Targeted therapy for malignant melanoma

About the research project

The incidence of melanoma has been increasing rapidly in Caucasian populations worldwide over the last 25 years at an annual rate of 3-7%. In the Czech Republic the incidence of melanoma has increased five fold between years 1970 and 2002. Despite such sharp increase in melanoma incidence, it still accounts for less than 5% of all dermatologic cancers. However, it is responsible for about 80 % of all deaths from skin cancers. Moreover, unlike most other cancers, melanoma is relatively frequent among young and middle-aged adults. In the United States, melanoma is the second leading cause of lost productive years of all cancers and it is the most common cancer among women 20 to 29 years of age.

Although the large majority of people diagnosed with early melanoma are cured after surgical excision of the primary tumour, advanced metastatic disease is usually refractory to all current forms of systemic therapy and has a very poor prognosis. The 5-year survival rate is currently estimated at only 6%, with a median survival time of 6 months. Among cytotoxic agents, dacarbazine (DTIC) and its analogue temozolomide remain the chemotherapy of choice but they produce objective response in only 15 to 20% of patients and the median duration of the response is only 4 months. New immunotherapeutic approaches have been also tested. High doses of interleukin-2 or interferon alpha as single agents have induced responses in 10 to 16% of patients but they are associated with significant toxicity and serious side effects. A potential benefit of combining chemotherapy with immunotherapy has been tested in several phase III trials. However, these trials failed to consistently demonstrate an improvement in either response rates or overall survival.

Currently the most intensely tested targeted therapeutic strategy for malignant melanoma is the inhibition of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway (ERK pathway). This signal transduction pathway, which normally regulates cell proliferation and survival mainly in response to extracellular signals, has been found constitutively activated in the majority of human melanomas, most commonly by activating mutations of N-Ras and B-RAF proto-oncogenes that are found in approx. 80% of malignant melanomas. Sorafenib (BAY 43-9006), an oral inhibitor of RAF kinase has demonstrated activity against melanoma in preclinical tests and it is currently the most promising drug in clinical trials for the targeted treatment of malignant melanoma. Even though early clinical studies failed to show efficacy of sorafenib as a single agent, preliminary results suggest that combinations of sorafenib with various chemotherapeutics are more effective in the treatment of advanced melanoma than chemotherapeutics alone. Interestingly, results of a recent research comparing the sensitivity to ERK pathway inhibitors of melanoma cell lines derived from different stages of melanoma progression suggest that multiple cellular signalling pathways may need to be targeted in order to achieve maximal therapeutic efficacy against the most aggressive metastatic melanomas.

While the activation of the ERK pathway is believed to be a critical early event in the development of melanoma, the role of other MAPK pathways (and other cellular signaling pathways generally) in the development of this cancer and its response to therapy remains largely unclear. That is why we are studying the role of selected cellular signaling pathways in melanoma cell survival and response to DNA-damaging chemotherapy, and in the regulation of p53 tumour suppressor activity in malignant melanoma cells. Our aim is to identify suitable cellular targets for the development of novel, more efficient targeted therapies for malignant melanoma.


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