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Pharmacotherapeutic added benefit on the use of combinations of targeted therapies in oncology
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Resumo(s)
Avanços recentes na compreensão dos mecanismos subjacentes da sinalização molecular da susceptibilidade e progressão do cancro, conduziram a um aumento no uso de terapias direcionadas para o tratamento do cancro. Apesar das melhorias na sobrevivência com as novas opções de tratamento em oncologia, a resistência à terapia é um dos principais obstáculos à eficácia a longo prazo no tratamento do cancro com metástases, culminando na insensibilidade ao tratamento e no crescimento do tumor.
A resistência adaptativa pode desempenhar um papel importante na resistência primária e inicial à terapia, bem como na resistência secundária ou adquirida. Ao longo do trabalho, será discutido como as combinações terapêuticas com base em drivers específicos de biologia tumoral podem ser usadas para superar a resistência e como a monitorização da dinâmica do tumor ao longo do tempo pode permitir a adaptação precoce do tratamento. Estrategias de combinação para superar a resistência adaptativa incluem combinações de inibidores de RTK, inibidores de SHP2 e inibidores de MAPK a jusante, cujos mecanismos serão explicados posteriormente.
Exemplos de combinações terapêuticas para aumentar a eficácia das terapêuticas direcionadas no melanoma BRAFV600, cancro colorretal e cancro do pulmão de células não pequenas (NSCLC) serão abordadas em pormenor ao logo desta revisão.
Irá ser também abordado de que forma a imunoterapia se revelou uma mais valia no tratamento oncológico pois a maioria das células cancerígenas fornecem antígenos associados a tumores que o sistema imunológico do hospedeiro pode reconhecer. Deste modo existem recetores importantes nas vias imunológicas como o CTLA4 e o PD-1 que serão a chave para evitar o bloqueio das respostas imunes por parte das celulas tumorais e para o desenvolvimento de combinações terapêuticas.
A combinação de imunoterapia com agentes citotóxicos no cancro do pulmão de células não pequenas (NSCLC) e no melanoma irá ser explorada e avaliada ao longo da monografia.
Recent advances in the understanding of underlying molecular signaling mechanisms of cancer susceptibility and progression have led to an increase in the use of targeted therapies for cancer treatment. Despite improvements in survival with new treatment options in oncology, resistance to therapy is a major obstacle to the long-term effectiveness of targeted agents in metastatic cancer treatment, culminating in insensitivity to treatment and tumor outgrowth. Adaptive resistance can play an important role in primary and upfront resistance to therapy as well as in secondary or acquired resistance. Throughout the review, it will be discussed how therapeutic combinations based on specific drivers of tumor biology can be used to overcome resistance and how monitoring tumor dynamics over time may allow early adaptation of treatment. Combination strategies to overcome adaptative resistance include combinations of RTK inhibitors, SHP2 inhibitors and downstream MAPK inhibitors whose mechanisms will be explained later. Examples of therapies to increase the effectiveness of targeted therapies in BRAFV600 melanoma, colorectal cancer, and non-small cell lung cancer (NSCLC) will be discussed in detail throughout this review. It will also be affirmed how immunotherapy has proved to be an added value in cancer treatment because most cancer cells provide tumour-associated antigens the host’s immune system can recognize. This way there are important receptors in the immunological pathways such as CTLA4 and PD-1 which will be the key to preventing the blocking of immune responses by the tumor cells and for the development of therapeutic combinations. The combination of immunotherapy with cytotoxic agents in non-small cell lung cancer (NSCLC) and melanoma will be explored and evaluated in this review.
Recent advances in the understanding of underlying molecular signaling mechanisms of cancer susceptibility and progression have led to an increase in the use of targeted therapies for cancer treatment. Despite improvements in survival with new treatment options in oncology, resistance to therapy is a major obstacle to the long-term effectiveness of targeted agents in metastatic cancer treatment, culminating in insensitivity to treatment and tumor outgrowth. Adaptive resistance can play an important role in primary and upfront resistance to therapy as well as in secondary or acquired resistance. Throughout the review, it will be discussed how therapeutic combinations based on specific drivers of tumor biology can be used to overcome resistance and how monitoring tumor dynamics over time may allow early adaptation of treatment. Combination strategies to overcome adaptative resistance include combinations of RTK inhibitors, SHP2 inhibitors and downstream MAPK inhibitors whose mechanisms will be explained later. Examples of therapies to increase the effectiveness of targeted therapies in BRAFV600 melanoma, colorectal cancer, and non-small cell lung cancer (NSCLC) will be discussed in detail throughout this review. It will also be affirmed how immunotherapy has proved to be an added value in cancer treatment because most cancer cells provide tumour-associated antigens the host’s immune system can recognize. This way there are important receptors in the immunological pathways such as CTLA4 and PD-1 which will be the key to preventing the blocking of immune responses by the tumor cells and for the development of therapeutic combinations. The combination of immunotherapy with cytotoxic agents in non-small cell lung cancer (NSCLC) and melanoma will be explored and evaluated in this review.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Targeted therapies Oncology Resistance Therapeutic combinations Drivers Immunotherapy Mestrado integrado -2021