A study recently published in the journal Oncogene revealed a new therapeutic strategy for advanced metastatic melanoma based on the interaction between two particular factors – Pin1 and FOXM1. The study is entitled “Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling”, and was led by researchers at the University Medical Center Utrecht and the Erasmus Medical Center Rotterdam in The Netherlands, and The Buck Institute for Research on Aging in the United States.
Melanoma is the most dangerous and lethal form of skin cancer accounting for 2% of all cases and almost all skin cancer related deaths. Melanoma rates in the United States have been rapidly increasing in the last few decades and successful treatment strategies for advanced melanoma still poses a challenge. This skin cancer is caused by damage to skin cells (usually by ultraviolet radiation from sunshine or tanning beds), which triggers mutations that are not repaired, allowing cells to rapidly multiply and generate malignant tumors. Melanoma is curable when detected and treated early; if it goes undetected or if it recurs, the cancer can proliferate and spread (metastasize) to other parts of the body, becoming more difficult to treat. The estimated average survival rate of patients with metastatic melanoma is 8 to 18 months if left untreated.
The treatment options for metastatic melanoma are mainly based on immunotherapy or targeted therapies against oncogenic pathways, however they have some limitations.
Around half of the individuals diagnosed with melanoma carry a mutation in the BRAF gene (V600E), which can provide melanoma with a resistance mechanism against several drug therapies commonly based on BRAF inhibitors. BRAF mutations lead to a constitutively activated state of a gene known as MEK (mitogen-activated protein kinase). Inhibition of either BRAF or MEK has been shown to significantly reduce the growth of melanoma; however, resistance to these inhibitors is common.
In the study, researchers hypothesize that one way to improve patient survival in melanoma cases is to inhibit MEK targets in an alternative manner. The team searched for markers highly expressed in melanoma and that were under the control of potentially druggable proteins.
Researchers found that many human melanomas have high levels of a pro-survival and pro-proliferative factor called FOXM1, which is targeted by MEK and regulated by an enzyme called Pin1, found to be an indicative of poor prognosis. The team reported that the Pin1-FOXM1 interaction was enhanced by BRAFV600E mutation, and that its inhibition could impair FOXM1 activity, tumor proliferation and cell survival in isolated human metastatic melanoma and three-dimensional-cultured patient-derived melanoids. When Pin1-FOXM1 inhibitors were combined with PLX4032, a BRAF V600E inhibitor, a robust repression in melanoma cells’ viability was observed.
The authors concluded that their results provide a proof-of-concept that Pin1-FOXM1 inhibitors could represent a novel therapeutic approach for metastatic melanoma.