Novel Drug Reduces Spread of Melanoma by 90%

A team of scientists at Michigan State University has discovered that a potential new drug, called CCG-203971, reduces the spread of melanoma cells by up to 90%. The findings are published in the journal Molecular Cancer Therapeutics.

Melanoma is a disease in which malignant cells form in melanocytes. Image credit: Ibdipcan2015 / Terese Winslow / CC BY-SA 4.0.

The small-molecule drug compound goes after a gene’s ability to produce RNA molecules and certain proteins in melanoma tumors.

This gene activity causes the disease to spread but the compound can shut it down. Up until now, few other compounds of this kind have been able to accomplish this.

“It’s been a challenge developing small-molecule drugs that can block this gene activity that works as a signaling mechanism known to be important in melanoma progression,” said Prof. Richard Neubig, from the Department of Pharmacology and Toxicology at Michigan State University.

“Our chemical compound is actually the same one that we’ve been working on to potentially treat the disease scleroderma, which now we’ve found works effectively on this type of cancer.”

Prof. Neubig and co-authors found that the compound was able to stop proteins, known as myocardin-related transcription factors (MRTFs), from initiating the gene transcription process in melanoma cells.

These triggering proteins are initially turned on by another protein called RhoC (Ras homology C), which is found in a signaling pathway that can cause the disease to aggressively spread in the body.

“Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease,” the authors said.

“Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional co-activator, myocardin-related transcription factor.”

“We highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis.”

CCG-203971 reduced the migration of melanoma cells by 85 to 90%. The researchers also discovered that the potential drug greatly reduced tumors specifically in the lungs of mice that had been injected with human melanoma cells.

“We used intact melanoma cells to screen for our chemical inhibitors. This allowed us to find a compound that could block anywhere along this RhoC pathway,” Prof. Neubig said.

Being able to block along this entire path allowed the team to find the MRTF signaling protein as a new target.

“Figuring out which patients have this pathway turned on is an important next step in the development of their compound because it would help them determine which patients would benefit the most,” said study co-author Kate Appleton, a postdoctoral student in the Department of Pharmacology and Toxicology at Michigan State University.

“The effect of our compound on turning off this melanoma cell growth and progression is much stronger when the pathway is activated.”

“We could look for the activation of the MRTF proteins as a biomarker to determine risk, especially for those in early-stage melanoma.”

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Andrew J. Haak et al. 2017. Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma. Mol Cancer Ther 16 (1): 193-204; doi: 10.1158/1535-7163.MCT-16-0482