Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice

Jiang, Qing; Du, Xiangnan; Chen, Yongmei; Chan, Pamela; Li, Hao; Wu, Ping; Marsters, Scot A.; Stawicki, Scott; Tien, Janet; Tótpál, Klára; Ross, Sarajane; Stinson, Susanna; Dornan, David; French, Dorothy; Wang, Qian-Rena; Stéphan, Jean-Philippe; Wu, Yan; Wiesmann, Christian; Ashkenazi, Avi

doi:10.1172/jci38017

Cited by 221 publications

(216 citation statements)

References 48 publications

(62 reference statements)

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“…Subcutaneous injections of recombinant sFGFR3 in a mouse model for achondroplasia was found to decrease mortality and improve skeletal growth (Garcia et al 2013). Inhibitory antibodies that specifically target the FGFR3 extracellular domain have been developed as potential cancer therapeutics but have not been evaluated for treatment of achondroplasia (Martinez-Torrecuadrada et al 2005;Hadari and Schlessinger 2009;Qing et al 2009). A recent drug screen of induced pluripotent stem cell-derived chondrocytes from patients with achondroplasia and thanatophoric dysplasia identified statin drugs as effective in improving chondrogenic differentiation in vitro and improving the phenotype (limb and body length) of achondroplasia mice in vivo (Yamashita et al 2014).…”

Section: Therapeutic Strategies In Achondroplasiamentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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Section: Therapeutic Strategies In Achondroplasiamentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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“…About 15% to 20% of patients with multiple myeloma harbor the chromosomal translocation t(4;14), which brings FGFR3 and the adjacent multiple myeloma SET domain ( MMSET) gene under the control of the Ig heavy chain promoter, thereby leading to the aberrant expression of FGFR3 and MMSET ( 33 ). The relative transforming contributions of FGFR3 and MMSET are still unclear; however, dependence on FGFR3 signaling has been shown in t(4;14) cell lines and mouse models ( 45 ).…”

Section: Fgfr3mentioning

confidence: 99%

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

et al. 2013

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The fi broblast growth factor/fi broblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifi cations, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, classspecifi c toxicity profi les and correctly designing clinical trials to address these different issues.Signifi cance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies. Cancer Discov;3(3);

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“…Although its role in human disease makes FGFR3 an attractive candidate for therapy, there is no treatment for FGFR3 disorders available to date, thus warranting development of novel approaches to target FGFR3 signaling (25)(26)(27). Here, we took advantage of RCS chondrocytes, which represent the most extensively studied cell model for FGFR3-related skeletal dysplasia (8 -12).…”

Section: Discussionmentioning

confidence: 99%

NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells

Krejčı́

Murakami

Procházková

et al. 2010

Journal of Biological Chemistry

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The FGFR3 receptor tyrosine kinase represents an attractive target for therapy due to its role in several human disorders, including skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas. By using molecular library screening, we identified a compound named NF449 with inhibitory activity toward FGFR3 signaling. In cultured chondrocytes and murine limb organ culture, NF449 rescued FGFR3-mediated extracellular matrix loss and growth inhibition, which represent two major cellular phenotypes of aberrant FGFR3 signaling in cartilage. Similarly, NF449 antagonized FGFR3 action in the multiple myeloma cell lines OPM2 and KMS11, as evidenced by NF449-mediated reversal of ERK MAPK activation and transcript accumulation of CCL3 and CCL4 chemokines, both of which are induced by FGFR3 activation. In cell-free kinase assays, NF449 inhibited the kinase activity of both wild type and a disease-associated FGFR3 mutant (K650E) in a fashion that appeared non-competitive with ATP. Our data identify NF449 as a novel antagonist of FGFR3 signaling, useful for FGFR3 inhibition alone or in combination with inhibitors that target the ATP binding site.FGFR3 (fibroblast growth factor receptor 3) is a transmembrane tyrosine kinase that serves as a receptor for the members of the fibroblast growth factor (FGF) 2 family and functions in many biological processes, including cell proliferation, differentiation, migration, and survival. To date, activating mutations in FGFR3 have been associated with several human disorders, such as skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas (1-4).Among the skeletal dysplasias, activating FGFR3 mutations cause achondroplasia, the most common form of human skeletal dysplasia, and thanatophoric dysplasia, the most common form of lethal skeletal dysplasia (1). Long bones of individuals suffering from FGFR3-related skeletal dysplasias show markedly shortened zones of chondrocyte proliferation and differentiation, whereas Fgfr3 knock-out mice and humans without functional FGFR3 demonstrate skeletal overgrowth, together implying the role of FGFR3 as a negative regulator of bone growth (5).Apart from cartilage, ϳ15% of patients suffering from multiple myeloma markedly up-regulate FGFR3 as a consequence of a t(4;14)(p16.3;q32) translocation, with a fraction of patients also harboring activating mutations in FGFR3, identical to those found in the skeletal dysplasias (2, 3). Ectopic expression of FGFR3 enhances multiple myeloma cell proliferation and survival, demonstrating the oncogenic potential of FGFR3 (6).Given its role in human disease, FGFR3 signaling represents an attractive target for therapy. There is no treatment available for achondroplasia at present, thus inciting the development of novel approaches to target FGFR3. The aim of this study was to identify novel inhibitors of FGFR3 signaling in cellular environments relevant to FGFR3-related disorders. We recently established a chondrocyte cell-based reporter assay suitable for identification of inhibitors of ...

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Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice

Abstract: Overexpression of FGF receptor 3 (FGFR3) is implicated in the development of t(4;14

Cited by 221 publications

References 48 publications

Fibroblast growth factor signaling in skeletal development and disease

Fibroblast growth factor signaling in skeletal development and disease

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells

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