Pan-FGFR Inhibition Leads to Blockade of FGF23 Signaling, Soft Tissue Mineralization, and Cardiovascular Dysfunction

Yanochko, Gina M.; Vitsky, Allison; Heyen, Jonathan R.; Hirakawa, Brad; Lam, Justine L.; May, Jeffrey V.; Nichols, Tim; Sace, Frederick; Trajkovic, Dusko; Blasi, Eileen

doi:10.1093/toxsci/kft161

Cited by 60 publications

(66 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we demonstrate cardio-protective effects of targeting FGFR4, and we show that anti-FGFR4 treatment does not interfere with physiological actions of FGF23 over an extended period of time. In contrast to FGF23 neutralizing antibodies and prolonged pan-FGFR blockade that have been shown to cause hyperphosphatemia, tissue calcification and increased mortality 27, 28 , the specific FGFR4 blocking antibody did not interfere with serum phosphate levels.…”

Section: Discussionmentioning

confidence: 73%

FGF23/FGFR4-mediated left ventricular hypertrophy is reversible

Grabner

Schramm

Silswal

et al. 2017

Sci Rep

114

109

View full text Add to dashboard Cite

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that directly targets cardiac myocytes via FGF receptor (FGFR) 4 thereby inducing hypertrophic myocyte growth and the development of left ventricular hypertrophy (LVH) in rodents. Serum FGF23 levels are highly elevated in patients with chronic kidney disease (CKD), and it is likely that FGF23 directly contributes to the high rates of LVH and cardiac death in CKD. It is currently unknown if the cardiac effects of FGF23 are solely pathological, or if they potentially can be reversed. Here, we report that FGF23-induced cardiac hypertrophy is reversible in vitro and in vivo upon removal of the hypertrophic stimulus. Specific blockade of FGFR4 attenuates established LVH in the 5/6 nephrectomy rat model of CKD. Since CKD mimics a form of accelerated cardiovascular aging, we also studied age-related cardiac remodeling. We show that aging mice lacking FGFR4 are protected from LVH. Finally, FGF23 increases cardiac contractility via FGFR4, while known effects of FGF23 on aortic relaxation do not require FGFR4. Taken together, our data highlight a role of FGF23/FGFR4 signaling in the regulation of cardiac remodeling and function, and indicate that pharmacological interference with cardiac FGF23/FGFR4 signaling might protect from CKD- and age-related LVH.

show abstract

Section: Discussionmentioning

confidence: 73%

FGF23/FGFR4-mediated left ventricular hypertrophy is reversible

Grabner

Schramm

Silswal

et al. 2017

Sci Rep

114

109

View full text Add to dashboard Cite

show abstract

“…Although dovitinib has been shown to increases the blood levels of FGF23, a biomarker of systemic FGFR inhibition, the drug produces little or no hyperphosphatemia which is a marker of more robust receptor inhibition (32–34). That dovitinib may not produce sufficient FGFR suppression in vivo is supported by phase II studies of patients with bladder cancer who were treated with dovitinib or the more potent and specific FGFR inhibitor BGJ398.…”

Section: Discussionmentioning

confidence: 99%

A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma

Dillon

Petroni

Horton

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Genetic and preclinical studies have implicated fibroblast growth factor receptor (FGFR) signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor FGFR activity, may be active in ACC. Methods In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate (ORR) and change in tumor growth rate (TGR). Progression-free survival (PFS), overall survival (OS), metabolic response, biomarker and QOL were secondary endpoints. Results Of thirty-four evaluable patients, two (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on-treatment (p<0.001). Toxicity was moderate; 63% of patients developed grade 3–4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18FDG-PET scans was seen in 3/15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with over-expression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusion Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably to those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine if FGFR signaling is a valid therapeutic target in ACC.

show abstract

“…However, since pan-FGFR inhibition is toxic in humans (60, 61) and induces cardiovascular dysfunction in rats (62), the development of more targeted approaches to block the specific culprit FGFR isoform is necessary. To do so, it is inevitable to experimentally determine activation rather than expression of specific FGFR isoforms in the heart, since the receptor's activity state and expression level do not necessarily correlate with each other.…”

Section: The Role Of Fibroblast Growth Factor Receptors In the Heartmentioning

confidence: 99%

Cardiac actions of fibroblast growth factor 23

Faul

2017

Bone

View full text Add to dashboard Cite

Fibroblast growth factors (FGF) are mitogenic signal mediators that induce cell proliferation and survival. Although cardiac myocytes are post-mitotic, they have been shown to be able to respond to local and circulating FGFs. While precise molecular mechanisms are not well characterized, some FGF family members have been shown to induce cardiac remodeling under physiologic conditions by mediating hypertrophic growth in cardiac myocytes and by promoting angiogenesis, both events leading to increased cardiac function and output. This FGF-mediated physiologic scenario might transition into a pathologic situation involving cardiac cell death, fibrosis and inflammation, and eventually cardiac dysfunction and heart failure. As discussed here, cardiac actions of FGFs - with the majority of studies focusing on FGF2, FGF21 and FGF23 - and their specific FGF receptors (FGFR) and precise target cell types within the heart, are currently under experimental investigation. Especially cardiac effects of endocrine FGFs entered center stage over the past five years, as they might provide communication routes that couple metabolic mechanisms, such as bone-regulated phosphate homeostasis, or metabolic stress, such as hyperphosphatemia associated with kidney injury, with changes in cardiac structure and function. In this context, it has been shown that elevated serum FGF23 can directly tackle cardiac myocytes via FGFR4 thereby contributing to cardiac hypertrophy in models of chronic kidney disease, also called uremic cardiomyopathy. Precise characterization of FGFs and their origin and regulation of expression, and even more importantly, the identification of the FGFR isoforms that mediate their cardiac actions should help to develop novel pharmacological interventions for heart failure, such as FGFR4 inhibition to tackle uremic cardiomyopathy.

show abstract

Pan-FGFR Inhibition Leads to Blockade of FGF23 Signaling, Soft Tissue Mineralization, and Cardiovascular Dysfunction

Cited by 60 publications

References 37 publications

FGF23/FGFR4-mediated left ventricular hypertrophy is reversible

FGF23/FGFR4-mediated left ventricular hypertrophy is reversible

A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma

Cardiac actions of fibroblast growth factor 23

Contact Info

Product

Resources

About