Periodic Reporting for period 1 - IDEAL (Inhibitor of DUX4-IGH to Erase Acute lymphoblastic Leukaemia)
Reporting period: 2020-02-01 to 2022-01-31
The second most important cause of death and morbidity in Europe is cancer and B-cell acute lymphoblastic leukaemia (BALL) is the most common paediatric cancer and cause of cancer-related death before 20 years. In up to 7-10% of cases, this disease is caused by genetic rearrangements giving rise to the DUX4-IGH fusion. A specific treatment for these patients is currently unavailable, therefore this project aims to investigate the possibility to develop new therapeutic strategies for the treatment of B-ALL with DUX4-IGH rearrangements. In particular we aim to test a novel inhibitor of DUX4-IGH transcriptional activity and its pathological consequences, using both cellular and animal model of the disease.
During the reporting period, I used an approach combining in vitro and in vivo analyses to test the potential antileukemic activity of a new inhibitor of DUX4-IGH+ve leukemia.
In particular I exploited both a cellular model and a humanized animal model to test the efficacy of this inhibitor.
I found that delivery of the inhibitor is associated to inhibition of DUX4-IGH leukemia cell growth and inhibition of DUX4-IGH biological functions (such us modulation of target genes and proteins).
I tested the specificity of the inhibitor exploiting different cell lines and approaches.
I demonstrated that the expression of this inhibitor is detrimental to DUX4-IGH leukemia cells expansion in immunocompromised animals.
In particular I exploited both a cellular model and a humanized animal model to test the efficacy of this inhibitor.
I found that delivery of the inhibitor is associated to inhibition of DUX4-IGH leukemia cell growth and inhibition of DUX4-IGH biological functions (such us modulation of target genes and proteins).
I tested the specificity of the inhibitor exploiting different cell lines and approaches.
I demonstrated that the expression of this inhibitor is detrimental to DUX4-IGH leukemia cells expansion in immunocompromised animals.
The results of the projects overall support the antileukemic activity of the DUX4-IGH inhibitor.
Pre-clinical validation of the DUX4-IGH inhibitor will help defining effective therapeutic strategies for DUX4-IGH B-ALL patients, improving clinical outcome and lowering treatment toxicity, thus overall promoting Europe's healthcare.
Pre-clinical validation of the DUX4-IGH inhibitor will help defining effective therapeutic strategies for DUX4-IGH B-ALL patients, improving clinical outcome and lowering treatment toxicity, thus overall promoting Europe's healthcare.