LIH scientists demonstrate the therapeutic value of new drug inhibiting oncogene translation
Researchers from the Tumor Stroma Interactions (TSI) research group at the LIH Department of Cancer Research (DoCR) investigated how the inhibition of mRNA translation, particularly of oncogenes such as MYC, in chronic lymphocytic leukemia (CLL) cells can rewire their metabolism and decrease their proliferative capacity, thus slowing down the progression of the disease. The findings, which were published in the prestigious international journal Blood, bring forward the enormous potential of the drug FL3 in inhibiting MYC translation through a newly-elucidated mechanism, thereby opening up new therapeutic avenues for CLL patients.
Chronic lymphocytic leukemia (CLL), the most common type of leukemia, is characterised by the increased production, proliferation and accumulation of mature but dysfunctional B lymphocytes in the blood, spleen, lymph nodes and bone marrow. A well-established feature of CLL and of some of its rarer but aggressive complications is the excessive level of aberrant MYC proteins, encoded by the MYC oncogene. Indeed, it has been increasingly acknowledged that the increase in the general rate of translation, including that of specific oncogenes such as MYC, is a feature of a large variety of cancers. Molecules that inhibit translation therefore hold great therapeutic potential for the treatment of CLL.
In order to confirm the key role of aberrant protein translation in CLL and exploit this finding to test new potential drugs in vivo, Drs Jérôme Paggetti and Etienne Moussay, leaders of the TSI group and corresponding authors of the study, worked with samples collected from a cohort of 144 patients representative of the CLL population, as well as murine models. Through gene-expression experiments, they showed that translation-related genes and their proteins are indeed upregulated in CLL cells, both in humans and mice, and that treatment of patient samples with the synthetic flavagline FL3 – a known inducer of cancer cell death – inhibits translation. Specifically, the team observed that FL3 treatment affected particularly the translation and synthesis of proteins involved in a variety of key cellular processes including translation itself, metabolism and cell cycle regulation, as well as of oncogenic proteins such as MYC and ETS-1.
Based on these results, the researchers sought to investigate the biological consequences of inhibiting translation. Interestingly, patient-derived CLL cells were more sensitive to FL3-induced death than healthy cells. Similarly, by inhibiting the translation of MYC, low doses of FL3 induced major changes in cellular metabolism, consequently blocking the cell cycle and impairing growth and proliferation in both human and murine CLL cells. “Our findings therefore confirm the therapeutic window for selectively treating CLL with translation inhibitors”, says Dr Anne Largeot, scientist within the TSI group and first author of the study.
The research team also demonstrated that FL3 targets a group of proteins known as prohibitins (PHBs), which are directly involved in translation. Namely, the interaction between FL3 and PHBs physically disrupts this translation initiation machinery, thereby interfering with the process.
“When we tested the efficacy of FL3 treatment in inhibiting translation and slowing down CLL progression in vivo in mice, we observed a drastically reduced percentage of CLL cells in their spleen and a significantly improved survival rate”, she explains.
Moreover, we showed that FL3 specifically inhibited the translation rate in malignant CLL cells in vivo but had no effect on non-leukemic B cells, demonstrating the value of this therapeutic strategy in selectively targeting cancerous cells without affecting healthy ones,adds Dr Moussay.
Interestingly, combining FL3 with anti-PD1 immunotherapy resulted in an even better outcome in vivo, suggesting that FL3 also acts by removing the brakes on anti-tumor immunity.
“Importantly, we showed that high expression of translation initiation-related genes and PHBs genes correlates with disease progression, poor survival and unfavorable clinical parameters in CLL patients. As translation also confers cancer cells resistance to several therapies, our work brings forward the possibility to combine translation inhibition with standard of care in CLL, giving our findings a highly translational dimension and representing a very promising approach, particularly in a malignancy characterised by relapse and resistance to treatment”, concludes Dr Paggetti.
The study, published in the journal Blood with the full title “Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as therapeutic strategy in CLL”, was selected to be featured on the cover page of the journal. The research was supported by grants 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 process of translating the sequence of a messenger RNA (mRNA) molecule to a sequence of amino acids during protein synthesis.