Highlights Fingolimod represses triple negative breast cancer cells survival in vitro by inducing cell apoptosis. Fingolimod represses triple negative breast cancer progression in orthotopic graft murine in vivo models. Fingolimod represses spleen and liver metastases without affecting lung metastasis in murine in vivo models. In contrast with Cisplatin, Fingolimod is well tolerated in murine in vivo models.

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New therapies are required for patients with non-small cell lung cancer (NSCLC) for which the current standards of care poorly affect the patient prognosis of this aggressive cancer subtype. In this preclinical study, we aim to investigate the efficacy of Fingolimod, a described inhibitor of sphingosine-1-phosphate (S1P)/S1P receptors axis, and Dimethyl Fumarate (DMF), a methyl ester of fumaric acid, both already approved as immunomodulators in auto-immune diseases with additional expected anti-cancer effects. The impact of both drugs was analyzed with in vitro cell survival analysis and in vivo graft models using mouse and human NSCLC cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated that Fingolimod and DMF repressed tumor progression without apparent adverse effects in vivo in three preclinical mouse NSCLC models. In vitro, Fingolimod did not affect either the tumor proliferation or the cytotoxicity, although DMF reduced tumor cell proliferation. These results suggest that Fingolimod and DMF affected tumor progression through different cellular mechanisms within the tumor microenvironment. Fingolimod and DMF might uncover potential therapeutic opportunities in NSCLC.

Ethical considerations, cost, and time constraints have highlighted the need to develop alternatives to rodent in vivo models for evaluating drug candidates for cancer. The tumor chicken chorioallantoic membrane (TCAM) model provides an affordable and fast assay that permits direct visualization of tumor progression. Tumors from multiple species including rodents and human cell lines can be engrafted. In this study, we engrafted several tumor models onto the CAM and demonstrated that the TCAM model is an alternative to mouse models for preliminary cancer drug efficacy testing and toxicity analysis. Tumor cells were deposited onto CAM, and then grown for up to an additional 10 days before chronic treatments were administered. The drug response of anticancer therapies was screened in 12 tumor cell lines including glioblastoma, melanoma, breast, prostate, colorectal, liver, and lung cancer. Tumor-bearing eggs and tumor-bearing mice had a similar chemotherapy response (cisplatin and temozolomide) in four human and mouse tumor models. We also demonstrated that lethality observed in chicken embryos following chemotherapies such as cisplatin and cyclophosphamide were associated with corresponding side-effects in mice with body weight loss. According to our work, TCAM represents a relevant alternative model to mice in early preclinical oncology screening, providing insights for both the efficacy and the toxicity of anticancer drugs.