MMP Research – utilising melanoma tissue generously donated by our MMP patients

Dr Clare Fedele and Dr Mark Shackleton, from the Peter MacCallum Cancer Centre, have contributed to a prestigious scientific publication in collaboration with fellow melanoma researchers. Dr Fedele explains the research conducted below.

Our bodies have inbuilt mechanisms to prevent cancer. One of the most important mechanisms revolves around an important protein called p53, which recognizes when a cell has been damaged. If this happens and if the p53 protein is working properly, then the body fixes or eliminates the damaged cell.

If the p53 protein is not working properly, then damaged cells are allowed to survive, to multiply and to accumulate more abnormalities, sometimes resulting in cancer. Indeed, many cancers contain p53 proteins that are not working properly. Usually, this is due to damage to the p53 protein itself through genetic mutation. Another reason is because other proteins can inhibit p53 through direct binding. One of these inhibitory proteins is called MDM4, which is normally present in some cells at low levels.

Human Melanoma - MDM4

“A section of human melanoma showing abnormally high levels of MDM4 (red staining). Melanoma cells are shown in green”

Strangely, p53 mutations are rare in melanoma, unlike other common cancers. This has puzzled melanoma researchers for a long time. However, recent research has solved the p53 ‘puzzle’ in melanoma by showing that about two-thirds of melanomas have abnormally high levels of MDM4 (ref figure here). This results in p53 being suppressed and unable to protect the cells from damage, leading to melanoma.

Most excitingly, the researchers found that a new drug could block the inhibitory effect of MDM4 on p53. In laboratory tests, treatment of melanoma cells with the drug had the effect of reactivating p53 so that this important protein could go back to work in reducing melanoma formation and causing tumors to reduce dramatically in size, even when those tumors were resistant to other treatments.

The research, which was led by Belgium scientists with critical support from laboratories at Peter Mac and from the Melbourne Melanoma Project, has opened up a new possibility for melanoma treatment. Work is underway to continue developing p53 reactivating therapy towards clinical trials in melanoma patients.

 

Gembarska A, Luciani F, Fedele C, Russell E, Dewaele M, Villar S, Zwolinska A, Haupt S,  de Lange J,  Yip D,  Goydos J, Haigh J.J, Haupt Y,  Larue ,  Jochemsen A, Shi H, 4  Moriceau G, Roger  Lo R.S, Ghanem G,  Shackleton M,  Bernal F & Marine J.C. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 2012 18:1239-47 [0; 25.4]