Porsolt (France)

The five-year survival rate for pancreatic cancer is notably low, posing a significant challenge to patient health. The primary treatments are radiotherapy and chemotherapy, sometimes combined with targeted therapy; however, their clinical benefits are limited. Therefore, developing new models to evaluate the therapeutic potential of novel molecules is essential. Fingolimod and Dimethyl Fumarate (DMF), currently used to treat multiple sclerosis, have recently been shown to have anti-cancer effects in several preclinical tumor models. This study aims to evaluate the therapeutic potential of Fingolimod and DMF in pancreatic cancer by investigating their respective in vitro cytotoxicity and in vivo antitumor effects. In this study, we evaluated for the first time these two drugs in pancreatic preclinical models in vitro using 3D spheroid tumor models and in vivo, which are compared to two standard-of-care consisting of Gemcitabine and Erlotinib. In vitro, both Fingolimod and DMF induced cytotoxicity in spheroids from two pancreatic cell lines. Additionally, Fingolimod and DMF displayed anticancer effects in two subcutaneous xenograft models using PANC-1 and CFPAC-1 cells. Although the responses observed with Fingolimod and DMF were similar to those of Gemcitabine and Erlotinib, these findings indicate a potential emerging interest in Fingolimod and DMF for the treatment of pancreatic cancer. However, further work is still necessary to fully characterize how these drugs affect tumor progression.

Glioblastomas are malignant brain tumors which remain lethal due to their aggressive and invasive nature. The standard treatment combines surgical resection, radiotherapy, and chemotherapy using Temozolomide, albeit with a minor impact on patient prognosis (15 months median survival). New therapies evaluated in preclinical translational models are therefore still required to improve patient survival and quality of life. In this preclinical study, we evaluated the effect of Temozolomide in different models of glioblastoma. We also aimed to investigate the efficacy of Fingolimod, an immunomodulatory drug for multiple sclerosis also described as an inhibitor of the sphingosine-1-phosphate (S1P)/S1P receptor axis. The effects of Fingolimod and Temozolomide were analyzed with in vitro 2D and 3D cellular assay and in vivo models using mouse and human glioblastoma cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated both in in vitro and in vivo models that Temozolomide has a varied effect depending on the tumor type (i.e., U87MG, U118MG, U138MG, and GL261), demonstrating sensitivity, acquired resistance, and purely resistant tumor phenotypes, as observed in patients. Conversely, Fingolimod only reduced in vitro 2D tumor cell growth and increased cytotoxicity. Indeed, Fingolimod had little or no effect on 3D spheroid cytotoxicity and was devoid of effect on in vivo tumor progression in Temozolomide-sensitive models. These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation.

The recent development of immunotherapy represents a significant breakthrough in cancer therapy. Several immunotherapies provide robust efficacy gains in a wide variety of cancers. However, in some patients the immune checkpoint blockade remains ineffective due to poor therapeutic response and tumor relapse. An improved understanding of the mechanisms underlying tumor-immune system interactions can improve clinical management of cancer. Here, we report preclinical data evaluating two murine antibodies corresponding to recent FDA-approved antibodies for human therapy, e.g. anti-CTLA-4 and anti-PD-1. We demonstrated in two mouse syngeneic grafting models of triple negative breast or colon cancer that the two antibodies displayed an efficient anticancer activity, which is enhanced by combination treatment in the breast cancer model. We also demonstrated that CTLA-4 targeting reduced metastasis formation in the colon cancer metastasis model. In addition, using cytometry-based multiplex analysis, we showed that anti-CTLA-4 and anti-PD-1 affected the tumor immune microenvironment differently and in particular the tumor immune infiltration. This work demonstrated anti-cancer effect of CTLA-4 or PD-1 blockade on mouse colon and triple negative breast and on tumor-infiltrating immune cell subpopulations that could improve our knowledge and benefit the breast and colon cancer tumor research community.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers, and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e. performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.