MELANOMA is a deadly type of skin cancer due to its aggressive and therapy-resistant nature. An initial melanoma tumour is well known to break away and invade other organs in the body, a process known as metastasis.
The evolution of melanoma occurs in five stages based on the Clark model (see accompanying image). The first stage begins when normal pigment-forming cells called melanocytes excessively multiply to become the commonly acquired mole. In the second stage, the mole, also known as the benign nevus, then has its DNA erroneously changed often through long, intense exposure to UV radiation from the sun.[ihc-hide-content ihc_mb_type=”show” ihc_mb_who=”2,3,5″ ihc_mb_template=”1″ ]
Such a change is called a genetic mutation. The DNA change occurs either at the existing nevus or at a new location. The benign nevus now becomes the dysplastic nevus. Unique to this stage is the formation of multiple random pigmentation with an irregular border. The dysplastic nevus will then progress to the radial growth phase (RGP).
Cells in this phase have the ability to multiply within the outermost layer of the skin but cannot break away and invade other organs. With the loss of a protein called E-cadherin, the fourth stage begins. Cells can now invade other layers of the skin.
The final stage of the progression is called metastatic melanoma where the cells gone rogue conquer other areas of the body. The first site of invasion is the lymph nodes, then to other parts of the skin, lungs, liver and the brain.
Melanoma is rare in Malaysia with a total of 61 cases reported in 2007, according to the National Cancer Registry Report. Among the 61 cases reported, 34 were males – 11 Malay, ten Chinese and two Indians. Out of the total 27 female melanoma patients, 14 of them were Malays, 11 were Chinese and one Indian.
In a study conducted at the University Malaya Medical Centre from 1998 to 2008, 32 cases of the most aggressive form of melanoma, called cutaneous melanoma were recorded within ten years of the study.
The largest group of 19 patients were Chinese, followed by ten Malays and three Indians. According to a news report in The Star (February 2015), data from the Dermatology Clinic of Hospital Kuala Lumpur from 2006 to 2014 revealed that melanoma is uncommon in Malaysia as it only accounted for 5.4% of the patients in the Dermatology Clinic of Hospital Kuala Lumpur.
The same data listed more common and less aggressive forms of skin cancer like basal cell carcinoma as the most common type of skin cancer in Malaysia, accounting for 34.9% of cases. Another less aggressive form of skin cancer called squamous cell carcinoma corresponded to 20.6% of cases.
Among Caucasian populations, Australia and New Zealand have the highest number of melanoma cases in the world. It was estimated that one person becomes a victim of melanoma every six hours in Australia, specifically Queensland.
From 2009 to 2013, 71 out of 10,000 people were diagnosed with melanoma in Queensland alone, exceeding all other number of cases reported worldwide.
In early stages, melanoma is usually treated through surgery.
Dacarbazine (DTIC) was among the first drugs to be developed for the treatment of metastatic melanoma in 1975.
However, the research and development of melanoma treatment plunged into its dark ages for the following 20 years. No new and improved drugs were developed until 1995. A better understanding of the role of the immune system during the onset of melanoma saw the development of three new drugs namely Intron A, Proleukin and Sylatron.
From then on, the development of drugs for melanoma treatment progressed to deeper understanding of proteins – the way cells communicate with each other and how these components were errant in melanoma.
Recent years have seen cancer researchers embracing personalised medicine for melanoma treatment. Personalised medicine utilises the understanding of the unique genetic and clinical information of each individual patient at a molecular level to optimise the strategy used for their treatment and healthcare.
Drugs such as Vemurafenib and Trametinib which inhibit specific parts of cell to cell communication in the Mitogen Activated Protein Kinase (MAPK) pathway have been widely used in personalised medicine with remarkable response. With the introduction and development of personalised medicine as a treatment option in melanoma and other cancers, a more effective and less toxic treatment can be provided to patients.
Besides targeting cell signalling pathways, drugs like Navitoclax (ABT-263) which specifically target BCL-2 proteins that regulate naturally programmed cell death, in combination with other drugs have exhibited favourable response in human melanoma experimental cells and animal models. Future clinical trials should include these drugs to be tested in advanced melanoma patients.
NOTE: This article by the authors is part of the introduction for their Masters thesis.
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