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Experimental and Molecular Therapeutics 48: Growth Factor Receptors as Therapeutic Targets

Insulin-like growth factor-1 receptor (IGF-1R/CD221): A target for monoclonal antibody-based therapy to overcome drug-resistance in multiple myeloma (MM), other hematologic malignancies and solid tumors

Constantine S. Mitsiades, Nicholas Mitsiades, Ciaran J. McMullan, Reshma Shringarpure, Rajeeva Singh and Kenneth C. Anderson
Constantine S. Mitsiades
Dana-Farber Cancer Institute, Harvard Med. School, Boston, MA and Immunogen Inc., Boston, MA
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Nicholas Mitsiades
Dana-Farber Cancer Institute, Harvard Med. School, Boston, MA and Immunogen Inc., Boston, MA
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Ciaran J. McMullan
Dana-Farber Cancer Institute, Harvard Med. School, Boston, MA and Immunogen Inc., Boston, MA
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Reshma Shringarpure
Dana-Farber Cancer Institute, Harvard Med. School, Boston, MA and Immunogen Inc., Boston, MA
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Rajeeva Singh
Dana-Farber Cancer Institute, Harvard Med. School, Boston, MA and Immunogen Inc., Boston, MA
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Kenneth C. Anderson
Dana-Farber Cancer Institute, Harvard Med. School, Boston, MA and Immunogen Inc., Boston, MA
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DOI:  Published April 2004
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Proc Amer Assoc Cancer Res, Volume 45, 2004

Abstract

5331

We have shown that insulin-like growth factor-1 receptor (IGF-1R) signaling can attenuate responsiveness of multiple myeloma (MM) cells to pro-apoptotic agents, including dexamethasone (Dex), cytotoxic chemotherapy, Apo2L/TRAIL or the proteasome inhibitor bortezomib (PS-341). We have also shown that small molecule inhibitors of IGF-1R kinase activity have both in vitro and in vivo activity against MM and a broad spectrum of other hematologic malignancies and solid tumors. Due to the functional roles of IGF-1R in broad spectrum of neoplasias, we have explored diverse therapeutic approaches targeting IGF-1R function, including specific anti-human IGF-1R neutralizing monoclonal antibodies (mAb), such as EM-164 (Immunogen Inc., Boston, MA) and aIR3. Consistent with their specificity for only IGF-1R, these mAb completely abrogated IGF-1-induced IGF-1R autophosphorylation, but had no effect on phosphorylation of its more closely homologous receptor, the insulin receptor. EM-164 was active against primary MM tumor cells and a broad panel of MM cell lines (including cells resistant to cytotoxic chemotherapy, thalidomide and its immunomodulatory derivatives {IMiDs} or PS-341) and cell lines from solid tumors (e.g. breast, prostate, lung, colon, thyroid, ovarian, renal Ca, retinoblastoma, sarcoma), leukemias and lymphomas (consistent with our previous findings of cell surface IGF-1R expression in these diseases). MM cells were among the most sensitive tumor types to IGF-1R inhibition indicating a prominent role for IGF-1R signaling in MM pathophysiology. Using transcriptional and proteomic profiling, we found that EM-164 and aIR3 confer pleiotropic anti-proliferative/pro-apoptotic sequelae, including inhibition of key growth/survival cascades (e.g. PI-3K/Akt, Ras/Raf/MAPK, IKK-α/NF-κB); decreased expression of caspase inhibitors (e.g. FLIP, cIAP-2); neutralization of pro-apoptotic Forkhead transcription factors; and suppression of constitutive and IGF-induced increase in proteasome and telomerase activities. These molecular sequelae can explain why anti-IGF-1R mAb sensitized tumor cells (e.g. MM, PrCa, BrCa) to other anti-cancer drugs (e.g. Dex, cytotoxic chemotherapy or PS-341); blunted tumor cell responses to other growth factors (e.g. MM or PrCa cell response to IL-6); overcame the drug-resistance phenotype conferred by bone marrow stromal cells (BMSCs); and abrogated VEGF production in co-culture models of MM cells with BMSCs. Our current findings, coupled with our recent results on the safety and efficacy of selective IGF-1R inhibition in mouse MM models, indicate that mAb-based targeting of IGF-1R can also be part of therapeutic strategies to comprehensively abrogate the critical role of IGF-1R signaling in tumor cell proliferation and drug resistance.

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April 2004
Volume 64, Issue 7 Supplement
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Insulin-like growth factor-1 receptor (IGF-1R/CD221): A target for monoclonal antibody-based therapy to overcome drug-resistance in multiple myeloma (MM), other hematologic malignancies and solid tumors
Constantine S. Mitsiades, Nicholas Mitsiades, Ciaran J. McMullan, Reshma Shringarpure, Rajeeva Singh and Kenneth C. Anderson
Cancer Res April 1 2004 (64) (7 Supplement) 1229-1230;

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Insulin-like growth factor-1 receptor (IGF-1R/CD221): A target for monoclonal antibody-based therapy to overcome drug-resistance in multiple myeloma (MM), other hematologic malignancies and solid tumors
Constantine S. Mitsiades, Nicholas Mitsiades, Ciaran J. McMullan, Reshma Shringarpure, Rajeeva Singh and Kenneth C. Anderson
Cancer Res April 1 2004 (64) (7 Supplement) 1229-1230;
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