Researchers have discovered a protein that can be used to predict the prognosis and response to treatment of malignant melanoma, a process that is currently done primarily by observing features of the tumor.
The findings, presented in the study “Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss ofATG5,” published in the journal Autophagy, may be used to improve monitoring of patients at high risk for disease progression, and might also advance drug development efforts for melanoma.
A research team from the Spanish National Cancer Research Centre found that the protein, called ATG5, is partially lost in some melanoma patients. The loss of the factor makes the tumor more aggressive, resulting in metastasis and resistance to drug treatment.
Pathologists make predictions of melanoma development based on how the tumor looks under the microscope. For example, a tumor depth of two millimeters is linked to a poor prognosis. When a measurement is based on observation, estimates may be inaccurate, revealing the need for novel and more accurate prognostic markers.
The road to the discovery did not start as a search for biomarkers. Instead, Marisol Soengas and her research team wanted to explore the role of a process called autophagy in malignant melanoma compared to other cancers.
Autophagy is a process that cells use to get rid of proteins and other parts they no longer need. Tumor cells tend to control the process to their advantage, so the team analyzed up to 20 genes related to autophagy in more than 25 types of cancer using database information from nearly 5,000 patients.
When screening the data, they found that changes in ATG5 were linked only to the prognosis of malignant melanoma, but not other cancers. And the changes they observed were quite specific: Melanoma cells lose one of the gene copies of ATG5.
To better understand how this loss affects disease development, they engineered a mouse lacking one gene copy, just like patients. They observed the same thing in the mice as they had noted in patients; loss of one copy made tumors more prone to metastasize and become resistant to treatment.
“This study has relevant implications for drug design, as it suggests that the partial blockage of autophagy could worsen the malignant behavior of metastatic melanomas,” Soengas said in a news release.
The findings may also have an impact on knowledge of other types of melanomas, as there is evidence that ATG5 is changed in ocular melanoma.