Approaches Targeting the FGF–FGFR System: a Review of the Recent Patent Literature and Associated Advanced Therapeutic Agents

Herbert, Corentin; Lassalle, Gilbert; Alcouffe, Chantal; Bono, Françoise

doi:10.4155/ppa.14.45

Cited by 21 publications

(14 citation statements)

References 51 publications

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“…Mutations were found in 5 of 15 tumors. PIK3CA mutations were identified in 3 tumors, 2 of which also harbored mutations in fibroblast growth factor receptor (FGFR) family members.This is an interesting finding, because phosphatidylinositol 3-kinase (PI3K) inhibitors and FGFR inhibitors are currently in development [50,51]. In the study of Ang et al, an activating mutation of vascular endothelial growth factor receptor 2 (VEGFR2), was found [49], and in another study using immunohistochemistry, VEGF-C was reported to be strongly expressed in NECB [52].…”

Section: Future Perspectivesmentioning

confidence: 94%

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

et al. 2015

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Neuroendocrine carcinoma of the breast is considered a rare entity, and for this reason there are no data from prospective clinical trials on its optimal management. Early stage tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Anthracycline-and taxane-based regimens represent the most frequently administered chemotherapy in neoadjuvant and adjuvant setting, as well as for metastatic disease, although combinations of platinum compounds and etoposide have been widely used, in particular for small-cell histology and tumors with a high proliferation index. For metastatic disease, a multimodality therapeutic strategy can be considered on an individual basis, with chemotherapy, endocrine therapy, peptide receptor radionuclide therapy, radiation therapy, surgery, or a combination of the above. In the near future, a better knowledge of the biology of these tumors will hopefully provide new therapeutic targets for personalized treatment. In this review, we discuss the current evidence and the future perspectives on diagnosis and treatment of neuroendocrine carcinoma of the breast. The Oncologist 2016;21:28-32 Implications for Practice: Neuroendocrine carcinoma of the breast (NECB) is a distinct entity of breast cancer. Clinical features and morphology are not helpful to distinguish NECB from other subtypes of breast cancer; therefore, immunohistochemistry markers for neuroendocrine differentiation, mainly chromogranin and synaptophysin, should be routinely used to confirm the diagnosis, especially in cases of mucinous or solid papillary carcinoma in which the suspicion of NECB may be relevant. Adjuvant treatment should be offered according to the same recommendations given for the other types of invasive breast cancer. An accurate diagnosis of NECB is also important in the metastatic setting, in which a multimodality approach including specific therapies such as peptide receptor radionuclide therapy can be considered.

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Section: Future Perspectivesmentioning

confidence: 94%

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

et al. 2015

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“…Finally, FGFR1 has a crucial feature of undergoing rapid internalization, predominantly through clathrin-mediated endocytosis, and subsequent sorting to lysosomes (40), which should ensure efficient drug release from the internalized antibody-drug complexes (44). Recently, the first ADC therapy has been proposed for FGFR2-positive cancer patients, which inhibited tumor growth in xenograft models (45,46). In this study, we report the selection and detailed characterization of a novel internalizing anti-FGFR1 antibody in the scFv-Fc format, named scFvD2-Fc, and its use for targeting FGFR1-expressing lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

Sokołowska-Wędzina

Chodaczek

Chudzian

et al. 2017

Molecular Cancer Research

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Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smokingassociated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040-50. Ó2017 AACR.

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“…As an example, the peptide comprising the amino acid sequence FGF2 impaired the interaction of FGF2 with FGFR1 [125] and similar peptides were successfully employed to specifically deliver antiblastic drugs to FGFR-overexpressing tumor cells [126]. In addition, vaccination against FGFR1 showed antitumor activity in vivo [127] and anti-FGFR neutralizing antibodies blocked FGF2-mediated angiogenesis in vivo [113,[128][129][130].…”

Section: Preventing Fgf/fgfr/co-receptor Interactionsmentioning

confidence: 99%

“…One of the most exploited approaches for the design of inhibitors of the FGF/FGFR system is based on the production of neutralizing anti-FGF antibodies [103,113] and the search for natural and synthetic FGF binders that sequester the growth factor in the extracellular compartment, thus acting as FGF traps [114,115]. Natural FGF binders (Table 2) have been identified in the ECM and body fluids.…”

Section: Preventing Fgf/fgfr/co-receptor Interactionsmentioning

confidence: 99%

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Giacomini

Chiodelli

Matarazzo

et al. 2016

Pharmacological Research

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a b s t r a c tFibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments.The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies.Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising.Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

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Approaches Targeting the FGF–FGFR System: a Review of the Recent Patent Literature and Associated Advanced Therapeutic Agents

Cited by 21 publications

References 51 publications

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

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