Диссеминированная меланома кожи
Surgical. Radical removal of visceral metastases increases the life expectancy of certain patients.
Pharmacological. Over a fifty-year history of chemotherapy of malignant tumors, almost all classes of chemotherapeutic agents, including alkylating agents, nitroso derivatives, platinum-based drugs, antimetabolites and vinca alkaloids, have been used to treat advanced cutaneous melanoma. Clinical results suggest that the objective response rate for the chemotherapy alone never exceeded 20%. Polychemotherapy regimens also did not significantly increase life expectancy of the patients, according to the US randomized studies of efficacy of dacarbazine (DTIC) and its combination with other antitumor agents. Thus, adding vinca alkaloids increases the objective response rate insignificantly as compared to dacarbazine alone.
Personalized therapy of disseminated melanoma
With the development of science, a significant success was achieved in studying the pathogenetic origin of melanoma and a huge step has been made to detect potential molecular targets. A hope to improve the results of its pharmacological treatment for the first time emerged in 2002 when activating mutations in BRAF oncogene were detected as a result of DNA studies of melanoma (Davies H., et al). It was determined that these point mutations affecting predominantly codon 600 of BRAF’s kinase domain change a three-dimensional configuration of a protein kinase BRAF. Catalytic activity of mutated protein kinase is many times higher than that of a normal molecule. Excessive signaling activity of RAS/RAF/MEK/ERK module constituting MAPK cascade stimulates chaotic cell proliferation and implements their metastatic potential (Govindarajan B., et al). The incidence of mutations in BRAF gene in melanoma, according to different investigators, varies from 30–40 to 70% (Schlaak M., Bauer J.). Activating mutations in other genes (KIT, NRAS etc.) are detected significantly rarer. BRAF, NRAS and KIT mutations are mutually exclusive, i.e. they are not detected within one tumor. V600E is the most common (69–94% of the cases) type of BRAF mutations (when valine is replaced by glutamine in codon 600). This mutation is dominating; however, it is by far not the only type of BRAF disorder (Long G.V., Ponti G.). The second most common mutation is V600K, its incidence may reach 30%. V600D and V600R mutations are observed significantly rarer (Cheng S.).
An optimal selection of therapy for melanoma patients requires a flawless molecular diagnostics. In particular, a key milestone in making therapeutic decisions is to determine the status of BRAF oncogene. If its mutation is detected, preferable treatment method is to prescribe BRAF inhibitors, while the drugs of this group must not be used if there is no such genetic defect. Therefore, molecular genetic analysis is a mandatory component of examining melanoma patients.
Discovery of a molecular target BRAF formed the basis of a thoroughly planned program of biotechnological studies; as a result a specific low molecular weight inhibitor of a mutated enzyme —vemurafenib — was designed. Vemurafenib was a revolutionary step in treatment of melanoma: with a targeted drug, objective response rate for tumors with BRAF mutation V600E is 6 times as high as similar parameters for standard cytostatic therapy (McArthur G.A.). Vemurafenib affects the mutated cells in a targeted manner inhibiting their activity; however, it has a paradoxical activating effect on the cells with normal BRAF sequence (Pratilac C.). This phenomenon shows that correct diagnosis of BRAF gene status is of paramount importance (Halaban R.).
It should be noted that capabilities of melanoma’s pharmacological treatment continue expanding. Besides BRAF inhibitors (vemurafenib, dabrafenib), drugs to treat KIT- and NRAS-mutated tumors are being developed (Asciero P.A., Hodi F.S.). Significant success was achieved in immune therapy of melanoma: if such treatment was limited to high-dosage interleukin in the intensive care unit settings, in the current decade specific immune modulators, which affect certain regulatory components of an antitumor immune system (CTLA-4, PD-1, PDL-1 molecules), have appeared.
Currently. a top priority task in the therapy of disseminated cutaneous melanoma is to search for new targets and to create molecules for blocking these targets.