Dasatinib alters the metastatic phenotype of B16-OVA melanoma in vivo

Fraser, Cara K.; Lousberg, Erin L.; Guerin, Leigh R.; Hughes, Timothy P.; Brown, Michael P.; Diener, Kerrilyn R.; Hayball, John D.

doi:10.4161/cbt.10.7.12926

Cited by 13 publications

(10 citation statements)

References 70 publications

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“…The secretion of granulocyte-macrophage colony stimulating factor (GM-CSF) has also been shown to be increased by dasatinib treatment (30). Previously, Fraser and colleagues (31) reported that a higher dose of dasatinib (25 mg/kg/day) reduced the number of extrapulmonary B16.OVA metastases compared with a lower dose (5 mg/kg/day). The higher dose used by Fraser and colleagues was In vivo effects were studied in mice, which had been given a subcutaneous inoculation of 1 Â 10E6 tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Hekim

Ilander

Yan

et al. 2017

Cancer Immunology Research

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Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8 þ T cells in PB, together with a higher amount of tumor-infiltrating CD8 þ T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4 þ and CD8 þ T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Hekim

Ilander

Yan

et al. 2017

Cancer Immunology Research

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“…Dasatinib treatment of uveal melanoma cells injected into zebrafish models has also demonstrated potent anti-migratory effects [137]. Mice inoculated with B16-ovalbumin overexpressing (B16-OVA) cells showed decreased extrapulmonary metastases when treated with high doses of dasatanib, but lung metastases were not inhibited [138]. In vemurafenib-resistant cell lines, dasatinib inhibited melanoma invasion in vitro .…”

Section: Effects Of Small Molecule Inhibitors On Emt In Melanomamentioning

confidence: 99%

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

et al. 2017

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Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others. Downstream effectors of these pathways induce expression of EMT transcription factors including Snail, Slug, Twist, and Zeb that promote repression of epithelial and induction of mesenchymal character. Emerging research has demonstrated that a variety of small molecule inhibitors as well as phytochemicals can influence the progression of EMT and may even reverse the process, inducing re-expression of epithelial markers. Phytochemicals are of particular interest as supplementary treatment options because of their relatively low toxicities and anti-EMT properties. Modulation of EMT signaling pathways using synthetic small molecules and phytochemicals is a potential therapeutic strategy for reducing the aggressive progression of metastatic melanoma. In this review, we discuss the emerging pathways and transcription factor targets that regulate EMT and evaluate potential synthetic small molecules and naturally occurring compounds that may reduce metastatic melanoma progression.

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“…The Src family kinases has critical roles in the process of cancer invasion (Kim et al , 2009), and preclinical data indicates that Src inhibition may add to tumour control in advanced malignancies including melanoma (Eustace et al , 2008; Homsi et al , 2009; Fraser et al , 2010). In the current study, we show that dasatinib, a Src/abl kinase inhibitor, can be safely combined with dacarbazine at an adequate dose intensity.…”

Section: Discussionmentioning

confidence: 99%

“…In melanoma cell lines that have not been selected for c-Kit mutations, dasatinib decreases cellular proliferation (Eustace et al , 2010) and enhances apoptosis (Niu et al , 2002), and dasatinib decreases cell migration even in cells in which it has no antiproliferative effect (Eustace et al , 2008, 2010). Dasatinib may also inhibit the formation of new melanoma lung metastases in vivo (Fraser et al , 2010). Dasatinib monotherapy is only modestly active in melanoma patients unselected for c-Kit mutations.…”

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confidence: 99%

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma

et al. 2011

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Background:Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma.Methods:Patients had ECOG performance status 0–2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m−2 of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations.Results:Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m−2, and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response.Conclusion:The recommended phase II dose is dasatinib70 mg b.i.d with dacarbazine 800 mg m−2. PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.

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Dasatinib alters the metastatic phenotype of B16-OVA melanoma in vivo

Cited by 13 publications

References 70 publications

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma

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