A novel monovalent FGFR1 antagonist: Preclinical safety profiles in rodents and non-human primates

Yu, Ping; Knippel, Anja; Onidi, Manuela; Vigna, Enrico; Hellmann, Jürgen; Esdar, Christina

doi:10.1016/j.taap.2020.115215

Cited by 3 publications

(2 citation statements)

References 35 publications

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“…Therefore, we screened a large panel of NSCLC PDX models (n Z 96) for FGFR1 amplification by FISH and identified ten (10.4%) positive cases based on the criteria previously defined by Schildhaus et al [32]. These ten tumour models were assessed for response to the selective monovalent FGFR1 antagonist M6123 [42,43]. Inhibition of tumour growth following M6123 treatment was observed in two of the PDX models, while the other eight models did not respond.…”

Section: Targeting Fgfr1 In Patient-derived Xenograft Models Of Lung Cancermentioning

confidence: 99%

FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response

Bogatyrova

Mattsson

Ross

et al. 2021

European Journal of Cancer

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Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response.In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n Z 298) or DNA microarray (n Z 189). FGFR1 gene expression (n Z 369) and immune cell profiles (n Z 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123.A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of

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Section: Targeting Fgfr1 In Patient-derived Xenograft Models Of Lung Cancermentioning

confidence: 99%

FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response

Bogatyrova

Mattsson

Ross

et al. 2021

European Journal of Cancer

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“…Consistent with these findings, FGFR inhibitors such as pemigatinib and erdafitinib, have been approved by the FDA for the treatment of advanced or metastatic cholangiocarcinoma and urothelial cancer; both characterized by genetic amplifications, mutations, rearrangements, and fusions of the FGFR genes [83]. Therefore, these inhibitors target primarily tumour cells and have not shown significant effects in tumour angiogenesis [83,84], further supporting a role of the FGF family primarily in cell types other than ECs [85]. Furthermore, although autocrine VEGF signalling appears important for vascular homeostasis in the mouse [86], there is little evidence that long‐term VEGF (or VEGFR) inhibition with a variety of inhibitors is associated with significant detrimental effects on the normal vasculature in patients with cancer or eye disorders [87].…”

Section: Molecular Endothelial Heterogeneitymentioning

confidence: 87%

Endothelial cell diversity: the many facets of the crystal

2022

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Endothelial cells (ECs) form the inner lining of blood vessels and play crucial roles in angiogenesis. While it has been known for a long time that there are considerable differences among ECs from lymphatic and blood vessels, as well as among arteries, veins and capillaries, the full repertoire of endothelial diversity is only beginning to be elucidated. It has become apparent that the role of ECs is not just limited to their exchange functions. Indeed, a multitude of organ‐specific functions, including release of growth factors, regulation of immune functions, have been linked to ECs. Recent years have seen a surge into the identification of spatiotemporal molecular and functional heterogeneity of ECs, supported by technologies such as single‐cell RNA sequencing (scRNA‐seq), lineage tracing and intersectional genetics. Together, these techniques have spurred the generation of epigenomic, transcriptomic and proteomic signatures of ECs. It is now clear that ECs across organs and in different vascular beds, but even within the same vessel, have unique molecular identities and employ specialized molecular mechanisms to fulfil highly specialized needs. Here, we focus on the molecular heterogeneity of the endothelium in different organs and pathological conditions.

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Pharmacological and Biological Targeting of FGFR1 in Cancer

Fan,

Chen,

Wang

et al. 2024

CIMB

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FGFR1 is a key member of the fibroblast growth factor receptor family, mediating critical signaling pathways such as RAS-MAPK and PI3K-AKT. which are integral to regulating essential cellular processes, including proliferation, differentiation, and survival. Alterations in FGFR1 can lead to constitutive activation of signaling pathways that drive oncogenesis by promoting uncontrolled cell division, inhibiting apoptosis, and enhancing the metastatic potential of cancer cells. This article reviews the activation mechanisms and signaling pathways of FGFR1 and provides a detailed exposition of the types of FGFR1 aberration. Furthermore, we have compiled a comprehensive overview of current therapies targeting FGFR1 aberration in cancer, aiming to offer new perspectives for future cancer treatments by focusing on drugs that address specific FGFR1 alterations.

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A novel monovalent FGFR1 antagonist: Preclinical safety profiles in rodents and non-human primates

Cited by 3 publications

References 35 publications

FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response

FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response

Endothelial cell diversity: the many facets of the crystal

Pharmacological and Biological Targeting of FGFR1 in Cancer

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