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

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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.