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Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing's sarcoma.

ABSTRACT: IGF system contributes significantly to many human malignancies. Targeting IGF-I receptor (IGF-IR) has been reported to be active against several tumors, but particular efficacy was observed only against a minority of Ewing's sarcoma patients. Identification of mechanisms of acquired resistance to anti-IGF-IR agents is mandatory to individualize their use in clinics and optimize cure costs. In this study, we compared gene expression profiles of cells made resistant with three different anti-IGF-IR drugs (human antibodies AVE1642, Figitumumab, or tyrosine kinase inhibitor NVP-AEW541) to highlight common and distinctive mechanisms of resistance. Among common mechanisms, we identified two molecular signatures that distinguish sensitive from resistant cells. Annotation analysis indicated some common altered pathways, such as insulin signaling, MAPK pathway, endocytosis, and modulation of some members of the interferon-induced transmembrane protein family. Among distinctive pathways/processes, resistance to human antibodies involves mainly genes regulating neural differentiation and angiogenesis, whereas resistance to NVP-AEW541 is mainly associated with alterations in genes concerning inflammation and antigen presentation. Evaluation of the common altered pathways indicated that resistant cells seem to maintain intact the IGF-IR internalization/degradation route of sensitive cells but constantly down-regulated its expression. In resistant cells, the loss of proliferative stimulus, normally sustained by IGF-I/IGF-IR autocrine loop in Ewing's sarcoma cells, is compensated by transcriptional up-regulation of IGF-II and insulin receptor-A; this signaling seems to favor the MAPK pathway over the v-akt murine thymoma viral oncogene homolog 1 pathway. Overall, complexity of IGF system requires analytical evaluation of its components to select those patients that may really benefit from this targeted therapy and support the idea of cotargeting IGF-IR and insulin receptor-A to increase the efficacy.

SUBMITTER: Garofalo C

PROVIDER: S-EPMC5416976 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing's sarcoma.

Garofalo Cecilia C Mancarella Caterina C Grilli Andrea A Manara Maria Cristina MC Astolfi Annalisa A Marino Maria Teresa MT Conte Alexia A Sigismund Sara S Carè Alessandra A Belfiore Antonino A Picci Piero P Scotlandi Katia K

Molecular endocrinology (Baltimore, Md.) 20120713 9

IGF system contributes significantly to many human malignancies. Targeting IGF-I receptor (IGF-IR) has been reported to be active against several tumors, but particular efficacy was observed only against a minority of Ewing's sarcoma patients. Identification of mechanisms of acquired resistance to anti-IGF-IR agents is mandatory to individualize their use in clinics and optimize cure costs. In this study, we compared gene expression profiles of cells made resistant with three different anti-IGF- ...[more]

PMID: 22798295

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Project description:BackgroundFigitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases.MethodsBetween January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760.Findings29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6.1, range 1-24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer.InterpretationFigitumumab is well tolerated and has antitumour activity in Ewing's sarcoma, warranting further investigation in this disease.FundingPfizer Global Research and Development.

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Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing's sarcoma.

Publications

Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing's sarcoma.

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