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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Cluster Analysis, Docetaxel, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, Insulin-Like Growth Factor I, Mice, Mice, Inbred NOD, Mice, SCID, NIH 3T3 Cells, Pyrazoles, Receptor, ErbB-2, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Estrogen, Receptors, Progesterone, Reverse Transcriptase Polymerase Chain Reaction, Taxoids, Triazines, Xenograft Model Antitumor Assays.
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Does high IGF-IR activity in triple-negative breast cancer cell lines and tumorgrafts correlate with sensitivity to anti-IGF-IR therapy? Context: We previously reported an insulin-like growth factor (IGF) gene expression signature, based on genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. We tested whether the IGF signature was affected by anti-IGF-I receptor (IGF-IR) inhibitors and whether the IGF signature correlated with response to a dual anti-IGF-IR/insulin receptor (InsR) inhibitor, BMS-754807. An IGF gene expression signature was examined in human breast tumors and cell lines and changes were noted following treatment of cell lines or xenografts with anti-IGF-IR antibodies or tyrosine kinase inhibitors. Sensitivity of cells to BMS-754807 was correlated with levels of the IGF signature. Human primary tumorgrafts were analyzed for the IGF signature and IGF-IR levels and activity, and MC1 tumorgrafts were treated with BMS-754807 and chemotherapy. The IGF gene expression signature was reversed in three different models (cancer cell lines or xenografts) treated with three different anti-IGF-IR therapies. The IGF signature was present in triple-negative breast cancers (TNBC) and TNBC cell lines, which were especially sensitive to BMS-754807, and sensitivity was significantly correlated to the expression of the IGF gene signature. The TNBC primary human tumorgraft MC1 showed high levels of both expression and activity of IGF-IR and IGF gene signature score. Treatment of MC1 with BMS-754807 showed growth inhibition and, in combination with docetaxel, tumor regression occurred until no tumor was palpable. Regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe.
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These studies provide a clear biological rationale to test anti-IGF-IR/InsR therapy in combination with chemotherapy in patients with TNBC. Final Decision: yes