Approximately half of all melanoma patients have mutations in the BRAF gene that promote cancer growth. Drugs that target BRAF and the downstream signaling protein MEK have significantly improved patient outcomes, but patients with advanced melanoma are rarely cured with these drugs and most will eventually develop drug resistance and relapse. However, some patients with BRAF-mutated melanoma can be successfully retreated with BRAF or MEK inhibitors. Moffitt researchers wanted to determine how differences between cells of a single tumor lead to better responses to BRAF/MEK inhibitors in certain patients.
The research team assessed the variability of melanoma cells and their responses to BRAF inhibitor treatment by analyzing the RNA expression patterns in single cells from melanoma cell lines and patient samples. They discovered that melanoma cells can reside within four different states with distinct patterns of gene expression. Their analysis predicted the following:
- State 1: Cells that divided more frequently and were more sensitive to BRAF inhibitors
- State 2: Cells that were less proliferative with a higher level of MAPK signaling
- State 3: Cells enriched for expression of the genes EGFR, c-JUN and Axl and were more resistant to BRAF inhibitors
- State 4: Cells undergoing cell death
The researchers found that maintaining a population of cells within the drug sensitive State 1 was critical to maintaining drug sensitivity. Cell lines that lacked a population of cells within State 1 were more resistant to BRAF inhibitor treatment and could not be successfully rechallenged with a BRAF inhibitor.
These observations, along with evolutionary principles, were used to create a mathematical model to show that it is possible to maintain drug-sensitive cell populations in State 1 by using an adaptive dosing schedule. Normally, melanoma patients are treated with a continuous dosing schedule with the intent of killing many cancer cells as quickly as possible. This continuous dosing approach often leads to the development of drug resistant tumor cell populations. During an adaptive dosing schedule, the decision to hold or initiate drug treatment is based on predicted tumor growth and individual factors.
“Our goal was to achieve initial tumor shrinkage and then to maintain sensitive cells within the tumor, preventing the uncontrolled expansion of the more resistant cellular states,” explained Inna Smalley, Ph.D., a member of Moffitt’s Department of Tumor Biology.
The researchers validated their mathematical model in mouse experiments by showing that adaptive dosing schedules resulted in stronger anti-tumor responses compared to standard continuous dosing schedules. They hope that their studies in cell lines and mouse models will lead to improved treatment approaches for patients.
“Our findings further provide the proof-of-concept that resistance can be delayed through adaptive scheduling of existing FDA-approved drugs, with the advantages of reduced drug exposure and toxicity to the patient,” said Smalley.
The research team will assess the feasibility of this adaptive treatment approach in a phase 1 clinical trial of BRAF-MEK inhibitors in advanced melanoma patients at Moffitt.
Their work was supported by funds from the National Institute of Health.
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt is a Top 10 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 6,500 team members, Moffitt has an economic impact in the state of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter, Instagram and YouTube.
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