FGFR expression

Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

These results contribute to clarifying the biological effects and molecular mechanisms mediated by the anti-FGFR TKI pemigatinib in distinct tumor settings and support its exploitation for combined therapies.

However, despite the availability of Pemigatinib, a very limited group of patients benefit from this treatment...Accordingly, dual inhibition of FGFRs and EGFR by PD173074 and EGFR inhibitor erlotinib was synergistic in CCA. Hence, the findings from this study provide support for further clinical investigation of PD173074, as well as other FGFR inhibitors, to benefit a larger cohort of patients. Altogether, this study shows for the first time the potential of FGFRs and the importance of dual inhibition as a novel therapeutic strategy in CCA.

The combination showed synergy (5) or additivity (2), and no antagonism, with synergy significantly associated (P < 0.05) with higher levels of M2-type macrophages. The association of strong efficacy of the combination in vivo with M2 macrophages, which are known to express CSF1R, and the absence of synergy in vitro is consistent with the tumor microenvironment also being a factor in DZB efficacy and suggests additional means by which DZB could be stratified for cancer treatment in the clinic.

Interestingly, the IO score predicted benefit in patients with high FGFR expression, despite conflicting data regarding response rates among the FGFR aberrant population. Taken together, these results demonstrate that the IO score assessment of the TIME is associated with a clinical benefit from ICI therapy and that this novel biomarker may inform therapeutic sequencing decisions in mUC, potentially improving outcomes for this notoriously difficult-to-treat disease.

Treatment with recombinant FGF9 significantly enhanced the proliferation of UM cells, and this effect was efficiently blocked by the FGFR1/2/3 inhibitor BGJ398. Our study indicates that FGF9 released by HSCs promotes the tumorigenicity of UM cells, and thus suggests FGF9 as a promising therapeutic target in hepatic metastasis.

NGS revealed known pathogenic FGFR2,3 variants, an FGFR3::TACC3 fusion, and a novel TACC1::FGFR1 fusion together with FGFR1,2 variants of uncertain significance not previously reported in Sq-NSCLC. These findings expand our knowledge of the Sq-NSCLC molecular background and show that combining different methods increases the rate of FGFR aberrations detection, which may improve patient selection for FGFRi treatment.

Nonetheless, FGF/FGFR has been a promising target for HNSCC treatment, and recent preclinical studies demonstrate the potential of the combination treatment regimens involving FGFR inhibitors on HNSCC. Therefore, there are a number of FGFR inhibitors currently in clinical trials for the treatment of head and neck cancers.

Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising...FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

We found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated.

At present, several inhibitors targeting FGF/FGFR, such as multikinase inhibitors, specific FGFR4 inhibitors, and FGF ligand traps, exhibit antitumor activity in preclinical or early development phases in HCC. In this review, we summarize the research progress regarding the molecular implications of FGF/FGFR-mediated signaling and the development of FGFR-targeted therapeutics in hepatocarcinogenesis.

Our results indicate that, besides targeting FGFR-amplified BCs with selective FGFRis, also BCs without FGFR amplification/activation may benefit from FGFRi-treatment. Combination with other treatment modalities, such as radiotherapy, may allow the use of FGFRis at relatively low concentrations and, thereby, contribute to better BC treatment outcomes.

We provide evidence that the FGFR pathway has therapeutic potential for a subset of DDLPS and that an FGFR1/FGFR4 expression might constitute a powerful biomarker to select patients for FGFR inhibitor clinical trials. In addition, we show that combining erdafitinib with RG7388 is a promising strategy for patients with DDLPS that deserves further investigation in the clinical setting.

Our study demonstrated that DCE-MRI is a reliable non-invasive imaging technique to monitor tumor microcirculatory response to FGFR inhibition and VEGF inhibition in high-FGFR-expressing HCC xenografts. Furthermore, the microcirculatory changes from FGFR inhibition manifested early upon treatment initiation and were reliably detected by DCE-MRI, creating possibilities of combinatorial therapy for synergistic effect.

A mUCB high-risk group with FGFR3-mRNA overexpression could be identified, which shows a lower CSS despite OK. Standardized, locally available FGFR mRNA analyzes could identify an FGFR inhibitor target population that is twice as large as the population that is only detected by FGFR alterations.

Next-generation sequencing data mining has shown that high levels of FGF/FGFR expression are associated with reduced overall survival (OS) in CAA, which indicates that the FGF/FGFR pathway may be an effective target for CAA treatment. This paper reviews the effect of FGF/FGFR signaling on CCA from onset to treatment and highlights the promise of FGF/FGFR signaling pathway inhibitors for targeting CCA.

High positive FGFR1 or 3 expression ratios were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), and ovarian cancer (34%). FGFR expression was a promising predictive biomarker for FGFR inhibition response in clinical trials, and different combinations of FGFR genes should be used in screening for patients in certain tumor types.

The assessment of FGFR mRNA by standardized RT-qPCR identified a high risk UCB patient cohort, which does have inferior disease specific survival despite IO treatment and does overexpress FGFR3 mRNA. The assessment of FGFR mRNA levels by using this standardized, locally applicable FGFR testing could identify an FGFR inhibitor target population with poor response to IO treatment which is twice the size as currently detected by FGFR genomic alterations alone. Source of Funding: Janssen, Research & Development, LLC, USA

This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR expressing NSCLC in vitro and in vivo model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.

The assessment of FGFR mRNA by standardized RT-qPCR identified a high risk UCB patient cohort, which does have inferior disease specific survival despite IO treatment and does over express FGFR3 mRNA. The assessment of FGFR mRNA levels by using this standardized, locally applicable FGFR testing could identify an FGFR inhibitor target population with poor response to IO treatment which is twice the size as currently detected by FGFR genomic alterations alone.

This data suggests that while FGFR1-3 genes are overall expressed in CRC and lung, some cases may have significantly high expression of FGFR1-3 and perhaps these cases should be singled out for treatment with FGFR inhibitors. Furthermore, NGS testing for mutations significantly more efficient and can detect significant number of mutations that can be missed if PCR-based testing is used. NGS testing of DNA and RNA is the most appropriate testing for abnormalities in FGFR1-4.

These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.

P1, N=168, Completed, Bayer | Active, not recruiting --> Completed