Malignant Mesothelioma (MM) is an aggressive tumor appearing in the thin layer that covers important organs like the lungs, the abdominal cavity organs or the heart. MM burden is rising at an annual growth rate of 4.5% and with a mortality rate of 4.9 per million people (30,433 new cases/year; 25,576 deaths/year according to WHO Global Cancer Observatory). Prevalence is 13.197 cases/year, accounting pleural MM for 90% all cases. Current treatment includes surgery, chemotherapy and radiation and is potentially curative. Unfortunately, most patients (>90%) are diagnosed with advanced disease where chemotherapy combination (pemetrexed/platinum approved in 2004) is still first line treatment in many countries. However it has limited efficacy, drug resistance and progression appears in 6 months and side-effects are still major concerns.

Among the many molecular mechanisms that lead to cancer development, progression and drug-resistance, gain-of-function alterations in oncogenes (genes with potential to contribute to the development of cancer) are central elements.

Four-stranded G-quadruplex (G4) composed of guanines into stacked tetrads are structures present regulatory regions of various genes. Experiments using chemical, molecular and cell biology methods have demonstrated that G4s exist in DNA and in RNA, and are linked with genetic instability and cancers.

We have demonstrated its revolutionary mechanism of action: it is a first-in-class small molecule targeting a specific G4 present in the RNA of a selected oncogene (thymidylate synthase). By binding this RNA, NAX035 does not block the activity of the protein, but suppresses the protein creation at an earlier stage.

Team application materials