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

描述（由申请人提供）：反应评估是至关重要的，早期的获益信号对于新药治疗的开发是令人信服的。FDG-PET用于伊马替尼（imatinib， IM）的早期试验，伊马替尼是一种口服酪氨酸激酶抑制剂，具有抗KIT和PDGFRA的活性，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，通常是gist的肿瘤驱动因素，对IM治疗反应较差。我们的研究小组已经证明，胰岛素样生长因子1受体（IGF- 1R）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。IGF1R和IGF信号通路已被证明在恶性细胞的生长、转移和对化疗药物的耐药性中发挥作用。许多主要关注胰岛素生长因子-1和-2 （IGF-1和IGF-2）和IGF-1R的研究表明，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细胞系的临床前研究表明，单独使用IGF-1R抑制剂或与IM联合使用IGF-1R抑制剂可降低细胞增殖。因此，测试抗igf - 1r抗体单独或联合IM对晚期GIST患者的疗效是合理的。本提案旨在以初步的方式评估FDG-PET在评估晚期gist患者的抗IGF-1R抗体BIIB022单独或联合IM中的作用。抗igf1r抗体治疗的主要毒性是高血糖，这表明正常的胰岛素稳态受到干扰。关于FDG-PET成像用于评估IGF-1R抑制剂治疗反应的可靠性的有限的已发表数据，也没有关于IGF-1R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。我们将开展一项I/II期研究，结合FDG-PET以及常规成像和血清葡萄糖、胰岛素和IGF- 1r配体IGF-1和IGF-2的循环水平，以及它们的抑制剂IGF结合蛋白（igfbp）。我们将探讨FDG-PET与晚期GIST患者单独或联合使用抗igf1r抑制剂BIIB022治疗时肿瘤代谢活性变化与肿瘤大小、血清葡萄糖、胰岛素、IGF-1R配体或igfbp水平的相关性。

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.