Abstract

We have shown that insulin-like growth factors (IGFs) and their receptor IGF-1R play critical roles in proliferation, survival and drug-resistance of a broad spectrum of hematologic malignancies and solid tumors and that selective inhibitors of IGF-1R kinase activity have in vivo anti-tumor activity in clinically relevant orthotopic tumor models (

Cancer Cell
2004
;
5
:
221
–30
). We now describe the in vitro and in vivo activity of NVP-AEW541, a novel pyrrolo[2,3-d] pyrimidine selective IGF-1R tyrosine kinase inhibitor with 27-fold selectivity for IGF-1R vs. its highly homologous insulin receptor. NVP-AEW541 is active (at sub-uM levels) against diverse tumor types, including >30 MM cell lines and >10 primary tumor cells from MM patients (including cells resistant to Dex, alkylating agents, anthracyclines, thalidomide, or its immunomodulatory derivatives, IMiDs, bortezomib, and/or Apo2L/TRAIL); and cell lines from diverse hematologic malignancies (including B- and T-ALL, AML, CML, and lymphoma subtypes) and solid tumors (e.g. breast, prostate, lung, thyroid, ovarian, renal Ca, retinoblastoma and sarcomas). All studied tumor cells expressed IGF-1R, without any correlation between mean fluorescence intensity of expression of IGF-1R (or its decoy non-signaling counterpart IGF-2R/CD222) and the degree of tumor cell sensitivity to NVP-AEW541. The in vitro anti-tumor effects of NVP-AEW541 were highly consistent with those of other selective anti-IGF-1R neutralizing agents, including another IGF-IR inhibitor of the pyrrolo[2,3-d] pyrimidine structural class (NVP-ADW742) or anti-human IGF-1R-specific neutralizing mAb’s (aIR3). NVP-AEW541 counteracts the proliferative/anti-apoptotic effect of serum on tumor cells from the entire spectrum of diseases that were studied, but more prominently against MM cells. Importantly, NVP-AEW541 had in vivo anti-tumor activity in a SCID/NOD mice model of diffuse MM. Mechanistically, IGF-1R inhibition by NVP-AEW541 blocks key growth/survival pathways (e.g. PI-3K/Akt, Ras/Raf/MAPK, IKK-a/NF-kB); blocks expression of inhibitors of apoptosis (e.g. FLIP, cIAP-2, survivin); and suppresses both constitutive and serum- or IGF-1-induced upregulation of proteasome activity. These molecular sequelae can explain why NVP-AEW541 sensitized tumor cells (e.g. MM, PrCa, BrCa or sarcomas) to other anti-cancer drugs (e.g. Dex, cytotoxic chemotherapeutics and 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; and abrogated VEGF production in co-cultures of MM cells with BMSCs. These studies further confirm that IGF-1R plays major role in growth/survival of neoplastic cells, indicate that IGF-1R pathway can be targeted with multiple clinically applicable approaches; and provide proof-of-principle for clinical trials of NVP-AEW541, e.g. in MM, a disease particularly dependent upon IGF-1R function.

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