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TITLY Report Summary

Project ID: 661106
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - TITLY (Inhibition of the T-cell receptor signalling pathway for treatment of T-cell lymphoma)

Reporting period: 2015-11-01 to 2016-10-31

Summary of the context and overall objectives of the project

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 of 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 signalling pathways crucially involved in the tumour 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.

Given the critical unmet medical needs for T-cell lymphoma treatment, we undertook in November 2015 an unbiased approach using wole-genome CRISPR/Cas9 screening in T-cell lymphoma cell lines to decipher essential signalling pathways for tumor cell survival and proliferation.

The ultimate goal of the project is to provide new therapeutic targets in the disease for rapid early phase clinical trial development.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The CRISPR/Cas9 technique enables inactivation of virtually any gene of the genome. By designing a specific 20 base-pair sequence complementary to the targeted DNA sequence, a RNA fragment named single-guide RNA (sgRNA) allows for recruiting the Cas9 endonuclease resulting in blunt ends DNA fragments and gene disruption (Figure 1).

During the outgoing phase of the action (from November 2015 to October 2016) that took place at the National Institute of Health (Bethesda, MD, USA), nine peripheral T-cell lymphoma (PTCL) cell lines have been engineered to express the Streptococcus pyogenes Cas9 enzyme : HuT78, HuT102, MyLa, HH and Sez4 (cutaneous PTCL); OCI-Ly12 and OCI-Ly13.2 (nodal PTCL); SUDHL1 and DEL (ALK+ anaplastic PTCL).

Whole genome CRISPR/Cas9 screens have been performed in all of these lines (Figure 2).

Preliminary results shows that all mature T-cell lines strongly relies on NF-kB pathway for survival. Currently, several signalling components leading to this constitutive NF-kB activation are under scrutiny.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Although major progresses have been made in several hematological malignancies, no breakthrough has been observed for years in PTCL and the disease remains an unmet medical need. Lack of improvement comes from the rarity and the poor understanding of the disease. To the best of our knowledge, no whole-genome CRISPR/Cas9 screen for new potential inhibitor identification has been undertaken to date.

During one year, a major effort has been accomplished for cell lines engineering and whole-genome screening.

New potential targets for drug discovery from the results of the screen are now under scrutiny. A small compound drug screen is currently performed (more than 4,000 drugs; team of Craig Thomas, NIH, Bethesda, USA). By matching CRISPR/Cas9 genetic and drug screen results, we expect being able to start early phase clinical trials with new compounds as soon as in 2018. Preliminary results will be provided at international meetings in 2017 (International Conference on Malignant Lymphoma, 14-17th of June, Lugano, Switzerland; American Society of Hematology meeting, 9-12th of December, Atlanta, USA).

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