Co-targeting IGF-1R and c-kit: synergistic inhibition of proliferation and induction of apoptosis in H 209 small cell lung cancer cells

Camirand, Anne; Pollak, Michael

doi:10.1038/sj.bjc.6601682

Cited by 43 publications

(34 citation statements)

References 27 publications

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“…In fact, there is experimental evidence which suggests that trastuzimabresistant breast cancer is particularly sensitive to IMC-A12 (54). These observations, together with other examples, such as synergistic induction of apoptosis when small cell lung cancer is targeted by both c-KIT and IGF-IR inhibitors, suggest that IGF-IR blockade might enhance tumor sensitivity to other kinase inhibitors (66).…”

Section: Prospects For Combinations With Targeted Therapiesmentioning

confidence: 98%

IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor

Rowinsky¹,

Youssoufian²,

Tonra³

et al. 2007

Clinical Cancer Research

153

112

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Section: Prospects For Combinations With Targeted Therapiesmentioning

confidence: 98%

IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor

Rowinsky¹,

Youssoufian²,

Tonra³

et al. 2007

Clinical Cancer Research

153

112

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“…Consequently, novel therapies are urgently required and these will most likely arise from an improved understanding of the disease biology. There is now considerable evidence implicating multiple growth factors that act in an autocrine or paracrine fashion to drive SCLC proliferation (1)(2)(3)(4)(5). In particular, our laboratory has established the role of basic-fibroblast growth factor (FGF-2) in this disease (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

The Fibroblast Growth Factor Receptor Inhibitor PD173074 Blocks Small Cell Lung Cancer Growth In vitro and In vivo

et al. 2009

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Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of <5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3′-deoxy-3′-

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“…We have therefore used tissue arrays to analyze the protein expression of the six TKs which are believed to play the most significant roles in the progression of a number of human malignancies, and which are potential clinical targets for kinase inhibition (Blume-Jensen & Hunter 2001). We selected EGF-R, Her-2/neu, PDGF-R, insulinlike growth factor 1 receptor (IGF-1R), c-Abl and c-Kit for their pivotal involvement in a number of solid tumors and for the fact that each of these kinases can be targeted by newly developed, clinically available TKIs (George 2001, Scheijen & Griffin 2002, Janmaat & Giaccone 2003, Camirand & Pollak 2004. Furthermore, in each case, preclinical studies have already confirmed that these targets can be selectively neutralized by highly specific TKIs.…”

Section: Introductionmentioning

confidence: 99%

Expression of tyrosine kinases in human malignancies as potential targets for kinase-specific inhibitors

Singer¹,

Hudelist²,

Lamm³

et al. 2004

Endocr Relat Cancer

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Tyrosine kinase (TK) inhibition has been identified as a promising strategy in the treatment of human malignancies and several synthetic inhibitors have been developed. While the selective blockage of specific TKs is highly effective in vitro, clinical results have been less impressive. It has been suggested that the simultaneous inhibition of multiple TKs might lead to more favorable therapeutic results in vivo. We have therefore performed a systematic analysis of intra-tumoral TK expression in order to identify potential targets for a simultaneous kinase inhibition. To this end, we have analyzed the protein expression of membrane-associated epidermal growth factor receptor (EGF-R), Her-2/neu, platelet-derived growth factor receptor (PDGF-R), insulin-like growth factor receptor (IGF-R), c-Kit and of cytoplasmatic c-Abl in 500 human tumors of epithelial, stromal and mesenchymal origin by immunohistochemistry, and found a distinct pattern of kinase expression: EGF-R, PDGF-R and c-Abl were expressed in the majority of malignant tumors, whereas c-Kit, Her-2/neu and IGF-R protein expression was considerably less frequent. Overall, the EGF-R protein expression was correlated with PDGF-R, c-Kit and c-Abl immunoreactivity (P ¼ 0:003, P ¼ 0:001 and P < 0:001, respectively). c-Abl was co-expressed with IGF-R and PDGF-R (P ¼ 0:003 and P < 0:001, respectively). Kinase coexpression was also seen in tumor subgroups and was particularly significant in breast cancer where IGF-R protein was expressed together with PDGF-R and c-Abl (P ¼ 0:003 and P ¼ 0:004, respectively), and in colon cancer where PDGF-R was correlated with EGF-R (P < 0:001). With the exception of Her-2/neu expression and age, intra-tumoral TK expression was not associated with parameters such as grading or histological subtypes. Taken together, we have found a specific pattern of kinase co-expression and have identified several potential targets for a tumor-specific multimodal TK inhibition.

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Co-targeting IGF-1R and c-kit: synergistic inhibition of proliferation and induction of apoptosis in H 209 small cell lung cancer cells

Cited by 43 publications

References 27 publications

IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor

IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor

The Fibroblast Growth Factor Receptor Inhibitor PD173074 Blocks Small Cell Lung Cancer Growth In vitro and In vivo

Expression of tyrosine kinases in human malignancies as potential targets for kinase-specific inhibitors

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