TITLY · Inhibition of the T-cell receptor signalling pathway for treatment of T-cell lymphoma

Inhibition of the T-cell receptor signalling pathway for treatment of T-cell lymphoma

Non-Hodgkin lymphoma (NHL) is a form of cancer emerging from the transformation of a mature B- or T-cell lymphocyte. Clinically, NHL is usually characterized by lymph nodes and/or spleen enlargement, variable bone marrow or peripheral blood involvement and occasionally extra-nodal spreading of the disease. NHL is a highly heterogeneous disease with the last 2008 World Health Organization (WHO) classification encompassing more than 30 sub-entities. Heterogeneity of the disease translates into a highly variable prognosis for patients suffering from NHL ranging from 5-year overall survival (OS) of more than 90% in case of indolent B-cell lymphomas to less than 10% in the most aggressive subtypes of T-cell malignancies. NHL is the 11th most common cancer in Europe, approaching 100,000 new cases diagnosed in 2012. Worldwide, NHL is the 10th most common cancer with the highest incidence in Northern America and the lowest in South Central Asia. This heterogeneity reflects potential underlying risk factors, quality of data collection and diagnostic screening methods. Among NHL, roughly 90% are of B-cell type (ie arising from the transformation of a mature B-cell lymphocyte) whereas 10% are of T-cell origin. Recently, major advances have been made in the treatment of B-cell NHL from the understanding of signaling pathways crucially involved in the tumor cell survival and proliferation. On the contrary, pathophysiology of T-cell lymphomas is poorly understood and almost no therapeutic progress has been made for the last 20 years in the disease. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Type II system is a bacterial immune system that has been modified for genome engineering. Largely due to its simplicity and adaptability, CRISPR has rapidly become one of the most popular approaches for genome engineering. CRISPR consists of two components: a single guide RNA (sgRNA) and a CRISPR-associated endonuclease (Cas9 for the streptococcus pyogenes endonuclease which is broadly used). The sgRNA is a short synthetic RNA composed of a “scaffold” sequence necessary for Cas9-binding and a user-defined ∼20 nucleotide “spacer” or “targeting” sequence which defines the genomic target to be modified. Thus, one can change the genomic target of Cas9 by simply changing the targeting sequence present in the sgRNA. When targeted to a locus defined by the sgRNA sequence, the Cas9 generates a double-stranded blunt cut ultimately leading to inactivating missense or frameshift mutations. Therefore, the CRISPR/Cas9 system was originally employed to “knock-out” target genes in various cell types and organisms. Given the critical unmet medical needs for T-cell lymphoma treatment, we undertook in November 2015 an unbiased approach using whole-genome CRISPR/Cas9 screening in T-cell lymphoma cell lines to decipher essential signaling pathways for tumor cell survival and proliferation. The ultimate goal of the project was to provide new therapeutic targets in the disease for rapid early phase clinical trial development.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз