Cell level research on the Wnt-5a protein extends the knowledge about mechanisms involved in malignant melanoma. The results, which also includes first steps towards what in the future may be developed into cancer therapy, are presented in a new thesis from Lund University.
Malignant melanoma is one of the most common cancers in western countries, and in late stage-patients it is still waiting for a powerful therapy.
- The paradox of malignant melanoma is that therapy outcome in its early stages often is extremely good. But in its later stages the prognosis is, on the contrary, one of the weakest among cancer diseases with a five-year survival rate less than 20%, says Farnaz Moradi, Doctor of Philosophy in Medical Science at The Department of Translational Medicine, Lund University.
The Wnt-5a protein plays an important role in the embryonic development. Its role in various cancer diseases has for several years been in focus at Lund University where Professor Tommy Andersson has discovered that the expression level of Wnt-5a in tumor’s cancer cells correlates to poor prognosis in several malignancies. His research team has developed a peptide, which partly inhibits the Wnt-5a protein, called Box-5. The peptides target the migration and invasion of melanoma cells.
Farnaz Moradi has in her research focused on some of the mechanisms of Wnt-5a in malignant melanoma where the Wnt-5a protein is upregulated and how the Box-5 peptide could be used as a Wnt-5a inhibitor.
She has investigated several different concepts, testing Box-5 both as a single and combined inhibitor in malignant melanoma. The two most promising consists of Box-5 in combination with anti-IL-6, an antibody against the IL-6 protein, and Box-5 together with the MS-444 molecule. The MS-444, a low molecular weight inhibitor of the RNA binding protein HuR, is a recently developed inhibitor with so far only a few scientific studies performed around the world.
- These two models target both migration and invasion, with more or less the same efficiency. In our cell studies they inhibited about 70 percent of the invasion in malignant melanoma. However, I personally think the Box-5/MS-444 combination is the most promising. This since it strikes directly against the HuR protein, which produces several proteins important in cancer metastasis such as Wnt-5a and MMP-9.
In the field of malignant melanoma BRAF inhibitors over the last decade have become the dominant drug in clinical use. Even though the treatment initially is successful, the melanoma cells later may become drug resistant. Farnaz Moradi’s thesis includes initial studies of the function of Wnt-5a and HuR in the development of melanoma resistance.
- In our study, inhibitors blocking the Wnt-5a signaling and HuR protein could pave the way for a combination treatment which includes cancer drugs which already are in clinical use, like BRAF inhibitors, says Farnaz Moradi.
Future research embraces extended studies of the Box-5/MS-444 concept in cell lines, and further on mice studies.
Farnaz Moradi defended her thesis “Regulation of WNT5A Expression in Malignant Melanoma: Role in Tumor Progression” on 6 December 2017 at Lund University.
The studies were funded by Swedish Research Council, (VR) The Skåne University Hospital Research Foundation, The Gunnar Nilsson’s Cancer Foundation and Governmental Funding of Clinical Research (within the National Health Service).
Background/Wnt5a-protein and the Foxy-5/Box-5 peptides
The Foxy-5 and Box-5 peptides have been developed by Professor Tommy Andersson and his research group at Lund University. The Foxy-5 peptide mimics the Wnt-5a protein while the Box-5 peptide inhibits Wnt-5a. Depending on the Wnt-5a expression in various cancer diseases the two peptides are potential Wnt5a-regulators.
Foxy-5 and Box-5 are patented by the company WntResearch which currently performs clinical studies of breast and prostate cancer therapies including the Foxy 5- peptide.
Box-5 yet has to prove its capacity, but early scientific studies indicating future potential.
Text: Björn Martinsson