Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma

Chua, Vivian; Orloff, Marlana; Teh, Jessica L.F.; Sugase, Takahito; Liao, Connie; Purwin, Timothy J.; Lam, Bao; Terai, Mizue; Ambrosini, Grazia; Carvajal, Richard D.; Schwartz, Gary K.; Sato, Takami; Aplin, Andrew E.

doi:10.15252/emmm.201809081

Cited by 53 publications

(57 citation statements)

References 49 publications

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“…The combination of the fibroblast growth factor receptor (FGFR) inhibitor AZD4547 with PLX51107 inhibited the growth of UM cells co-implanted with human stellate cells, indicating that the concomitant inhibition of the BRD4 and FGFR pathways might be a novel option for UM liver metastases. 203 …”

Section: Therapeutic Optionsmentioning

confidence: 99%

Uveal melanoma: progress in molecular biology and therapeutics

Shi

Yang

et al. 2020

Ther Adv Med Oncol

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Uveal melanoma (UM) is the most common intraocular malignancy in adults. So far, no systemic therapy or standard treatment exists to reduce the risk of metastasis and improve overall survival of patients. With the increased knowledge regarding the molecular pathways that underlie the oncogenesis of UM, it is expected that novel therapeutic approaches will be available to conquer this disease. This review provides a summary of the current knowledge of, and progress made in understanding, the pathogenesis, genetic mutations, epigenetics, and immunology of UM. With the advent of the omics era, multi-dimensional big data are publicly available, providing an innovation platform to develop effective targeted and personalized therapeutics for UM patients. Indeed, recently, a great number of therapies have been reported specifically for UM caused by oncogenic mutations, as well as other etiologies. In this review, special attention is directed to advancements in targeted therapies. In particular, we discuss the possibilities of targeting: GNAQ/GNA11, PLCβ, and CYSLTR2 mutants; regulators of G-protein signaling; the secondary messenger adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6); downstream pathways, such as those involving mitogen-activated protein kinase/MEK/extracellular signal-related kinase, protein kinase C (PKC), phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR), Trio/Rho/Rac/Yes-associated protein, and inactivated BAP1; and immune-checkpoint proteins cytotoxic T-lymphocyte antigen 4 and programmed cell-death protein 1/programmed cell-death ligand 1. Furthermore, we conducted a survey of completed and ongoing clinical trials applying targeted and immune therapies for UM. Although drug combination therapy based on the signaling pathways involved in UM has made great progress, targeted therapy is still an unmet medical need.

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Section: Therapeutic Optionsmentioning

confidence: 99%

Uveal melanoma: progress in molecular biology and therapeutics

Shi

Yang

et al. 2020

Ther Adv Med Oncol

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“…25 It was reported that FGF-2 is a key contributor to bevacizumab resistance 26 and the drug resistance of chemotherapy in breast cancer and melanoma. [27][28][29] FGF-2 directly stimulates the survival and proliferation of tumor cells and indirectly facilitates tumor growth and metastasis by promoting the proliferation and migration of endothelial cells. 30 Many kinds of FGF-2 signaling inhibitors have been developed in preclinical studies or clinical trials, including nonspecific small-molecule tyrosine kinase inhibitors, such as dovitinib 31 and nintedanib, 32 as well as specific antagonistic large protein drugs, such as monoclonal antibodies 33 and soluble receptor fusion proteins.…”

Section: Introductionmentioning

confidence: 99%

<p>Virus-Like Particles Presenting the FGF-2 Protein or Identified Antigenic Peptides Promoted Antitumor Immune Responses in Mice</p>

Shu¹,

Sun²,

Xie³

et al. 2020

IJN

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Background: Fibroblast growth factor (FGF)-2 is overexpressed in various tumor tissues. It affects tumor cell proliferation, invasion and survival, promotes tumor angiogenesis and is tightly involved in the development of systemic and local immunosuppressive tumor mechanisms. Purpose: This study aimed to develop an effective vaccine against FGF-2 and to investigate the effects of anti-FGF-2 immunization on tumor growth and antitumor immune responses. Methods: A set of thirteen synthesized overlapping peptides covering all possible linear B-cell epitopes of murine FGF-2 and a recombinant FGF-2 protein were conjugated to viruslike particles (VLPs) of recombinant hepatitis B core antigen (HBcAg). The VLPs were immunized through a preventive or therapeutic strategy in a TC-1 or 4T1 grafted tumor model. Results: Immunization with FGF-2 peptides or full-length protein-coupled VLPs produced FGF-2-specific antibodies with a high titer. Peptide 12, which is located in the heparin-binding site of FGF-2, or protein-conjugated VLPs presented the most significant effects on the suppression of TC-1 tumor growth. The levels of IFN-γ-expressing splenocytes and serum IFN-γ were significantly elevated; further, the immune effector cells CD8 + IFN-γ + cytotoxic T lymphocytes (CTLs) and CD4 + IFN-γ + Th1 cells were significantly increased, whereas the immunosuppressive cells CD4 + CD25 + FOXP3 + Treg cells and Gr-1 + CD11b + myeloidderived suppressor cells (MDSCs) were decreased in the immunized mice. In addition, VLP immunization significantly suppressed tumor vascularization and promoted tumor cell apoptosis. In mice bearing 4T1 breast tumor, preventive immunization with FGF-2-conjugated VLPs suppressed tumor growth and lung metastasis, and increased effector cell responses. Conclusion: Active immunization against FGF-2 is a new possible strategy for tumor immunotherapy.

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“…The present study by Chua et al () suggests that inhibition of the FGF receptor (FGFR) pathway improves the response of UMM to BET inhibitors. Specifically, they found that FGF2, but not other growth factors, provides resistance to growth suppression by BET inhibitors in UMM cells as well as in vivo .…”

mentioning

confidence: 56%

“…Intriguingly, different cancer types may share some of these deregulations, suggesting that very diverse cancers might display a common denominator for resistance development. As also described by Chua et al (), resistance to BET inhibitors in ovarian cancer was associated with elevated expression of FGFRs (Kurimchak et al , ). The mechanisms underlying BET inhibitor‐induced overexpression of FGFRs are unclear, but may involve modulation of BRD4‐induced regulation of FGFR transcription.…”

mentioning

confidence: 56%