Melanoma is the most lethal form of skin cancer with high mortality rates. While new drugs have been approved to treat the disease, patients nearly always develop resistance to the therapies and the cancer advances. This is especially relevant for patients with a mutation in the BRAF gene who generally have a robust, but temporary, response to BRAF inhibitor therapies. Researchers have been trying to identify therapies that can be combined to improve patient response.
A new study, led by first author Anna Vilgelm, M.D., Ph.D., postdoctoral fellow, Vanderbilt University, and corresponding author Ann Richmond, Ph.D., Ingram Professor of Cancer Research, Vanderbilt University, and Senior Research Career Scientist, Tennessee Valley Healthcare System Department of Veterans Affairs, indicates that two therapies already in clinical development as single agents may work in combination to treat many subtypes of melanoma. The study was published online recently in Cancer Research.
The investigators’ ultimate target was to block cell proliferation and induce cell death by targeting two proteins: MDM2, a protein which facilitates degradation of the tumor suppressor p53, and Aurora kinase A (AURKA), a protein that regulates cell division and growth. TP53, the gene that encodes p53, is seldom mutated in melanoma which makes the activation of the p53 cellular pathway through MDM2 targeting feasible. AURKA is often highly expressed in melanoma tumor cells.
Early tests of an AURKA inhibitor found that the drug was stopping tumor cells from multiplying, making them big and sluggish (senescent), but the cells still weren’t dying. So Vilgelm decided to combine this therapy with a second drug (MDM2 antagonist) which kills tumor cells by restoring p53 function.
“The tumor cells made senescent by treatment with the AURKA inhibitor were not dying and might later start growing again, so we wanted to treat them with this agent that induces p53 and death of the senescent cells. The senescent cells also release cytokines that bring in immune cells to help remove and kill the senescent tumor cells,” said Vilgelm.
The investigators tested the combination therapy in several melanoma mouse models, including one that grafts human melanoma tumor samples directly into the mouse.
Richmond said combining the MDM2 antagonist drug with the AURKA inhibitor worked as a form of indirect immunotherapy and blocked the growth of the tumors.
“The combined effect of inducing senescence and then blocking MDM2 led to massive production of chemokines that recruited immune cells that helped participate in the inhibition of tumor growth,” explained Richmond.
“The majority of the tumors that we tested were able to respond to the therapy, regardless of BRAF gene mutation, suggesting that a large cohort of patients could be treated with these drugs including patients whose tumors had developed resistance to BRAF inhibitor therapy,” said Vilgelm.
The authors say the results provide a sound rationale for further studies of the combination therapy.
Mdm2 and Aurora Kinase A Inhibitors Synergize to Block Melanoma Growth by Driving Apoptosis and Immune Clearance of Tumor Cells, Anna E. Vilgelm, Jeff S. Pawlikowski, Yan Liu, Oriana E. Hawkins, Tyler A. Davis, Jessica Smith, Kevin P. Weller, Linda W. Horton, Colt M. McClain, Gregory D. Ayers, David C. Turner, David C. Essaka, Clinton F. Stewart, Jeffrey A. Sosman, Mark C. Kelley, Jeffrey A. Ecsedy, Jeffrey N. Johnston, and Ann Richmond, Cancer Research, doi: 10.1158/0008-5472.CAN-14-2405, published online 14 November 2014.
The study was supported by funding from the Department of Veterans Affairs (5101BX000196-04), the National Institutes of Health (CA116021, CA116021-S1, CA90625, 5T32CA119925-03, 1F32CA171895-01, GM084333 and CA68485), and a Senior Research Career Scientist Award to Richmond.
Source: Vanderbilt-Ingram Cancer Center