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Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma

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Universitat de Barcelona. Facultat de Medicina

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[eng]  Constitutive activation of the chemokine receptor CXCR4 is associated with tumor progression, invasion and resistance to treatment. Overexpression of CXCR4 in diffuse large B-cell lymphoma (DLBCL) confers a reduced prognosis. However, the biological relevance of this receptor in DLBCL progression remains underexplored. In this thesis, the new CXCR4 inhibitor IQS-01.01 has been preclinicaly evaluated in in vitro and in vivo models of DLBCL. It has been concluded that 1) inhibition of CXCR4 presents antitumor properties in DLBCL, 2) that IQS-01.01RS holds better pharmacological properties than the reference CXCR4 inhibitor, AMD3100 3) that treatment with IQS- 01.01RS reduces the levels of the oncogene MYC and 4) that the combinantion of IQS- 01.01RS with the BET-bromodomain inhibitor, CPI203, is synergistic in DLBCL. The results of this doctoral thesis unravel a cooperation between CXCR4 and MYC in DLBCL, and indicate that CXCR4 inhibition in combination with inhibition of MYC is a promising novel therapeutic approach in DLBCL.

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[spa]  La activación constitutiva del receptor de quemocinas CXCR4 está asociada a la progresión tumoral, invasión y resistencia al tratamiento. En el linfoma difuso de células grandes (LDCG) la sobreexpresión de CXCR4 concede un peor pronóstico, pero la relevancia biológica de este receptor no se ha estudiado en profundidad. En esta tesis se ha evaluado un nuevo inhibidor de CXCR4 (IQS-01.01) en modelos preclínicos de LDCG. Usando tanto modelos in vitro como in vivo de LDCG se ha concluido 1) que la inhibición de CXCR4 en LDCG tiene un efecto antitumoral, 2) que IQS-01.01RS tiene mayores propiedades farmacológicas que el inhibidor de referencia, AMD3100 3) que el tratamiento con IQS-01.01RS reduce los niveles del oncogén MYC y 4) que la combinación de IQS-01.01 RS con el inhibido de BET, CPI203, confiere un efecto antitumoral sinérgico. Los resultados de esta tesis doctoral ponen en evidencia una cooperación entre MYC y CXCR4 en LDCG e indican que la inhibición de CXCR4 en combinación con un inhibidor de MYC es una terapia prometedora contra el LDCG.

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Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma