Targeting fibroblast-growth-factor-receptor-dependent signaling for cancer therapy

Heinzle, Christine; Sutterlüty, Hedwig; Grusch, Michael; Grasl‐Kraupp, Bettina; Berger, Walter; Marian, Brigitte

doi:10.1517/14728222.2011.566217

Cited by 51 publications

(50 citation statements)

References 191 publications

(37 reference statements)

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“…Therefore, FGFRs represent a potential therapeutic target, raising their currently significant interest. 5 Until now, small molecule tyrosine kinase inhibitors and specific antibodies have been developed and tested to target FGFRs in various cancer types. 6 In this study, we employed a natural ligand of FGFR, fibroblast growth factor 1 (FGF1) as a targeting agent specifically aimed at cancer cells.…”

Section: Introductionmentioning

confidence: 99%

FGF1-gold nanoparticle conjugates targeting FGFR efficiently decrease cell viability upon NIR irradiation

Szlachcic¹,

Pala²,

Zakrzewska³

et al. 2012

IJN

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Fibroblast growth factor receptors (FGFRs) are overexpressed in a wide variety of tumors, such as breast, bladder, and prostate cancer, and therefore they are attractive targets for different types of anticancer therapies. In this study, we designed, constructed, and characterized FGFR-targeted gold nanoconjugates suitable for infrared-induced thermal ablation (localized heating leading to cancer cell death) based on gold nanoparticles (AuNPs). We showed that a recombinant ligand of all FGFRs, human fibroblast growth factor 1 (FGF1), can be used as an agent targeting covalently bound AuNPs to cancer cells overexpressing FGFRs. To assure thermal stability, protease resistance, and prolonged half-life of the targeting protein, we employed highly stable FGF1 variant that retains the biological activities of the wild type FGF1. Novel FGF1 variant, AuNP conjugates are specifically internalized only by the cells expressing FGFRs, and they significantly reduce their viability after irradiation with nearinfrared light (down to 40% of control cell viability), whereas the proliferation potential of cells lacking FGFRs is not affected. These results demonstrate the feasibility of FGF1-coated AuNPs for targeted cancer therapy.

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Section: Introductionmentioning

confidence: 99%

FGF1-gold nanoparticle conjugates targeting FGFR efficiently decrease cell viability upon NIR irradiation

Szlachcic¹,

Pala²,

Zakrzewska³

et al. 2012

IJN

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show abstract

“…FGFR-targeted therapeutics using small-molecule compounds is an active topic in the field of clinical oncology because FGF signaling is involved in various aspects of cancer biology such as proliferation, anti-apoptosis, drug resistance, angiogenesis, and invasion (Heinzle et al 2011;Ota et al 2009). …”

Section: Fgfr Targeting Cancer Therapeuticsmentioning

confidence: 99%

FGFR4 as a Biomarker in Squamous Cell Cancers of the Mouth and Oropharynx

Dutra¹,

Santos²,

Mendes³

et al. 2014

Biomarkers in Cancer

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Head and neck squamous cell carcinoma (HNSCC) is a malignancy associated with severe mortality despite advances in therapy, and it ranks among the top ten most common cancers worldwide, with a large incidence variation according to sex and geographical location. At the moment, no biomarkers are currently available for HNSCC patients; prognosis depends largely on the stage at presentation, with the most important prognostic factor. Fibroblast growth factor receptors (FGFRs) and ligand binding are among the many molecules that are involved in the tumorigenesis process. These receptors, including FGFR4, belong to the receptor tyrosine kinase family leads to cell growth, mitosis, and differentiation. Mutations and amplifications in FGFR4 have been linked to aggressive tumor progression, and metastasis is associated with poor prognosis in HNSCC. In this review, we summarize the FGF/FGFR complex, signalization mechanisms, and the molecular implications of FGFR4 as potential biomarker for HNSCC.

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“…Alterations of the FGFR pathway in cancer include: gene amplification with receptor over-expression, FGFR mutations with constitutive active receptor or reduced dependency on ligand binding, translocation to produce FGFR fusion proteins with constitutive kinase activity, alternative FGFR splicing leading to a different but broader ligand specificity and up-regulation of the FGF expression with subsequent paracrine/autocrine activation of the pathway [6], [7], [8]. The dependency on FGFR pathway has been reported in different human malignancies [9], [10]. Amplification of FGFR1 has been reported in breast cancers (~10%) [11], [12], ovarian cancers (5%), lung squamous cell carcinomas (~20%) and lung adenocarcinomas (~3.5%) [13], [14], [15].…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models

et al. 2017

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The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1–3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.

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Targeting fibroblast-growth-factor-receptor-dependent signaling for cancer therapy

Cited by 51 publications

References 191 publications

FGF1-gold nanoparticle conjugates targeting FGFR efficiently decrease cell viability upon NIR irradiation

FGF1-gold nanoparticle conjugates targeting FGFR efficiently decrease cell viability upon NIR irradiation

FGFR4 as a Biomarker in Squamous Cell Cancers of the Mouth and Oropharynx

In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models

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