McInnes Lands Pilot Grant for Blocking Paradoxical Signaling behind Melanoma Drug Resistance

Melanoma strikes more than 76,000 Americans a year and kills 9,000 of them, making it both the least common and most deadly of skin cancers. Campbell McInnes, associate professor of drug discovery and biomedical sciences at the South Carolina College of Pharmacy (SCCP), and his team have discovered a new way of intefering with the process that makes melanoma so resistant to treatment.

The Melanoma Research Alliance (MRA) has awarded McInnes’ lab at SCCP’s University of South Carolina (USC) campus a two-year pilot grant for $50,000/year to further this research, which includes teaming with scientists at the Albert-Ludwigs University in Freiburg, Germany.

“The goal of this research is to enable us to accelerate progress to combat deadly forms of melanoma and to improve outcomes for patients,” McInnes said.

Melanoma is so dangerous because when it is not recognized in time, it metastasizes to other parts of the body and becomes more resistant to drugs.

In recent years, new targeted drugs have been developed which initially were thought to be transformative in the treatment of metastatic melanoma. These new agents include the drug vemurafenib and were designed to block the activity of a protein which is found only in the tumors and frequently is the underlying cause of this type of skin cancer. Despite dramatic initial responses from the majority of treated individuals (where tumors shrunk and in many cases disappeared altogether), resistance to these targeted agents quickly emerged and patients relapsed in many cases even worse than before treatment.

Further studies revealed that the cause of such resistance results from the melanoma becoming dependent on what is called “paradoxical signaling.”

“This occurs when rather than the drug inhibiting the mutant protein, it is instead activates it by binding to an additional site thereby stimulating its activity and having the opposite effect,” said McInnes. “As a consequence, regrowth of the tumor occurs over time and therefore leads to the resistance to vemurafenib.”

McInnes’ team discovered a new way of interfering with this paradoxical signaling that involves the use of smaller segments of the protein drug target.  “Peptide inhibitors” based on these smaller segments have been shown to block paradoxical signaling and therefore have promise for development as a new class of drugs that might treat patients resistant to current treatments and which might be used in combination with vemurafenib and other similar agents. These also could be effective against tumors with activated Ras protein, a frequent occurrence in many cancers.

“In this application, we propose to carry out a detailed investigation of how these ‘proteomimetics’ function in blocking paradoxical signaling with the aim of improving their effectiveness and making such compounds more like molecules that can be developed as anti-melanoma therapeutics,” said McInnes.  

The MRA is a public charity formed under the auspices of the Milken Institute, with the generous founding support of Debra and Leon Black.  The mission of the MRA is to end suffering and death due to melanoma by collaborating with all stakeholders to accelerate powerful research, advance cures for all patients, and prevent more melanomas.