Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro

BMC Cancer

Thomas M Cardillo³  Preeti Trisal³  Roberto Arrojo³  David M Goldenberg²  Chien-Hsing Chang¹ 

[1] IBC Pharmaceuticals, Inc, 300 American Rd, Morris Plains, NJ 07950, USA

[2] Center of Molecular Medicine and Immunology, Garden State Cancer Center, 300 American Rd, Morris Plains, NJ, 07950, USA

[3] Immunomedics, Inc, 300 American Rd, Morris Plains, NJ 07950, USA

关键词: mTOR inhibitors;    1R-2b;    Hex-hR1;    Insulin-like growth factor-I receptor;    Renal cell carcinoma;    Dock-and-Lock;   

Others  :  1079820
DOI  :  10.1186/1471-2407-13-170

 received in 2012-10-17, accepted in 2013-03-19,  发布年份 2013

【 摘 要 】

Background

Advanced or metastatic renal cell carcinoma (RCC) has a poor prognosis, because it is relatively resistant to conventional chemotherapy or radiotherapy. Treatments with human interferon-α2b alone or in combination with mammalian target of rapamycin (mTOR) inhibitors have led to only a modest improvement in clinical outcome. One observation made with mTOR inhibitors is that carcinomas can overcome these inhibitory effects by activating the insulin-like growth factor-I (IGF-I) signaling pathway. Clinically, there is an association of IGF-I receptor (IGF-IR) expression in RCC and poor long-term patient survival. We have developed a humanized anti-IGF-IR monoclonal antibody, hR1, which binds to RCC, resulting in effective down-regulation of IGF-IR and moderate inhibition of cell proliferation in vitro. In this work, we evaluate the anti-tumor activity of two novel IGF-1R-targeting agents against renal cell carcinoma given alone or in combination with an mTOR inhibitor.

Methods

hR1 was linked by the DOCK-AND-LOCK™ (DNL™) method to four Fabs of hR1, generating Hex-hR1, or to four molecules of interferon-α2b, generating 1R-2b. Eight human RCC cell lines were screened for IGF-1R expression and sensitivity to treatment with hR1 in vitro. Synergy with an mTOR inhibitor, temsirolimus, was tested in a cell line (ACHN) with low sensitivity to hR1.

Results

Hex-hR1 induced the down-regulation of IGF-IR at 10-fold lower concentrations compared to the parental hR1. Sensitivity to growth inhibition mediated by hR1 and Hex-hR1 treatments correlated with IGF-1R expression (higher expression was more sensitive). The potency of 1R-2b to inhibit the in vitro growth of RCC was also demonstrated in two human cell lines, ACHN and 786-O, with EC₅₀–values of 63 and 48 pM, respectively. When combined with temsirolimus, a synergistic growth-inhibition with hR1, Hex-hR1, and 1R-2b was observed in ACHN cells at concentrations as low as 10 nM for hR1, 1 nM for Hex-hR1, and 2.6 nM for 1R-2b.

Conclusions

Both Hex-hR1 and 1R-2b proved to be more potent than parental hR1 in inhibiting growth of RCC in vitro. Synergy was achieved when each of the three hR1-based agents was combined with temsirolimus, suggesting a new approach for treating RCC.

【 授权许可】

   
2013 Cardillo et al.; licensee BioMed Central Ltd.

【 图 表 】

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