Structure-based drug design targeting peroxisome proliferator-activated receptors in mesothelioma

Lesterhuis WJ, Piggott M, Vrielink A, Lake RA.

Funding: Cancer Council Western Australia

Plain language summary: Mesothelioma is a universally fatal cancer of the lungs that often grows rapidly and invades surrounding tissues, causing severe symptoms, such as shortness of breath and pain. We identified two related proteins that drive this extreme local invasiveness fast-growing behaviour of mesothelioma. In this project, we aim to design and test drugs that inhibit these proteins, with the aim to discover a new drug that could be effective against mesothelioma, and potentially other cancers.

Synopsis (lay): Mesothelioma is a fatal cancer caused by exposure to asbestos. Western Australia has the highest incidence of this cancer in the world, because of the mining, transport and high use of asbestos here. The outcome for people with mesothelioma has not improved in more than a decade. Mesothelioma starts in the lining of the lungs, but once it is diagnosed it often rapidly grows into surrounding organs such as the ribcage and heart. This causes severe shortness of breath and pain. The fast growth into surrounding organs makes it an ‘invasive’ cancer. It is not known why mesothelioma is so invasive.

Mesothelioma is unique in that asbestos causes exactly the same tumours in humans and animals. We study mesothelioma in mice, because mice can develop both invasive and non-invasive mesotheliomas. By comparing tumours from invasive and non-invasive mesotheliomas we can address the question ‘what makes mesothelioma such an invasive cancer?’ In doing so, we identified two related proteins that fuel the invasiveness and fast-growing behaviour of mesothelioma. These proteins are involved in the metabolism of sugar and fats, which is often abnormal in cancer cells. When we inhibited these proteins in mesothelioma cells from patients, the cancer cells died, while normal cells remained unharmed. This strongly suggests that these two proteins are not only very important in mesothelioma growth but that a drug that inhibits them could be very effective.

In this project, we aim to design drugs that specifically bind to these mesothelioma proteins, and thereby neutralize their activity. We will observe the interaction between the drug and proteins to create an optimal ‘fit’, and we will test these variants against cancer cells from mesothelioma patients to identify the most effective drug. Using this approach, we aim to develop a drug that is effective against mesothelioma, which we can then take further into the clinic.

NCARD Research Team

Joost Lesterhuis, Richard Lake

Students: Lizeth Orozco Morales (PhD 2019-2022)