NVP-AEW541：一种选择性小分子 IGF-1R 酪氨酸激酶抑制剂对多发性骨髓瘤和其他血液肿瘤和实体瘤具有活性。,Blood

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NVP-AEW541：一种选择性小分子 IGF-1R 酪氨酸激酶抑制剂对多发性骨髓瘤和其他血液肿瘤和实体瘤具有活性。
Blood ( IF 21.0 ) Pub Date : 2004-11-16 , DOI: 10.1182/blood.v104.11.766.766
Nicholas Mitsiades _{1,

2} , Ciaran J. McMullan ₂ , Vassiliki Poulaki ₂ , Reshma Shringarpure ₂ , Towia A. Libermann ₃ , Teru Hideshima ₂ , Dharminder Chauhan ₂ , Robert L. Schlossman ₂ , Paul G. Richardson ₂ , Nikhil C. Munshi ₂ , Carlos Garcia-Echeverria ₄ , Francesco Hoffmann ₄ , Kenneth C. Anderson ₂ , Constantine S. Mitsiades ₂

Affiliation

我们已经表明，胰岛素样生长因子 (IGF) 及其受体 IGF-1R 在广谱血液系统恶性肿瘤和实体瘤的增殖、存活和耐药性中起关键作用，并且 IGF-1R 激酶活性的选择性抑制剂具有临床相关原位肿瘤模型中的体内抗肿瘤活性 (Cancer Cell2004;5:221-30)。我们现在描述 NVP-AEW541 的体外和体内活性，NVP-AEW541 是一种新型吡咯并 [2,3-d] 嘧啶选择性 IGF-1R 酪氨酸激酶抑制剂，对 IGF-1R 的选择性比其高度同源的胰岛素受体高 27 倍。NVP-AEW541 对多种肿瘤类型具有活性（亚 uM 水平），包括 > 30 MM 细胞系和 > 10 来自 MM 患者的原发肿瘤细胞（包括对 Dex、烷化剂、蒽环类、沙利度胺、或其免疫调节衍生物、IMiD、硼替佐米和/或 Apo2L/TRAIL)；和来自各种血液系统恶性肿瘤（包括 B 和 T-ALL、AML、CML 和淋巴瘤亚型）和实体瘤（例如乳腺癌、前列腺癌、肺癌、甲状腺癌、卵巢癌、肾癌、视网膜母细胞瘤和肉瘤）的细胞系。所有研究的肿瘤细胞都表达 IGF-1R，而 IGF-1R（或其诱饵非信号对应物 IGF-2R/CD222）表达的平均荧光强度与肿瘤细胞对 NVP-AEW541 的敏感性程度之间没有任何相关性。NVP-AEW541 的体外抗肿瘤作用与其他选择性抗 IGF-1R 中和剂的作用高度一致，包括另一种吡咯 [2,3-d] 嘧啶结构类的 IGF-IR 抑制剂 (NVP-ADW742 ) 或抗人 IGF-1R 特异性中和 mAb (aIR3)。NVP-AEW541 抵消了血清对来自所研究的整个疾病谱的肿瘤细胞的增殖/抗细胞凋亡作用，但更突出的是针对 MM 细胞。重要的是，NVP-AEW541 在弥漫性多发性骨髓瘤的 SCID/NOD 小鼠模型中具有体内抗肿瘤活性。从机制上讲，NVP-AEW541 对 IGF-1R 的抑制阻断了关键的生长/存活途径（例如 PI-3K/Akt、Ras/Raf/MAPK、IKK-a/NF-kB）；阻断细胞凋亡抑制剂（例如 FLIP、cIAP-2、存活蛋白）的表达；并抑制组成型和血清或 IGF-1 诱导的蛋白酶体活性上调。这些分子后遗症可以解释为什么 NVP-AEW541 使肿瘤细胞（例如 MM、PrCa、BrCa 或肉瘤）对其他抗癌药物（例如 Dex、细胞毒性化学疗法和 PS-341）敏感；减弱肿瘤细胞对其他生长因子的反应（例如 MM 或 PrCa 细胞对 IL-6 的反应）；克服了骨髓基质细胞赋予的耐药表型；并在 MM 细胞与 BMSCs 的共培养中消除了 VEGF 的产生。这些研究进一步证实了 IGF-1R 在肿瘤细胞的生长/存活中起主要作用，表明 IGF-1R 通路可以用多种临床适用的方法靶向；并为 NVP-AEW541 的临床试验提供原理证明，例如在 MM 中，一种特别依赖于 IGF-1R 功能的疾病。

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NVP-AEW541: A Selective Small Molecule IGF-1R Tyrosine Kinase Inhibitor Is Active Against Multiple Myeloma and Other Hematologic Neoplasias and Solid Tumors.

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 Cell2004;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.

更新日期：2004-11-16

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