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Targeting therapeutic resistance in glioblastoma
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Contexto O glioblastoma (GB) é o tumor cerebral maligno primário mais comum em adultos. Apesar de avanços significativos na compreensão da biologia do GB, o atual tratamento recomendado permite uma sobrevida média dos pacientes de 15-18 meses e uma sobrevivência a 5 anos de 5%. A maioria dos GBs recorrem após terapêutica e são frequentemente inoperáveis devido à invasão de estruturas eloquentes do cérebro. Não existe também um tratamento alternativo eficaz para o GB recurrente por resistência adquirida à terapêutica. Existe, portanto, uma necessidade urgente para o desenvolvimento de novas e mais eficazes terapias-alvo para o tratamento de pacientes com GB. A importância das metaloproteinase da matriz 19 (MMP19) e da Anexina 4 (ANXA4) no cancro sobressão objecto de investigação ativa. Embora se tenham encontrado elevados níveis de expressão do MMP19 e da ANXA4 em GBs, o seu papel na progressão da doença ainda se encontra por determinar. Objetivos O principal objetivo deste trabalho foi analisar os níveis de expressão de MMP19 e ANXA4 em amostras de GB primário e recorrente utilizando imunohistoquimica, e correlacionar os níveis de expressão das proteínas com os dados clínicos dos pacientes. Métodos Os níveis do MMP19, ANXA4, Ki67 (marcador de proliferação) e CD133 (marcador de células-estaminais) em 19 amostras de tecido tumoral primário e recorrente de amostras emparelhadas de GB foram avaliados por imunohistoquímica (IHC). Aplicando um score semiquantitativo para a percentagem de células marcadas (fIHC) e para a intensidade de coloração (iIHC), as amostras emparelhadas de GB primário e recorrente foram comparadas quanto aos seus níveis de expressão de Ki67, CD133, MMP19 e ANXA4. Com o produto de iHC e fIHC, foram derivados scores de imunohistoquímica combinada (cIHC), com limiares usados para categorizar as amostras em cIHC baixo e alto para ANXA4 e MMP19. Comparámos nestes grupos o IHC score para Ki67 e CD133, assim como a sobrevida livre de progressão (SLP) e a sobrevida global (SG) dos pacientes. Resultados Os níveis de MMP19 e ANXA4 não apresentaram diferenças entre GB primários e recorrentes e não apresentaram relação com a proliferação tumoral ou características de células estaminais do tumor. Também não se verificou uma relação com os tempos de SG ou SLD dos pacientes. Não se verificou igualmente uma diferença entre os níveis de proliferação e características de células estaminais entre GB primários e recorrentes. Conclusão Com base nos resultados, não foi possível validar o MMP19 e a ANXA4 como biomarcadores de progressão no GB. Estudos posteriores serão realizados com uma coorte maior de amostras emparelhadas de GB primários e recorrentes.
Background Glioblastoma (GB) is the most common primary malignant brain tumor in adults. Despite substantial advances in understanding disease biology, the current standard-of-care treatment usually leads to a patient median overall survival (OS) of 15-18 months and a 5-year OS of 5%. Most GBs recur after treatment and are usually inoperable due to tumor invasion of nearby brain structures. There are also no effective alternative treatments to recurrent GB due to acquired resistance to therapy. Therefore, there is an unmet medical need to develop new and more effective targeted therapies to treat GB patients. The roles of proteins from the matrix metalloproteinases (MMP) and the annexins (ANXA) family in cancer are subjects of active research. Although high expression levels of MMP19 and ANXA4 have been found in GBs, their role in disease progression has not been determined. Objectives The main goal of this work was to analyze the expression levels of MMP19 and ANXA4 in paired primary and recurrent GB samples using immunohistochemistry (IHC) and to correlate the protein expression levels with patients’ clinical data and outcome. Methods The protein levels of MMP19, ANXA4, Ki67 (proliferation marker) and CD133 (stem cell marker) were evaluated in 19 paired primary and recurrent GB tumor tissue samples by immunohistochemistry (IHC). By applying a semi-quantitative score for the percentage of stained cells (fIHC) and staining intensity (iIHC), paired primary and recurrent GB samples were compared in their Ki67, CD133, MMP19 and ANXA4 levels of expression. With the product of iIHC and fIHC, combined immunohistochemistry (cIHC) scores were derived, with thresholds used to categorize samples into low and high cIHC for ANXA4 and MMP19. We compared these groups with Ki67 and CD133 immunohistochemistry scores, as well as patients' progression-free survival (PFS) and overall survival (OS). Results The levels of MMP19 and ANXA4 showed no differences between primary and recurrent GBs and did not correlate with tumor proliferation or tumor stem cell characteristics. There was also no association with patient survival times or PFS. Similarly, no difference was found between proliferation levels and stem cell characteristics between primary and recurrent GBs. Conclusion Based on the observations, MMP19 and ANXA4 could not be validated as biomarkers of GB progression. Further studies will be conducted with a larger cohort of paired primary and recurrent GB samples.
Background Glioblastoma (GB) is the most common primary malignant brain tumor in adults. Despite substantial advances in understanding disease biology, the current standard-of-care treatment usually leads to a patient median overall survival (OS) of 15-18 months and a 5-year OS of 5%. Most GBs recur after treatment and are usually inoperable due to tumor invasion of nearby brain structures. There are also no effective alternative treatments to recurrent GB due to acquired resistance to therapy. Therefore, there is an unmet medical need to develop new and more effective targeted therapies to treat GB patients. The roles of proteins from the matrix metalloproteinases (MMP) and the annexins (ANXA) family in cancer are subjects of active research. Although high expression levels of MMP19 and ANXA4 have been found in GBs, their role in disease progression has not been determined. Objectives The main goal of this work was to analyze the expression levels of MMP19 and ANXA4 in paired primary and recurrent GB samples using immunohistochemistry (IHC) and to correlate the protein expression levels with patients’ clinical data and outcome. Methods The protein levels of MMP19, ANXA4, Ki67 (proliferation marker) and CD133 (stem cell marker) were evaluated in 19 paired primary and recurrent GB tumor tissue samples by immunohistochemistry (IHC). By applying a semi-quantitative score for the percentage of stained cells (fIHC) and staining intensity (iIHC), paired primary and recurrent GB samples were compared in their Ki67, CD133, MMP19 and ANXA4 levels of expression. With the product of iIHC and fIHC, combined immunohistochemistry (cIHC) scores were derived, with thresholds used to categorize samples into low and high cIHC for ANXA4 and MMP19. We compared these groups with Ki67 and CD133 immunohistochemistry scores, as well as patients' progression-free survival (PFS) and overall survival (OS). Results The levels of MMP19 and ANXA4 showed no differences between primary and recurrent GBs and did not correlate with tumor proliferation or tumor stem cell characteristics. There was also no association with patient survival times or PFS. Similarly, no difference was found between proliferation levels and stem cell characteristics between primary and recurrent GBs. Conclusion Based on the observations, MMP19 and ANXA4 could not be validated as biomarkers of GB progression. Further studies will be conducted with a larger cohort of paired primary and recurrent GB samples.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2024
Palavras-chave
Glioblastoma Metaloproteinase da matriz 19 (MMP19) Anexina 4 (ANXA4) Biomarcadores de progressão de doença Neurocirurgia