Too many people are still dying from cancer and there is an urgent need for innovative therapies. Our group is mainly focused on two cancer types: multiple myeloma and lung cancer. Multiple myeloma is a devastating hematological malignancy with a median survival of 7 years. Despite the recent development of novel pharmacological strategies, multiple myeloma patients still develop drug resistance that then leads to relapse.
Lung cancer is the leading cause of cancer-related death and one of the most diagnosed cancers worldwide. Despite the wide range of therapeutic and surgical options, lung cancer patients often face poor prognosis and are sometimes only diagnosed at advanced stages of progression. Therefore, there is a strong need to broaden the range of therapeutic options against these cancers. For this, we are using a range of screening assays using various in vitro models.
Cancer cells are known to highly proliferate with poor mechanisms of control. Therefore, the capacity of compounds to exert anti-proliferative activity is key in anti-cancer drug discovery. The activity of cytotoxic or cytostatic agents is measured through various anti-proliferative assays, which can be set in a wide range of cell lines, as well as in 3D co-culture spheroids. Besides, compound combinations are also used in order to find possible synergies between anti-cancer agents.
Inflammation is a physiological response of the innate immune system to tissue injury. Its onset is rapid and involves a complex signalization network, which aims at activating the leucocytes and bringing them to the site of interest. Although this process is usually self-limiting, it can become deregulated and be involved in several pathological conditions such as cancer. At the center of the inflammatory process stands the nuclear factor-kappa B (NF-κB), an inducible transcription factor in charge of the control of more than 200 genes involved in inflammation, but also in cell transformation, proliferation, angiogenesis, invasion, metastasis and chemoresistance. An intimate link between chronic inflammation and cancer has been hypothesized more than 150 years ago and is today a worldly accepted paradigm, often pointing NF-κB as a major player of inflammation-induced carcinogenesis. The central role of NF-κB in those pathologies makes it a very interesting target for the treatment and prevention of inflammatory diseases such as cancer (Monteillier et al., 2017). Therefore, a considerable effort is made to find NF-κB inhibitors, with already some of them making it to the clinic.
Epigenetic alterations have been the focus of many recent studies and offer valuable options for the control of carcinogenesis. Distinct epigenetic events are sufficient to drive tumor formation, progression, and metastasis. Epigenetic modifications such as DNA methylation, histone modification, chromatin remodeling and non-coding RNAs, lead to aberrant gene expression and may promote oncogenic transcriptional programs such as epithelial-mesenchymal transition (EMT), increased cancer cell stemness, and altered cellular metabolism. Histone acetylation is one of the posttranslational modifications that influences the chromatin state and contributes to the regulation of gene expression. Histone acetylation is controlled by the action of two enzyme families: HDACs and histone acetyltransferases (HATs). To date, 18 HDAC isoforms have been identified and classified into four classes (I-IV). The search for isoform specific HDAC inhibitors is a current topic in drug discovery, given that individual isoforms have been linked to distinct pathological processes. Some isoform-specific inhibitors were shown to be less toxic compared to pan-HDAC inhibitors. Four HDAC inhibitors have already been approved for cancer therapy by the FDA. All of them are showing a pan-HDAC inhibitory profile. The use of a mass spectrometry detection method developed in the lab allows to determine the isoform selectivity in a cellular environment (Zwick et al., 2016). Few inhibitors were characterized using this method (Francisco Hilario et al., 2017).
Angiogenesis refers to the formation of new blood vessels from pre-existing ones. Angiogenesis is crucial for survival but if it is deregulated, it may lead to severe features associated with cancer. Targeting neovascularization occurring during cancer development is a promising strategy. Some compounds target circulating angiogenic growth factors, while others target their receptors. They are currently in use in the clinics for the treatment of a wide range of tumors such as breast, gastric, and pancreatic tumors. However, these therapies were not demonstrated to be curative as many mechanisms of resistance to anti-angiogenic therapy have been identified. Screening is performed using a 3D in vitro angiogenesis model and the microsphere images analysis is performed using a plugin programed for the ImageJ software (Issa et al., 2016).