Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis |
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Authors: | Kai-Da Wu Li Zhou Douglas Burtrum Dale L Ludwig Malcolm A S Moore |
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Institution: | (1) James Ewing Laboratory of Developmental Hematopoiesis, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA;(2) ImClone Systems Incorporated, New York, NY 10014, USA |
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Abstract: | Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic
strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor
cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I
or serum -induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant
inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated
xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical
use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged
when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly
decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities
of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive
and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment
may contribute to its anti-tumor effect. |
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Keywords: | Multiple myeloma Receptor tyrosine kinase IGF-IR Human antibody Anti-angiogenesis Targeted therapy |
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