Vanderbilt-Ingram Cancer Center and the Department of Veterans Affairs conducted a study to identify possible second-line treatment for melanoma patients. This potential treatment would render CDK4/6 inhibitors, a class of drugs for some breast cancers, but also effective in treating melanoma when combined with MDM2 compounds—drugs presently in development.
ScienceDaily reports that the preclinical investigator team from Vanderbilt-Ingram Cancer Center and the VA utilized melanoma patient-derived xenografts in mouse models where the team uncovered the molecular mechanisms of CDK4/6 resistance which was then tested to determine whether the combination therapy would reverse the process.
In a positive finding, the effort revealed tumor regression in multiple mouse models as well as in human tumor slice culture assays as reported on August 14, 2019 edition of Science Translational Medicine.
A Key Challenge
Many effective melanoma therapies—particularly immunotherapies—are now available based on exciting clinical research breakthroughs over the past several years. However, nearly 50% of melanoma patients are not responsive to immunotherapies. Moreover, patients frequently develop resistance to targeted therapies and hence require a second-line treatment once resistance develops.
A Key Research Quest
The Vanderbilt and VA investigators understood that activation of CDK4/6 represents a key mechanism of melanoma development and that the inhibitors have not had the same efficacy with melanoma as they have had with breast cancer. Hence this research group sought to understand the reasons why. What they uncovered was the scarcity of a specific protein called p21 in melanoma cell lines as a likely cause.
The team believes that uncovering that a combination of CDK4/6 inhibitor with an MDM2 inhibitor can overpower a genetic driver of melanoma is an exciting discovery and can represent a program to further research in random controlled trials.
Anna Vilgelm, MD, Ph.D.
Ann Richmond, Ph.D.