Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

Ronca, Roberto; Giacomini, Arianna; Salle, Emanuela Di; Coltrini, Daniela; Pagano, Katiuscia; Ragona, Laura; Matarazzo, Sara; Rezzola, Sara; Maiolo, Daniele; Torella, Rubben; Moroni, Elisabetta; Mazzieri, Roberta; Escobar, Giulia; Mor, Marco; Colombo, Giorgio; Presta, Marco

doi:10.1016/j.ccell.2015.08.007

Cited by 18 publications

(32 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Relevant to this latter point, blockade of FGFR signalling by selective or broad-spectrum TK inhibitors has been associated with toxicity [146] and a monoclonal antibody directed against FGFR1 has failed because of severe weight loss associated with hypothalamic binding [156]. Interestingly, at variance with the hyperphosphatemic effect of FGFR TK inhibitors in preclinical models [157] and cancer patients [146], long-term administration of the small molecule FGF trap NSC12 does not affect the blood levels of phosphorus, calcium and FGF23 in tumor-bearing mice [120]. These observations are in keeping with the safety profile in murine tumor models of the FGFR1-derived FGF trap FP-1039 [124] and of the allosteric multi-FGFR blocker SSR128129E [148].…”

Section: Discussionmentioning

confidence: 99%

“…The information was translated into pharmacophore models for the screening of small molecule databases. This approach led to identification and characterization of TSP-1 peptidomimetics [116] and PTX3-derived peptides and small molecules [118][119][120] acting as FGF traps and endowed with antiangiogenic and antitumor properties.…”

Section: Preventing Fgf/fgfr/co-receptor Interactionsmentioning

confidence: 99%

See 1 more Smart Citation

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

Giacomini

Chiodelli

Matarazzo

et al. 2016

Pharmacological Research

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…36 The docking grid on the surface of FGF2 was centered on the residues that interact with the ligand in the binding mode described in a previous work, 14 i.e., Leu55, Ala57, Val63, Glu96, and Leu98. The bounding box, enclosing ligand center of mass, was extended for 15 Å in each axis.…”

Section: Hplc−esi-ms/ms Analytical Method a Hplc−esi-ms/msmentioning

confidence: 99%

“…14 In order to extend these observations in an immunocompetent syngeneic animal model, we designed a study to evaluate whether the different physicochemical and biological properties of compounds 9 and 11 also resulted in a different in vivo antitumor FGF trap activity when administered by oral gavage to syngeneic mice grafted subcutaneously with FGF-driven murine LLC lung carcinoma cells. 28 In keeping with the in vitro observations, daily treatment by oral gavage with compound 11 at the dose of 7.5 mg/kg for 7 days significantly reduced the growth of LLC tumor grafts, while administration of compound 9 did not affect the rate of tumor growth that was indistinguishable from that observed in vehicle-treated animals ( Figure 9A).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…This property resulted in a potent antiangiogenic and antitumor activity when tested in various FGF-dependent tumor models, designating 1 as the first nonpeptidic, orally available small molecule FGF trap endowed with potential implications for the therapy of FGF-dependent cancers. 14 However, a survey of the available information provided minimal data for this compound, with no details regarding its stereochemistry and its preparation, purification, and characterization. We report here the synthesis of 1, designed on the sole structure provided by the NCI, the assignment of its absolute configuration, in vitro and in vivo experiments that confirmed its biological activity, and characterization of its physicochemical properties and oral bioavailability.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis, Structural Elucidation, and Biological Evaluation of NSC12, an Orally Available Fibroblast Growth Factor (FGF) Ligand Trap for the Treatment of FGF-Dependent Lung Tumors

et al. 2016

Self Cite

View full text Add to dashboard Cite

NSC12 is an orally available pan-FGF trap able to inhibit FGF2/FGFR interaction and endowed with promising antitumor activity. It was identified by virtual screening from a NCI small molecule library, but no data were available about its synthesis, stereochemistry, and physicochemical properties. We report here a synthetic route that allowed us to characterize and unambiguously identify the structure of the active compound by a combination of NMR spectroscopy and in silico conformational analysis. The synthetic protocol allowed us to sustain experiments aimed at assessing its therapeutic potential for the treatment of FGF-dependent lung cancers. A crucial step in the synthesis generated a couple of diastereoisomers, with only one able to act as a FGF trap molecule and to inhibit FGF-dependent receptor activation, cell proliferation, and tumor growth when tested in vitro and in vivo on murine and human lung cancer cells.

show abstract

Rg3 inhibits gemcitabine‐induced lung cancer cell invasiveness through ROS‐dependent, NF‐κB‐ and HIF‐1α‐mediated downregulation of PTX3

Ahmmed

Kampo

Khan

et al. 2019

Journal Cellular Physiology

View full text Add to dashboard Cite

PTX3, a member of the long pentraxin subfamily, associated with innate immunity is indispensable for resistance to some cancer. Gemcitabine, an analog of cytosine arabinoside, has shown restrained benefits because of profound chemoresistance. The PTX3 expression on GEM in human lung cancer cells have not yet been clarified; the present study aimed to show reactive oxygen species (ROS) mediatory PTX3 expression through distinct mechanisms. Whereas ginsenoside Rg3 is a herbal medicine with strong antitumor activity. Furthermore, we tested the hypothesis; Rg3 abrogates GEM‐induced production of ROS‐mediated activation of Akt and extracellular signal‐regulated kinase (ERK) pathways and inhibits nuclear piling‐up of nuclear factor kappa B (NF‐κB) and HIF‐1α. On the basis of time and dose‐dependent manner, our data demonstrated that GEM‐induced PTX3 expression was dependent on ROS generation as it was abrogated by pretreatment of lung cancer cells with the free radical scavenger N‐acetyl‐l‐cysteine. Our data demonstrated that PTX3 upregulation by GEM correlated with the time‐dependent escalation of NF‐κB and HIF‐1α in the nucleus resulted from phosphorylation‐induced degradation of IκBα, whereas HIF‐1α upregulation was NF‐κB‐dependent. Increase in ROS expression in lung cancer cells on GEM treatment preceded the nuclear accumulation of NF‐κB and HIF‐1α and suppression of ROS diminished these effects. ERK1/2 and Akt activation mediated the effect of ROS on NF‐κB and HIF‐1α and their pharmacological inhibition suppressed GEM‐induced PTX3. Our study findings reinforced the role regarding PTX3 signaling in GEM‐induced resistance and pointed toward an unintended and undesired effect of chemotherapy and to get an active regimen; the synergy was associated with NF‐κB downregulation in lung cancer.

show abstract

Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

Abstract: Dr. Rubben Torella's name was spelled incorrectly as ''Torrella'' in the original article. It appears correctly in this erratum, and the error has been corrected in the original article online.

Cited by 18 publications

References 0 publications

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

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

Synthesis, Structural Elucidation, and Biological Evaluation of NSC12, an Orally Available Fibroblast Growth Factor (FGF) Ligand Trap for the Treatment of FGF-Dependent Lung Tumors

Rg3 inhibits gemcitabine‐induced lung cancer cell invasiveness through ROS‐dependent, NF‐κB‐ and HIF‐1α‐mediated downregulation of PTX3

Contact Info

Product

Resources

About