评估药物作用方面的作用的理解，特别是IGF-1 R靶向治疗剂的作用，目前正在多种挑战性和难治性恶性肿瘤中进行临床开发。

DESCRIPTION (provided by applicant): Evaluation of response is critical and early signals of benefit are compelling for the development of novel drug therapies. FDG-PET was utilized in early trials of imatinib (IM), an oral tyrosine kinase inhibitor with activity against KIT and PDGFRA, in patients with advanced gastrointestinal stromal tumors (GISTs). Treatment with IM led to dramatic metabolic responses that proved to be predictive of long term disease control. GISTs lacking mutations in c-KIT or PDGFRA, the usual oncologic drivers of GISTs, are less responsive to IM therapy. Our group has demonstrated that the insulin-like growth factor 1 receptor (IGF- 1R) is over-expressed and constitutively activated in GISTs, particularly those that lack mutations in c-KIT and PDGFRA. IGF1R and the IGF signaling pathway have been shown to play a role in malignant cell growth, metastasis, and resistance to chemotherapeutic drugs. Numerous studies focusing mainly on insulin growth factor-1 and -2 (IGF-1 and IGF-2) and IGF-1R have demonstrated that these genes are expressed, or over-expressed in numerous cancers as compared to normal tissue. Our preclinical studies in GIST cell lines have demonstrated decreased proliferation of cells with an IGF-1R inhibitor alone or in combination with IM. It is therefore rational to test the efficacy of an anti-IGF-1R antibody alone and in combination with IM in patients with advanced GIST. This proposal seeks to evaluate, in a preliminary fashion, the role of FDG-PET in the evaluation of the anti- IGF-1R antibody BIIB022 alone and in combination with IM in patients with advanced GISTs. A primary toxicity of anti-IGF1R antibody therapy is hyperglycemia, suggesting there is a perturbation of normal insulin homeostasis. Limited published data do not exist on the reliability of FDG-PET imaging for the assessment of response to therapy with an IGF-1R inhibitor therapy, nor is there information on the impact of IGF-1R antibodies on circulating levels of insulin family ligands. It is possible that perturbations in the levels of circulating IGF family members may affect the reliability of FDG-PET imaging. We will conduct a phase I/II study incorporating FDG-PET along with conventional imaging and measurements of serum glucose, insulin and circulating levels of the IGF-1R ligands IGF-1 and IGF-2, and their inhibitors the IGF binding proteins (IGFBPs). We will explore correlations between changes in tumor metabolic activity by FDG-PET and tumor size, serum levels of glucose, insulin, IGF-1R ligands or IGFBPs in patients with advanced GIST treated with an anti-IGF1R inhibitor BIIB022 alone or in combination with IM. PUBLIC HEALTH RELEVANCE: The incorporation of functional imaging in clinical trials is becoming an important tool to minimize the time of drug development. This proposal seeks to evaluate the effectiveness of FDG-PET scanning to measure biological effects and predict clinical benefit in a phase I/II clinical trial of an antibody targeting IGF-1R alone or in combination with IM in patients with advanced GIST. The results of this proposal would be applicable to all cancer types and extend our understanding the role of FDG-PET in assessing drug effect generally and in particular, the effects of IGF-1R targeted therapeutics, which are undergoing clinical development at this time in multiple challenging and refractory malignancies.