학술논문
Targeting mitosis in hormone-refractory prostate cancer
Document Type
Dissertation/Thesis
Author
Source
TDX (Tesis Doctorals en Xarxa)
Subject
Language
English
Abstract
El CaP es la segunda neoplasia maligna invasiva diagnosticada con mayor frecuencia y la tasa de supervivencia a 5 años de los hombres con enfermedad metastásica cae por debajo del 30%. Los andrógenos, a través del receptor de andrógenos, son cruciales para el inicio y la progresión del CaP y, por tanto, la ADT ha sido el principal tratamiento del CaP localmente avanzado, metastásico y recurrente. Las terapias de deprivación androgénica son capaces de conseguir inicialmente una respuesta bioquímica en la mayoría de los pacientes; sin embargo, las remisiones son temporales y la enfermedad acaba progresando a un estado independiente de andrógenos, también denominado CRPC. Tras la progresión a CRPC, la supervivencia media de estos pacientes es de menos de 2 años y la enfermedad acaba siendo prácticamente intratable. Los mecanismos moleculares que causan esta transición siguen siendo en gran parte desconocidos. La creciente evidencia en los últimos años sugiere que las células de CaP insensibles a andrógenos han sido reprogramadas genéticamente para regular de forma selectiva la expresión de genes de la fase M del ciclo celular. Los taxanos, dirigidos a los microtúbulos, ya se están utilizando en la práctica clínica para pacientes con CaP avanzado, pero la supervivencia sigue siendo modesta y los pacientes acaban desarrollando resistencia a la terapia. Debido a que la progresión mitótica es un proceso altamente regulado, nuestra hipótesis es que las proteínas de fase M expresadas de manera aberrante pueden conferir a las células CaP una ventaja para el crecimiento en condiciones de depleción de andrógenos y, en consecuencia, representan posibles dianas terapéuticas para la intervención molecular de pacientes con CRPC. Aunque varios inhibidores del ciclo celular no han logrado demostrar beneficio en el entorno clínico del CRPC, sigue habiendo un gran interés en este enfoque y todavía hay desafíos importantes para intentar tratar a estos pacientes con terapias dirigidas que sean eficaces. En este contexto, el objetivo principal de esta tesis es obtener nuevos conocimientos moleculares sobre la progresión del CaP, con especial énfasis en la participación de los reguladores mitóticos en la adquisición de la independencia a andrógenos de los tumores de próstata.
PCa is the second most frequently diagnosed invasive malignancy and the 5-year survival rate of men with metastatic disease drops below 30%. Androgens, through the AR, are crucial for the initiation and progression of PCa and thus, ADT has been the mainstay of treatment for locally advanced, metastatic and recurring PCa. Androgen-ablation therapies can initially achieve a biochemical response in the majority of patients; however, remissions are temporary and the disease invariably progresses to an androgen-independent state, also termed CRPC. Upon progression to CRPC, the median survival for those patients is less than 2 years, and the disease is essentially untreatable. The molecular mechanisms that cause this transition remain largely unknown. Increasing evidence in recent years suggest that androgen insensitive PCa cells have undergone a genetic reprogramming to selectively upregulate the expression of M-phase cell cycle genes. Microtubule-targeting taxanes are already being used in the clinical practice for patients with advanced PCa, but survival remains modest and resistance inevitably develops. Because mitotic progression is a highly regulated process, we hypothesized that aberrantly expressed M-phase proteins may confer PCa cells an advantage to growth in androgen-depleted conditions and consequently represent potential therapeutic targets for the molecular intervention of CRPC patients. Although several small molecule inhibitors of the cell cycle have failed to demonstrate benefit in the clinical setting of CRPC, there remains a keen interest in this approach and significant challenges persist to match patients with effective targeted therapies. In this context, the main goal of this thesis is to gain novel molecular insights into the progression of PCa, with special emphasis on the involvement of mitotic regulators in the acquisition of prostate tumors androgen independence.
Universitat Autònoma de Barcelona. Programa de Doctorat en Bioquímica, Biologia Molecular i Biomedicina
PCa is the second most frequently diagnosed invasive malignancy and the 5-year survival rate of men with metastatic disease drops below 30%. Androgens, through the AR, are crucial for the initiation and progression of PCa and thus, ADT has been the mainstay of treatment for locally advanced, metastatic and recurring PCa. Androgen-ablation therapies can initially achieve a biochemical response in the majority of patients; however, remissions are temporary and the disease invariably progresses to an androgen-independent state, also termed CRPC. Upon progression to CRPC, the median survival for those patients is less than 2 years, and the disease is essentially untreatable. The molecular mechanisms that cause this transition remain largely unknown. Increasing evidence in recent years suggest that androgen insensitive PCa cells have undergone a genetic reprogramming to selectively upregulate the expression of M-phase cell cycle genes. Microtubule-targeting taxanes are already being used in the clinical practice for patients with advanced PCa, but survival remains modest and resistance inevitably develops. Because mitotic progression is a highly regulated process, we hypothesized that aberrantly expressed M-phase proteins may confer PCa cells an advantage to growth in androgen-depleted conditions and consequently represent potential therapeutic targets for the molecular intervention of CRPC patients. Although several small molecule inhibitors of the cell cycle have failed to demonstrate benefit in the clinical setting of CRPC, there remains a keen interest in this approach and significant challenges persist to match patients with effective targeted therapies. In this context, the main goal of this thesis is to gain novel molecular insights into the progression of PCa, with special emphasis on the involvement of mitotic regulators in the acquisition of prostate tumors androgen independence.
Universitat Autònoma de Barcelona. Programa de Doctorat en Bioquímica, Biologia Molecular i Biomedicina