Skin cancer is becoming more and more common every year. Its variety – melanoma refers to tumors that are resistant to radiation therapy. Effective surgical treatment of melanoma is possible in the early stages. Therefore, so much attention is paid by clinicians to the possibilities of medical treatment of melanoma.
Learn in the article on estet-portal.com about modern drugs for the treatment of melanoma, which have been proven effective in numerous clinical studies.
BRAF kinase inhibitor in the treatment of melanoma
Dabrafenib, a sulfanilide drug, is a reverse ATP-competitive type I BRAF kinase inhibitor. This drug has been approved for the treatment of melanoma by the US Food and Drug Administration and the European Medicines Agency.
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The basis for this was the results of a multicenter, open-label, randomized phase III study BREAK-3. Preclinical studies have shown that the interaction of the drug dabrafenib at nanomolar concentrations with melanoma cell lines for 72 hours was characterized by a powerful inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and cell proliferation.
In an experimental model of melanoma with the BRAFV600E mutation, oral administration of dabrafenib provided ERK inhibition and inhibition of tumor growth.
The optimal regimen for dabrafenib is 150 mg orally twice daily as monotherapy or in combination with trametinib. After taking the drug reaches its maximum concentration in blood plasma after 2 hours; the average bioavailability is 95%. Several studies have also demonstrated a response to treatment with dabrafenib in brain metastases.
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New era of melanoma treatment
The discovery of the role of the RAS / RAF / MEK / ERK signaling pathway in melanogenesis and its further study marked the beginning of a new era in the treatment of melanomas. However, despite the excellent results of the use of I generation kinase inhibitors, which significantly exceeded the effectiveness of the traditional regimen − combination of surgery and chemotherapy, − the average duration of the therapeutic response was short due to the triggering of genetic and epigenetic mechanisms of resistance to treatment, mainly due to the paradoxical reactivation of the mitogen-activated protein kinase (MAPK) signaling pathway.
An innovative strategy to counteract this resistance has been the communication of BRAF kinase inhibitors with MAPK downstream phosphorylation kinase inhibitors, namely MEK and ERK.
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Such a combination overcomes paradoxical effects by blocking the most important pathway of tumor escape from therapeutic exposure, and is also characterized by a number of additional advantages, including a more powerful and prolonged clinical response, as well as less toxicity and a decrease in the number of side effects, due to paradoxical reactivation of the MAPK signaling pathway with BRAF inhibitor monotherapy.
In addition to overcoming this paradoxical activation, an important indication for the appointment of MEK inhibitors is the treatment of NRAS-mutant melanomas, which are characterized by greater aggressiveness and a worse prognosis than BRAF-mutant melanomas.
Trametinib for inoperable melanomas
Trametinib is a reverse allosteric, non-ATP competitive inhibitor of MEK1 and MEK2 type III. Trametinib can be given alone but is more commonly used in combination with dabrafenib for the treatment of adult patients with unresectable or metastatic melanoma.
Trametinib is given by mouth at a dose of 2 mg once/day; the bioavailability of this drug is 72%. Patients in the chemotherapy group who experienced disease progression were switched to trametinib. Compared with standard chemotherapy, trametinib monotherapy improved both overall survival and progression-free survival.
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The combination of trametinib and dabrafenib can significantly improve clinical response to treatment, as well as facilitate the control of toxicity associated with paradoxical activation of the MAPK pathway with BRAF inhibitors. In patients treated with the combination of dabrafenib and trametinib, progression-free survival and overall survival were higher than in the dabrafenib monotherapy group. Fewer side effects were also confirmed for the combination treatment group.
Thus, for a long time, the standard management of advanced melanoma was limited to chemotherapy, which was characterized by a low response rate and minimal impact on survival. The discovery of the role of BRAF mutations in the pathogenesis of melanomas has changed the views on the treatment of this neoplasm, making it possible to find out that the causative factor of melanogenesis is the activation of the MAPK signaling pathway under the influence of oncogenic mutations. It is this pathway that supports the growth, survival and spread of malignant melanocytes.
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Further pharmaceutical developments allow small molecules to inhibit the MAPK signaling pathway by acting on the mutated BRAF protein and downstream MEK kinases. Although monotherapy was clinically effective, combination treatment with BRAF and MEK inhibitors dramatically improved the clinical response and survival of patients with melanoma.
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