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Personalized BRAF inhibitor treatment: a new way to treat melanoma

Researchers from the Moffitt Cancer Centre & Research Institute found a new way to use BRAF inhibitor treatment to help treat melanoma.

Melanoma is a type of skin cancer that begins in the melanocyte cells of the skin. The melanocyte cells are the cells that produce melanin, which is what gives skin its colour. The melanoma tumour, caused by abnormal cell growth, is one in which the different cells of the tumour can have a varying form or structure from other cells and can have observable characteristics that are different from one another. For the tumour cells to grow and multiply, two cellular processes need to occur, known as ‘transcription’ and ‘translation’. Transcription is the process by which genetic information in one form (DNA) is converted to another form (RNA), and this is the first step cells undergo during the process of expressing the information that is contained in our genes.

Recent research has shown that melanoma has different, distinct transcriptional states and that the melanoma tumour may consist of groups of cells with varying levels of resistance to the drugs that are used to treat them. One of the most common forms of melanoma is ‘BRAF-mutant melanoma’, which simply means that the melanoma arose through an alteration in the original gene information for the BRAF gene. The current method of treatment for this melanoma is using a form of BRAF inhibitor therapy, in an attempt to inactivate the BRAF protein that comes from the BRAF gene, so that the tumour is unable to grow. But, even if this continuous BRAF inhibitor treatment is initially successful, it can end up eventually leading to therapy failure, as the cells of the tumour can develop a resistance to the drug

In a recent study, researchers wanted to investigate how initial differences in transcriptional states could predict for how sensitive the different cells are to BRAF inhibitor treatment. They also wanted to test to what extent the transcriptional state differences could accurately predict the success of a reintroduction of BRAF inhibitor treatment, following a period during which the treatment was stopped. In the study, published in EBioMedicine, 11 melanoma cell lines (groups of cells created from a single cancerous cell) and mouse models were used to determine transcriptional state diversity in tumours and the response to BRAF inhibitor treatment.

Transcriptional states differ among cell lines

Through their analyses, the researchers found that melanoma cell lines had four distinct transcriptional states, with different cell lines having varying numbers of cells in each transcriptional state. It appeared that state #1 was likely more sensitive to BRAF inhibitor treatment, and further analysis showed that melanoma cells lines that did not have a state #1 more quickly became resistant to inhibitor treatment (in comparison to cell lines where the majority of cells were in state #1). The researchers also saw that cell lines that did not initially have a state #1, were unable to return to a drug-sensitive state after the inhibitor treatment was removed for a period. This led them to the idea that it was likely that state #1 was a key player in the initial determination of how sensitive a cell line would be to inhibitor treatment and, how successful reintroduction of the drug would be. In addition, the data indicated that cells in state #2 were less likely to multiply frequently, and cells in state #3 were more likely to show resistance to BRAF-inhibitor treatment.

Developing personalized melanoma treatment

The researchers then used the data collected to come up with personalized schedules for administering BRAF inhibitor treatment, based on the initial makeup of the individual melanoma cells of the larger tumour. This was done in an effort to improve the response to treatment in the body. The researcher’s goal was to first shrink the melanoma tumour and then maintain a group of drug-sensitive cells as part of the tumour to prevent uncontrolled growth of drug-resistant cells. The test of the personalized schedules of inhibitor treatment within the mice models showed that a personalized treatment schedule was better at treating melanoma tumours than was continuous inhibitor treatment or a fixed schedule of periodic treatment.

These findings are the first of its kind to show that developing personalized treatment schedules, based on evolving characteristics of tumours, could be an effective way of dealing with melanoma. This research is important because it introduces a new, seemingly quite effective way of treating melanoma tumours, within a laboratory setting at least, which could provide hope to a lot of patients who suffer from this type of cancer. Plus, the advantages of this type of treatment, as the researchers point out, is that there would be “reduced drug exposure and toxicity to the patients”, compared to current forms of treatment. More research confirming these results and testing them in human cases is required, but the future of melanoma treatment looks a little brighter.

Written by Haritha Thevar, BSc

References:

Smalley, I., Kim, E., Li, J., Spence, P., Wyatt, C., Eroglu, Z., Sondak, V., Messina, J., Babacan, N., Maria-Engler, S., De Armas, L., Williams, S., Gatenby, R., Chen, Y., Anderson, A. and Smalley, K. (2019). Leveraging transcriptional dynamics to improve BRAF inhibitor responses in melanoma. EBioMedicine.

www.cancer.ca. (2019). Survival statistics for melanoma skin cancer – Canadian Cancer Society. [online] Available at: https://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/prognosis-and-survival/survival-statistics/?region=on [Accessed 12 Oct. 2019].

Image by fernando zhiminaicela from Pixabay

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