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Melanoma Cell Heterogeneity and Adaptive Dosing Schedules

By: Kayci Reyer
Posted: Thursday, January 9, 2020

According to research published in EBioMedicine, single-cell level transcriptional differences may predict the sensitivity of patients with melanoma to BRAF inhibitor treatment. Because of this heterogeneity, the use of an adaptive dosing schedule may result in improved patient outcomes.

“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,” noted Inna Smalley, PhD, of the Moffitt Cancer Center, in a Moffitt press release.

The study used single cell mRNA analysis of both melanoma cell lines and patient samples to determine the heterogeneity of melanoma cells and note their responses to BRAF inhibitor therapy. Cells were observed to exist in one of four states dependent on gene-expression patterns: state 1 included high cell proliferation and an increased sensitivity to BRAF inhibitor treatment; state 2 had less cell division and increased MAPK signaling; state 3 saw increased BRAF inhibitor treatment resistance and higher expression of certain genes; and state 4 included cell death.

After determining that cells in state 1 were more responsive to BRAF inhibitor therapy, the researchers created a mathematical model for keeping cells in this stage using an adaptive dosing schedule. This dosing plan manipulates the cell stage by initiating or pausing medication administration based on individualized analysis and expected tumor growth. The efficacy of this treatment schedule was validated in mouse models, where adaptive dosing led to improved antitumor responses versus a conventional continuous dosing schedule.

According to the investigators, the next step is to assess the feasibility of this adaptive treatment approach in a phase I clinical trial of BRAF-MEK inhibitors in patients with advanced melanoma at Moffitt.

Disclosure: For full disclosures of the study authors, visit thelancet.com.



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