Breakthrough Discovery for Leukaemia Therapy

Scientists at the Department of Cancer Research (DoCR) at the Luxembourg Institute of Health (LIH) have revealed the ground-breaking therapeutic potential of the compound FL3 in inhibiting oncogene translation and rewiring cancer cell metabolism, offering new hope for patients with chronic lymphocytic leukaemia (CLL), a prevalent form of cancer characterised by the overproduction and accumulation of dysfunctional B lymphocytes in various parts of the body.

Using patient samples and animal models, the study, led by Drs Jérôme Paggetti and Etienne Moussay from the LIH Tumour Stroma Interactions (TSI) research group, found that FL3 specifically targets a group of proteins called prohibitins (PHBs), that proved to be directly involved in translation (i.e. the cellular process producing proteins) of oncogenes, specifically the MYC gene, within CLL cells.  By disrupting this interaction FL3 hinders the initiation of translation, effectively interfering with the process and impeding cancer cell growth.

To validate the efficacy of FL3 in slowing down CLL progression, the researchers conducted in vivo experiments on mice with astounding results, as the treatment drastically reduced the percentage of CLL cells in the spleen and significantly improved overall survival rates. Importantly, FL3 selectively targeted malignant CLL cells without affecting healthy B cells, thus providing a promising strategy for selectively combating cancerous cells while leaving healthy cells unharmed.

When FL3 was combined with anti-PD1 immunotherapy, the outcomes were even more impressive, indicating that FL3 may also enhance anti-tumour immunity. Dr Anne Largeot, senior scientist within the TSI group and the first author of the study said: "Our research unveils a highly translational dimension to the field of CLL treatment. We found that high expression of translation initiation-related genes and PHBs genes correlates with disease progression, poor survival, and unfavourable clinical parameters in CLL patients. By inhibiting translation, we can potentially overcome treatment resistance and offer a promising approach to tackling relapse in this challenging malignancy."

This study was made possible through generous support from the Luxembourg National Research Fund (FNR), Fondation Cancer, FNRS-Télévie, Plooschter Projet, the Belgian Foundation for Cancer Research, the Swedish Children's Cancer Foundation, the Swedish Research Council and the Swedish Cancer Society.

The study, "Inhibition of MYC Translation through Targeting of the Newly Identified PHB-eIF4F Complex as Therapeutic Strategy in CLL," was published in the open-access journal Blood.

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