26 November 2014
By Marco Ranzani
Human melanoma cell undergoing cell division. Credit: Paul J.Smith &Rachel Errington, Wellcome Images.
Melanoma is a type of skin cancer that is not easy to treat, particularly once tumours have spread through the body. Indeed, 10-year survival rates for these cancers are between 10 and 15 per cent. At the moment protection from UV radiation and screening for abnormal moles that can be removed before they transform and invade other tissues are the best options to prevent and control the disease.
Nonetheless, since the mid-1970s, malignant melanoma incidence rates have increased more rapidly than any of the current 10 most common cancers in Great Britain, resulting in a lifetime risk of developing malignant melanoma of 1/55 in men and 1/56 for women. Additionally, 200,000 patients are still diagnosed each year worldwide when the disease has already spread, thus making malignant melanoma responsible of more than 75 per cent of skin cancer deaths.
Melanomas are tumours that arise from the pigmented cells of the skin: the melanocytes. Due to their physiological functions, melanocytes have inborn features that make them really nasty once they transform into a tumour. During an embryo’s development they originate from the neural crest, which later becomes the spinal cord, and migrate throughout the body to reach their natural location. This intrinsic migratory activity is reactivated in melanoma tumors, thus making them highly likely to spread into metastases and, consequently, to be lethal.
Additionally, as melanocytes are born to shield us from the mutagenic UV radiation that hits us from the sun every day, they can easily bear the accumulation of mutations, DNA lesions that drive the tumors themselves and increase their aggressiveness.
Recently, new therapeutic approaches have been deployed, including promising immunotherapy and targeted drug therapies. The latter rely on a small molecule that stops a gene that is mutated in melanoma from working, thus specifically killing the tumour cells. Unfortunately, for 20-30 per cent of melanomas (the so called BRAF/NRAS wild type melanomas), it is not known what the genes driving the disease are, hampering the development of targeted approaches.
I focused my research at the Wellcome Trust Sanger Institute on the discovery of new therapies for this subtype of melanomas. We used melanoma cell lines as a model of the human tumour, since they provide a versatile tool that can be easily used for screening. A useful approach when you do not know what mutated gene to target.
Upon characterisation of the genetic lesions carried by these cell lines, we screened them against different potential therapeutic agents. We discovered that trametinib, a specific inhibitor already used to treat melanoma with BRAF mutations, is also very effective in killing these BRAF/NRAS wild type melanoma cell lines. We then considered the mutations carried by the melanoma cell lines, and found that they are all sensitive to trametinib independent of their genetic lesions.
These results may indicate that trametinib could be broadly active in this subtype of melanoma. Therefore, trametinib could represent a new potential therapeutic option for the patients that are affected by BRAF/NRAS wild type melanoma. (Click here to see the paper on this research.)
I am now expanding this approach to screen for additional drugs active in this subclass of melanomas. I am also coupling this type of screening with a different approach I developed at the San Raffaele-Telethon Institute for Gene Therapy in Milan (TIGET) before joining the Sanger institute: lentiviral vector based insertional mutagenesis. This strategy uses a modified virus to screen for genes that are involved in the induction of drug resistance.
The combination of these tools can help us to develop new therapies that are highly effective and less prone to the occurrence of resistance, one of the major hurdles for targeted therapies in cancer.
Marco Ranzani is a Postdoctoral Fellow in Experimental Genetics group led by David Adams where he studies the development of new therapies for melanomas.
References
- Ranzani M et al (2014). BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib. Pigment Cell & Melanoma Research. DOI: 10.1111/pcmr.12316
- Ranzani M et al (2013). Lentiviral Vector-based Insertional Mutagenesis Identifies Genes Involved in the Resistance to Targeted Anticancer Therapies. Molecular Therapy. DOI:10.1038/mt.2014.174
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