Dataset Information

The Fibroblast Growth Factor Receptors in Breast Cancer: from Oncogenesis to Better Treatments.

ABSTRACT: Breast cancer (BC) is the most frequent form of malignancy and second only to lung cancer as cause of deaths in women. Notwithstanding many progresses made in the field, metastatic BC has a very poor prognosis. As therapies are becoming more personalized to meet the needs of patients, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level and functioning on such cancer-causing molecules expressed in cancer cells of patients, or present as antigens on the surface of cancer cell membranes. Fibroblast growth factor receptor (FGFR) is one of such druggable targets, activated by its own ligands -namely the Fibroblast Growth Factors (FGFs). This pathway provides a vast range of interesting molecular targets pursued at different levels of clinical investigation. Herein we provide an update on the knowledge of genetic alterations of the receptors in breast cancer, their role in tumorigenesis and the most recent drugs against this particular receptor for the treatment of the disease.

SUBMITTER: Navid S

PROVIDER: S-EPMC7139621 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The Fibroblast Growth Factor Receptors in Breast Cancer: from Oncogenesis to Better Treatments.

Navid Sobhani S Fan Chunmei C O Flores-Villanueva Pedro P Generali Daniele D Generali Daniele D Li Yong Y

International journal of molecular sciences 20200316 6

Breast cancer (BC) is the most frequent form of malignancy and second only to lung cancer as cause of deaths in women. Notwithstanding many progresses made in the field, metastatic BC has a very poor prognosis. As therapies are becoming more personalized to meet the needs of patients, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level and functioning on suc ...[more]

PMID: 32188012

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Project description:Ependymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

Dataset Information

The Fibroblast Growth Factor Receptors in Breast Cancer: from Oncogenesis to Better Treatments.

Publications

The Fibroblast Growth Factor Receptors in Breast Cancer: from Oncogenesis to Better Treatments.

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