A neutralizing anti‐fibroblast growth factor (FGF) 8 monoclonal antibody shows anti‐tumor activity against FGF8b‐expressing LNCaP xenografts in androgen‐dependent and ‐independent conditions

Maruyama-Takahashi, Kumiko; Shimada, Naoki; Imada, Teruyoshi; Maekawa-Tokuda, Yoshimi; Ishii, Toshihiko; Ouchi, Jun; Kusaka, Hideaki; Miyaji, Hiromasa; Akinaga, Shiro; Tanaka, Akira; Shitara, Kenya

doi:10.1002/pros.20728

Cited by 34 publications

(24 citation statements)

References 35 publications

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“…Also, FGF8b has been implicated in the inappropriate activation of growth factor signaling cascade that overcome steroid hormone sensitivity of these tumors, resulting in the progression toward a refractory neoplasm insensitive to hormone deprivation therapy (4,34,35). On this basis, the FGF/FGFR system has been hypothesized as a target for the treatment of steroid hormone-regulated tumors (2,(35)(36)(37)(38), also in a possible synergistic combination with g-irradiation or antineoplastic drug therapies (39). Here, we show that PTX3 represents a novel FGF8b antagonist endowed with antiangiogenic and antineoplastic activity.…”

Section: Discussionmentioning

confidence: 99%

“…It must be pointed out that S115 cells do not express FGF2 in vitro and in vivo, thus supporting the hypothesis that the inhibitory effect exerted by PTX3 on S155 tumors is related to its FGF8b antagonist activity. However, when compared with neutralizing anti-FGF8b antibodies (35), the ability to antagonize both FGF2 and FGF8b activities makes PTX3 a putative multitarget agent for those lesions characterized by the coexpression of the 2 angiogenic growth factors. Further studies are required to define the molecular bases of the selective interaction of PTX3 with distinct members of the FGF family.…”

Section: Discussionmentioning

confidence: 99%

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Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors

Leali

Alessi

Coltrini

et al. 2011

Molecular Cancer Therapeutics

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Fibroblast growth factor-8b (FGF8b) exerts nonredundant autocrine/paracrine functions in steroid hormone-regulated tumors. Previous observations had shown that the soluble pattern recognition receptor long pentraxin-3 (PTX3) is a natural selective antagonist for a restricted number of FGF family members, inhibiting FGF2 but not FGF1 and FGF4 activity. Here, we assessed the capacity of PTX3 to antagonize FGF8b and to inhibit the vascularization and growth of steroid hormone-regulated tumors. Surface plasmon resonance analysis shows that PTX3 binds FGF8b with high affinity (K d ¼ 30-90 nmol/L). As a consequence, PTX3 prevents the binding of FGF8b to its receptors, inhibits FGF8b-driven ERK1/2 activation, cell proliferation, and chemotaxis in endothelial cells, and suppresses FGF8b-induced neovascularization in vivo. Also, PTX3 inhibits dihydrotestosterone (DHT)-and FGF8b-driven proliferation of androgen-regulated Shionogi 115 (S115) mouse breast tumor cells. Furthermore, DHT-treated, PTX3 overexpressing hPTX3_S115 cell transfectants show a reduced proliferation rate in vitro and a limited angiogenic activity in the chick embryo chorioallantoic membrane and murine s.c. Matrigel plug assays. Accordingly, hPTX3_S115 cells show a dramatic decrease of their tumorigenic activity when grafted in immunodeficient male mice. These results identify PTX3 as a novel FGF8b antagonist endowed with antiangiogenic and antineoplastic activity with possible implications for the therapy of hormonal tumors. Mol Cancer Ther; 10(9); 1600-10. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors

Leali

Alessi

Coltrini

et al. 2011

Molecular Cancer Therapeutics

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“…Many preclinical models have done exactly this with the expression of FGF in either cancer cells or stromal cells, showing the autocrine and paracrine stimulation of cancer cells, respectively. Evidence of these autocrine and paracrine circuits have been identified in melanomas [67], in NSCLC [68], prostate adenocarcinomas [69], and in triple negative breast cancers [70]. Increased FGF release from stromal or tumor cells may have a role in cell survival, proliferation, and angiogenesis.…”

Section: Autocrine/paracrine Signalingmentioning

confidence: 99%

Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application

et al. 2016

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The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.

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“…This indicates a role of FGF8 in metastasis. Interestingly, a neutralizing antibody against FGF8 displays potent antitumor activity against mammary and prostate tumors in mouse models (126,127) and might be considered as a candidate for therapeutic treatment of cancers that are dependent on FGF8 signaling for growth and survival.…”

Section: Availability Of Ligandmentioning

confidence: 99%

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

Haugsten

Wiedlocha

Olsnes

et al. 2010

Molecular Cancer Research

278

226

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The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression.

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A neutralizing anti‐fibroblast growth factor (FGF) 8 monoclonal antibody shows anti‐tumor activity against FGF8b‐expressing LNCaP xenografts in androgen‐dependent and ‐independent conditions

Cited by 34 publications

References 35 publications

Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors

Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors

Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

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