RESUMO
The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/etiologia , Receptores Androgênicos/genética , Receptores Androgênicos/fisiologiaRESUMO
El eje de señalización de andrógenos desempeña un papel fundamental en la patogénesis del cáncer de próstata. Desde el descubrimiento histórico de Huggins y Hodges, la depleción androgénica permanece como la piedra angular en el tratamiento de la enfermedad avanzada. Sin embargo, de forma invariable, la progresión a cáncer de próstata resistente a la castración se produce dentro de los 2-3 años posteriores al inicio de la terapia de deprivación androgénica (TDA). Múltiples mecanismos de resistencia ayudan a la progresión a la enfermedad resistente a la castración, y el receptor de andrógenos (RA) sigue siendo un impulsor importante en esta progresión. Los mecanismos moleculares que subyacen a la reactivación del RA en el cáncer de próstata resistente a la castración (CPRC) incluyen la amplificación y sobreexpresión del RA, mutaciones del RA, expresión de variantes constitutivamente activas del RA, síntesis de andrógenos intratumorales y suprarrenales y activación promiscua del RA por otros factores. También se discuten otros mecanismos de resistencia independientes del RA, que incluyen la activación del receptor de glucocorticoides, la alteración de las vías de reparación del ADN, la resistencia mediada por mecanismos inmunes, la diferenciación neuroendocrina y la expresión de microARN. El cáncer de próstata resistente a la castración es una enfermedad compleja, se caracteriza por múltiples mecanismos de resistencia al tratamiento de deprivación de andrógenos, y sigue siendo una enfermedad incurable. La comprensión de los mecanismos que subyacen a esta resistencia es necesaria para identificar objetivos terapéuticos futuros, así como la identificación y validación de nuevos biomarcadores predictivos de resistencia, lo que puede conducir a una mejora terapéutica para pacientes con CPRC
The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients
Assuntos
Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/etiologia , Receptores Androgênicos/genética , Receptores Androgênicos/fisiologiaRESUMO
Bacilus Calmette-Guerin (BCG) administered intravesical is an effective therapy in non muscle invasive bladder cancer (NMIBC), but it presents limitations regarding recurrence and toxicity. For years, many case series have been published where sequential therapy with BCG and Mitomycin C (MMC) was tried. In this article, we perform a review of the data supplied by these articles with the aim to determine the safety and efficacy of combination, and what is the group of patients it should be indicated. Many studies show that combination therapy did not cause more toxicity and improved the interval free of disease with decrease of tumor progression compared to BCG or MMC monotherapy. Therefore, a combination of MMC and BCG therapy seems safe, but more clinical studies are required for a future evaluation.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Vacina BCG/administração & dosagem , Mitomicina/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Quimioterapia Combinada , Humanos , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/patologiaRESUMO
El Bacilo de Calmette-Guerin (BCG) administrado por vía intravesical es una terapia eficaz en el Cáncer Vesical no Músculo Invasivo (CVNMI), pero presenta limitaciones en términos de recurrencia y toxicidad. Desde hace años se han publicado muchos artículos de series de pacientes donde se ha probado la terapia secuencial entre BCG y Mitomicina C (MMC). En este trabajo se realiza una revisión de los datos aportados por esos artículos con la finalidad de determinar la seguridad y eficacia de la combinación, y en qué grupo de pacientes estaría indicada. Muchos estudios indican que la terapia de combinación frente a la monoterapia con BCG o MMC no causó más toxicidades y mejoró el intervalo libre de enfermedad con disminución de la progresión tumoral. Por lo tanto, la combinación de tratamiento con MMC y BCG parece ser segura, mientras que aún se necesitan más estudios clínicos para una evaluación posterior
Bacilus Calmette-Guerin (BCG) administered intravesical is an effective therapy in non muscle invasive bladder cancer (NMIBC), but it presents limitations regarding recurrence and toxicity. For years, many case series have been published where sequential therapy with BCG and Mitomycin C (MMC) was tried. In this article, we perform a review of the data supplied by these articles with the aim to determine the safety and efficacy of combination, and what is the group of patients it should be indicated. Many studies show that combination therapy did not cause more toxicity and improved the interval free of disease with decrease of tumor progression compared to BCG or MMC monotherapy. Therefore, a combination of MMC and BCG therapy seems safe, but more clinical studies are required for a future evaluation
