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Fármacos aprovados em 2018 para o tratamento do melanoma maligno metastático
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Orientador(es)
Resumo(s)
O melanoma maligno cutâneo consiste num tipo de tumor que surge a partir da
proliferação descontrolada dos melanócitos, devido a mutações genéticas hereditárias
e/ou adquiridas, cujo principal fator de risco é a exposição à radiação ultravioleta (UV).
Apesar de representar apenas 1% dos casos de cancro da pele, surge como o mais
agressivo e mortal de todos. A presença de metástases sugere geralmente um
prognóstico bastante desfavorável e constitui um desafio em termos terapêuticos.
A via MAPK está implicada na regulação da expressão genética, proliferação e
sobrevivência celular. A grande maioria dos pacientes com melanoma, nomeadamente
os que apresentam metástases distantes, possuem mutações em diferentes proteínas
cinase desta via. O proto-oncogene BRAF é o mais frequentemente mutado no
melanoma, levando a uma hiperativação da via e, por consequência, à proliferação
descontrolada das células. Estas descobertas permitiram o desenvolvimento de
fármacos direcionados para estas mutações. A partir de 2011 começaram a surgir os
inibidores da BRAF, com a promessa de revolucionarem o tratamento de pacientes com
melanoma metastático. Devido ao facto destes fármacos induzirem resistência após
alguns meses de tratamento, como alternativa, começaram a surgir terapêuticas
combinadas entre inibidores da BRAF e inibidores da MEK, sendo esta última, uma
proteína cinase da mesma via que, ao ser bloqueada, permitiria prevenir e adiar
possíveis mecanismos de resistência.
Ao longo dos anos, vários fármacos foram aprovados para o melanoma
metastático, sem, contudo, trazerem grandes benefícios a longo prazo. Após várias
combinações desenvolvidas, em 2018, a FDA aprova a combinação entre os fármacos
Encorafenib e Binimetinib, após resultados promissores nos seus ensaios clínicos. O
presente trabalho pretende expôr de uma forma geral as características e propriedades
farmacológicas diferenciadoras destas novas moléculas, dados de eficácia e atividade
clínica, bem como perfil de segurança, que levaram à sua aprovação para o melanoma
metastático.
Malignant cutaneous melanoma is a type of tumor that arises from the uncontrolled proliferation of melanocytes, due to inherited and / or acquired genetic mutations. The main risk factor for this tumor is the exposure to ultraviolet (UV) radiation. Despite representing only 1% of all skin cancer cases, it is the most aggressive and deadly. The presence of metastases generally suggests a very poor prognosis and constitutes a therapeutic challenge. The MAPK pathway is implied in the regulation of gene expression and cell proliferation and survival. The vast majority of melanoma patients, particularly those with distant metastases, have mutations in different protein kinases belonging to this pathway. The BRAF proto-oncogene is the most frequently mutated in melanoma, which leads to hyperactivation of the pathway and, as a consequence, uncontrolled proliferation of cells. These discoveries allowed the development of drugs aimed at these mutations. In 2011, BRAF inhibitors began to appear, with the promise of revolutionizing the treatment of patients with metastatic melanoma. However, these drugs induce resistance after a few months of treatment and, as an alternative, combined therapies between BRAF inhibitors and MEK inhibitors, began to appear. MEK is a protein kinase of the same pathway, which, when blocked, would prevent and delay possible mechanisms of resistance. Over the years, several drugs have been approved for metastatic melanoma, without, however, reaping major long-term benefits. After several combinations developed in 2018, the FDA approved the combination between the drugs Encorafenib and Binimetinib, after promising results in clinical trials. The present work intends to expose, in general, the differentiating characteristics and pharmacological properties of these new molecules, data on efficacy and clinical activity, as well as the safety profile, that led to their approval for metastatic melanoma.
Malignant cutaneous melanoma is a type of tumor that arises from the uncontrolled proliferation of melanocytes, due to inherited and / or acquired genetic mutations. The main risk factor for this tumor is the exposure to ultraviolet (UV) radiation. Despite representing only 1% of all skin cancer cases, it is the most aggressive and deadly. The presence of metastases generally suggests a very poor prognosis and constitutes a therapeutic challenge. The MAPK pathway is implied in the regulation of gene expression and cell proliferation and survival. The vast majority of melanoma patients, particularly those with distant metastases, have mutations in different protein kinases belonging to this pathway. The BRAF proto-oncogene is the most frequently mutated in melanoma, which leads to hyperactivation of the pathway and, as a consequence, uncontrolled proliferation of cells. These discoveries allowed the development of drugs aimed at these mutations. In 2011, BRAF inhibitors began to appear, with the promise of revolutionizing the treatment of patients with metastatic melanoma. However, these drugs induce resistance after a few months of treatment and, as an alternative, combined therapies between BRAF inhibitors and MEK inhibitors, began to appear. MEK is a protein kinase of the same pathway, which, when blocked, would prevent and delay possible mechanisms of resistance. Over the years, several drugs have been approved for metastatic melanoma, without, however, reaping major long-term benefits. After several combinations developed in 2018, the FDA approved the combination between the drugs Encorafenib and Binimetinib, after promising results in clinical trials. The present work intends to expose, in general, the differentiating characteristics and pharmacological properties of these new molecules, data on efficacy and clinical activity, as well as the safety profile, that led to their approval for metastatic melanoma.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Melanoma BRAF MEK Encorafenib Binimetinib Mestrado integrado - 2020