Andes 1537 como alternativa terapéutica para el tratamiento de tumores primarios y metástasis de pacientes con cáncer renal avanzado
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Archivos
Fecha
2021
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Profesor/a Guía
Facultad/escuela
Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
El carcinoma renal (RCC) es un tipo de cáncer localizado en el parénquima renal. Es el
sexto cáncer más común en hombres y el décimo en mujeres, con la segunda mayor
mortalidad de los cánceres urogenitales. El 30% de los pacientes debutan con metástasis
cuando son diagnosticados, y su supervivencia a 5 años es de 9% sin tratamiento. El
Carcinoma Renal de Células Claras (ccRCC), corresponde al 75% de los carcinomas renales y
es el subtipo más relevante. Uno de los principales problemas del RCC en etapa avanzada es
su resistencia a quimio y radioterapia. El desarrollo de terapias dirigidas, inmunoterapias y
terapias combinadas ha mejorado la sobrevida de estos pacientes en los últimos años, sin
embargo, solo un pequeño subgrupo es capaz de responder y los resultados siguen siendo
deficientes, lo que hace imperativo el desarrollo de nuevas alternativas terapéuticas.
En nuestro laboratorio se han descrito dos familias de RNAs no codificantes de origen
mitocondrial (ncmtRNAs), comprendidos por un transcrito sentido (SncmtRNA) y dos
transcritos antisentido (ASncmtRNA-1 y AsncmtRNA-2). La interferencia de los ASncmtRNAs
mediante el uso de un oligonucleótido antisentido (ASO) denominado "Andes 1537" dirigido
contra este transcrito, provoca la inducción de muerte celular masiva y apoptosis en líneas
celulares humanas. Demostramos la muerte celular masiva por apoptosis en 6 cultivos
primarios de pacientes con ccRCC metastásico post tratamiento con Andes 1537 in vitro, y
detectamos una disminución de proteínas del ciclo celular, tales como Ciclina B1 y D1, el
procesamiento de PARP-1, la activación de caspasa-3, la exposición de fosfatidilserina, la
disminución de Survivina y la fragmentación del DNA nuclear, e incluso hubo disminución de
N-cadherina post tratamiento con Andes 1537, una proteína involucrada en invasión y
metástasis. In vitro, terapias dirigidas como Sunitinib, tienen un efecto citotóxico moderado
en cultivos primarios de estos pacientes, mientras que Pazopanib, no tiene efecto citotóxico.
Andes 1537 contra los transcritos ASncmtRNAs, indujo un retardo del crecimiento
tumoral en 2 modelos ortotópicos de xenoinjerto in vivo (usando cultivos primarios PDX21 y
PDX46), con una media de peso tumoral 2 a 3 veces menor respecto del grupo control. Los
resultados de sobrevida obtenidos mediante un modelo subcutáneo de cáncer renal con
células PDX21, en comparación con Sunitinib y una terapia combinada, mostraron que la
terapia con Andes 1537 provocó no solo un retardo en el crecimiento tumoral, sino que
aumentó la sobrevida de los ratones en comparación al grupo control. El resultado más
interesante fue que, no existe diferencia significativa entre la sobrevida del grupo de ratones
tratados con Andes 1537 y los ratones tratados con la terapia Sunitinib. Estos resultados
obtenidos con cultivos primarios humanos sugieren fuertemente que la interferencia del
ASncmtRNA es una nueva alternativa selectiva y eficaz contra el ccRCC humano avanzado.
Renal carcinoma (RCC) is a type of cancer located in the renal parenchyma. It is the sixth most common cancer in men and tenth in women, with the second highest mortality of urogenital cancers. 30% of patients have a metastatic disease at the time of diagnosis, and their 5-year survival rate is 9% without treatment. Clear Cell Renal Carcinoma (ccRCC) corresponds to 75% of renal carcinomas and is the most relevant subtype. One of the main problems of RCC in advanced stages is its resistance to cherna and radiotherapy. In recent years, the development of targeted therapies, immunotherapies and combined therapies has improved the survival rate of these patients, however, only a small subgroup is capable of responding and the results remain poor, so the development of new therapeutic alternatives is urgent. In our laboratory, two families of non-coding mitochondrial RNAs (ncmtRNAs) have been described, comprised of a sense transcript (SncmtRNA) and two antisense transcripts (ASncmtRNA-1 and AsncmtRNA-2). The interference of ASncmtRNAs through the use of an antisense oligonucleotide (ASO) called "Andes 1537" directed against this transcript, causes the induction of massive cell death and apoptosis in human cell lines. We demonstrated massive cell death by apoptosis in 6 primary cultures from patients with metastatic ccRCC post treatment with Andes 1537 in vitro, and we detected a decrease in cell cycle proteins, such as Cyclin B1 and D1, the processing of PARP-1, the activation of caspase-3, the exposure of phosphatidylserine, the decrease in Survivin and the fragmentation of nuclear DNA, and there was even a decrease in N-cadherin after treatment with Andes 1537, a protein involved in invasion and metastasis. In vitro, targeted therapies such as Sunitinib have a moderate cytotoxic effect on primary cultures from these patients, while Pazopanib has no cytotoxic effect. Andes 1537 against ASncmtRNA, induced a delay of tumor growth in 2 orthotopic xenograft models in vivo (using PDX21 and PDX46 primary cultures), with a mean tumor weight 2 to 3 times lower compared to the control group. Survival results obtained using a subcutaneous model of kidney cancer with PDX21 cells, compared to Sunitinib and a combination therapy, showed that therapy with Andes 1537 caused not only a delay in tumor growth, but also increased the survival rate compared to the control group. The most interesting result was that, there is no significant difference between the survival of the group of mice treated with Andes 1537 and the mice treated with Sunitinib therapy. These results obtained with human primary cultures strongly suggest that ASncmtRNA interference is a new selective and effective alternative against advanced human ccRCC.
Renal carcinoma (RCC) is a type of cancer located in the renal parenchyma. It is the sixth most common cancer in men and tenth in women, with the second highest mortality of urogenital cancers. 30% of patients have a metastatic disease at the time of diagnosis, and their 5-year survival rate is 9% without treatment. Clear Cell Renal Carcinoma (ccRCC) corresponds to 75% of renal carcinomas and is the most relevant subtype. One of the main problems of RCC in advanced stages is its resistance to cherna and radiotherapy. In recent years, the development of targeted therapies, immunotherapies and combined therapies has improved the survival rate of these patients, however, only a small subgroup is capable of responding and the results remain poor, so the development of new therapeutic alternatives is urgent. In our laboratory, two families of non-coding mitochondrial RNAs (ncmtRNAs) have been described, comprised of a sense transcript (SncmtRNA) and two antisense transcripts (ASncmtRNA-1 and AsncmtRNA-2). The interference of ASncmtRNAs through the use of an antisense oligonucleotide (ASO) called "Andes 1537" directed against this transcript, causes the induction of massive cell death and apoptosis in human cell lines. We demonstrated massive cell death by apoptosis in 6 primary cultures from patients with metastatic ccRCC post treatment with Andes 1537 in vitro, and we detected a decrease in cell cycle proteins, such as Cyclin B1 and D1, the processing of PARP-1, the activation of caspase-3, the exposure of phosphatidylserine, the decrease in Survivin and the fragmentation of nuclear DNA, and there was even a decrease in N-cadherin after treatment with Andes 1537, a protein involved in invasion and metastasis. In vitro, targeted therapies such as Sunitinib have a moderate cytotoxic effect on primary cultures from these patients, while Pazopanib has no cytotoxic effect. Andes 1537 against ASncmtRNA, induced a delay of tumor growth in 2 orthotopic xenograft models in vivo (using PDX21 and PDX46 primary cultures), with a mean tumor weight 2 to 3 times lower compared to the control group. Survival results obtained using a subcutaneous model of kidney cancer with PDX21 cells, compared to Sunitinib and a combination therapy, showed that therapy with Andes 1537 caused not only a delay in tumor growth, but also increased the survival rate compared to the control group. The most interesting result was that, there is no significant difference between the survival of the group of mice treated with Andes 1537 and the mice treated with Sunitinib therapy. These results obtained with human primary cultures strongly suggest that ASncmtRNA interference is a new selective and effective alternative against advanced human ccRCC.
Notas
Tesis (Doctor en Biotecnología)
Palabras clave
Cáncer del Riñón, Tratamiento, Andes 1537