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

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.