{"id":114305,"date":"2018-03-11T10:42:15","date_gmt":"2018-03-11T10:42:15","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/new-potential-therapeutic-targets-in-chemoresistant-lymphomas\/"},"modified":"2018-03-11T10:42:15","modified_gmt":"2018-03-11T10:42:15","slug":"new-potential-therapeutic-targets-in-chemoresistant-lymphomas","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/bioquimica-molecular\/new-potential-therapeutic-targets-in-chemoresistant-lymphomas\/","title":{"rendered":"New potential therapeutic targets in chemoresistant lymphomas"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Esperanza Martin Sanchez <\/strong><\/h2>\n<p>Summaryrecent advances in genetics and molecular biology have highly increased the knowledge in the biology of some cancer types, allowing for the improvement of the therapeutic possibilities and expectancies of these patients, such as imatinib in chronic myeloid leukemia. But still, some lymphoproliferative disorders have currently limited therapeutic options, mainly because of a lack of targeted therapies. In this regard, although classical hodgkin lymphoma (chl) has a 70 \u00c2\u00bf 80 % of response to the standard anthracycline-based therapeutics (abvd regimens), there is a group of patients who does not respond, and 30 % of patients finally die due to the disease. On the other hand, peripheral t-cell lymphomas (ptcl) constitute a heterogeneous group of very aggressive malignancies which currently lacks efficient therapies. These patients are treated with anthracycline-based therapies (chop regimens), but the response rate is very poor: the overall survival is dependent on the ptcl subtype, but as an average, around 70 % of patients succumb to the disease. Therefore, studies identifying new therapeutic targets in refractory chl and ptcl are necessary in order to improve the prognosis of these patients with chemoresistant lymphomas.Since the understanding of the molecular alterations in other tumor types has significantly improved their therapeutic options, we hypothesized that the detection of the molecular abnormalities in chemoresistant chl and ptcl could help us to identify potential therapeutic targets in these lymphomas with restricted therapeutic possibilities. Our main objective was to find therapeutic targets in chemoresistant chl and ptcl.Regarding chl the in silico comparison of gene expression profile in chl patients with differential response to standard therapy has allowed us to identify histone deacetylase inhibitors (hdaci) as agents that could reverse this chemoresistance molecular signature. The in vitro experiments demonstrated that hdaci induced different antiproliferative effects on chl cell lines, such as cell cycle arrest at g2\/m phase and\/or apoptosis, by altering the expression of key genes involved in cell cycle and apoptosis (especially the extrinsic pathway). Interestingly, hdaci also downregulated the expression of genes associated with chemoresistance in chl. Adversely, we observed a potential negative effect, since hdaci treatment upregulated pim2 expression. Consequently, a highly synergistic effect was found between the hdaci saha and a pan-pim inhibitor (pimi). Therefore, we can take into consideration that the combined treatment saha + pimi could be therapeutically explored in abvd-resistant chl patients.Concerning ptcl the in silico study of gene expression features in ptcl patients compared with reactive lymph nodes has allowed us to identify pi3k and pim inhibitors as potential therapeutic agents in ptcl.We found that pi3k inhibitors (pi3ki) could reverse the ptcl molecular signature. Although genomic studies indicated that pi3k\u00c2\u00bf was the most important pi3k isoform in ptcl, the genetic or pharmacological single pi3k isoform inhibition did not affect ptcl survival. Pharmacological inhibition of all pi3k isoforms had a mainly cytostatic effect, being gsk3\u00edY and p70s6k phosphorylation a biomarker for pi3ki response in ptcl. Importantly, the pan-pi3ki increased erk phosphorylation in pi3ki-sensitive cell lines, and we observed that the simultaneous blockade of both pi3k and mek was highly synergistic in vitro and ex vivo.In addition, pim kinases were found to be overexpressed in ptcl cases, cell lines and primary tumoral t cells. Individual pim genetic silencing did not affect ptcl survival, possibly due to a compensatory mechanism among the 3 pim genes. In contrast, a pharmacological pan-pimi had a potent cytotoxic effect on ptcl, at least in part due to downregulation of genes involved in the dna repair machinery and enhancing the dna damage. Importantly, this pan-pimi reduced cell viability in primary tumoral t cells ex vivo, without affecting normal t cells. Finally, we observed that pim2 protein expression was associated with a worse outcome in the ptcl subtype anaplastic large cell lymphoma (alcl), and the double inhibition of this pathway at two points (alk and pim) was highly synergistic only in alk+ alcl and not in other ptcl cell lines.Taken together, these findings indicate that gene expression profiling studies in chemoresistant lymphomas are able to identify potential therapeutic targets, and we can take into consideration that: 1) the combination hdaci + pimi could be efficient in abvd-resistant chl; 2) the simultaneous inhibition of pi3k and mek could improve the therapeutical benefit in pi3ki-sensitive ptcl; and 3) a pim inhibition based therapy could be of therapeutic value in ptcl, and especially combined with alk inhibitors in alk+ alcl.Resumenlos recientes avances en gen\u00e9tica y biolog\u00eda molecular han ampliado enormemente el conocimiento en la biolog\u00eda de algunos tipos de tumores, lo que ha permitido mejorar las posibilidades terap\u00e9uticas y expectativas de estos pacientes, como ha sido el caso de imatinib en leucemia mieloide cr\u00f3nica. Sin embargo, actualmente a\u00fan existen enfermedades linfoproliferativas con limitadas opciones terap\u00e9uticas, principalmente debido a la ausencia de terapias dirigidas. As\u00ed, aunque el linfoma de hodgkin cl\u00e1sico (lh) tiene un 70 \u00c2\u00bf 80 % de respuesta a la terapia convencional basada en antraciclinas (de tipo abvd), existe un grupo de pacientes que no responde y un 30 % fallece por esta enfermedad. Por otra parte, los linfomas perif\u00e9ricos de c\u00e9lulas t (lpct) constituyen un grupo heterog\u00e9neo y muy agresivo para el cual no existe actualmente ninguna terapia eficaz. Estos pacientes se tratan con terapias basadas en antraciclinas (de tipo chop), pero su respuesta es muy mala: la supervivencia global depende del subtipo de lpct, pero de media el 70 % de estos pacientes fallece. Por tanto, se necesitan estudios que identifiquen nuevas dianas terap\u00e9uticas en lh refractarios y lpct para mejorar el pron\u00f3stico de estos pacientes con linfomas quimiorresistentes.Dado que el conocimiento de las alteraciones moleculares en otros tipos tumorales ha mejorado significativamente sus opciones terap\u00e9uticas, nos planteamos la hip\u00f3tesis de que la detecci\u00f3n de las anomal\u00edas moleculares en lh quimiorresistentes y lpct podr\u00eda ayudarnos a identificar posibles dianas terap\u00e9uticas en estos linfomas con limitadas posibilidades terap\u00e9uticas. Nuestro objetivo principal fue encontrar dianas terap\u00e9uticas en estos lh quimiorresistentes y lpct.En cuanto a lh, la comparaci\u00f3n del perfil de expresi\u00f3n g\u00e9nica en pacientes de lh con distinta respuesta a la terapia habitual, nos ha permitido identificar a los inhibidores de deacetilasas de histonas (idach) como agentes que podr\u00edan revertir esta firma molecular de quimiorresistencia. Los experimentos in vitro demostraron que los idach provocaban distintos efectos antiproliferativos en l\u00edneas celulares de lh, como parada de ciclo celular en g2\/m y\/o apoptosis, alterando la expresi\u00f3n de genes clave en ciclo celular y apoptosis (especialmente v\u00eda extr\u00ednseca). De forma interesante, encontramos que los idach inhibieron la expresi\u00f3n de genes asociados con quimiorresistencia en lh. Sin embargo, nos encontramos con un posible efecto adverso, dado que el tratamiento con idach activaba la expresi\u00f3n de pim2. En consecuencia, observamos un efecto muy sin\u00e9rgico entre el idach saha y un inhibidor de pim (ipim). Por tanto, consideramos que la combinaci\u00f3n saha + ipim podr\u00eda ser explorada terap\u00e9uticamente en lh resistentes a abvd.Con respecto al lpct, el estudio in silico del perfil molecular de expresi\u00f3n g\u00e9nica de pacientes con lpct comparado con ganglios linf\u00e1ticos reactivos nos ha permitido identificar a los inhibidores de pi3k y pim como posibles agentes terap\u00e9uticos en lpct.Encontramos que los inhibidores de pi3k (ipi3k) pod\u00edan revertir la firma molecular del lpct. A pesar de que los estudios gen\u00f3micos indicaban que pi3k\u00c2\u00bf era la isoforma de pi3k m\u00e1s importante en lpct, la inhibici\u00f3n gen\u00e9tica o espec\u00edficamente farmacol\u00f3gica de una sola isoforma de pi3k no afect\u00f3 a la supervivencia del lpct. Sin embargo, un inhibidor farmacol\u00f3gico de todas las isoformas de pi3k produjo un efecto principalmente citost\u00e1tico, y encontramos que la fosforilaci\u00f3n de gsk3\u00edY y p70s6k podr\u00edan ser biomarcador de respuesta a ipi3k en lpct. Cabe mencionar que el ipi3k aument\u00f3 la fosforilaci\u00f3n de erk en las l\u00edneas sensibles a ipi3k, y observamos que la inhibici\u00f3n simult\u00e1nea de todas las isoformas de pi3k junto con mek era altamente sin\u00e9rgica in vitro y ex vivo.Adem\u00e1s, observamos que las quinasas de la familia pim se encontraron sobreexpresadas en casos, l\u00edneas celulares y c\u00e9lulas primarias t tumorales de lpct. El silenciamiento gen\u00e9tico individual de cada pim no tuvo efectos en la supervivencia del lpct, posiblemente debido a un mecanismo compensatorio entre los 3 genes por contra, la inhibici\u00f3n farmacol\u00f3gica de todas las quinasas pim tuvo un potente efecto citot\u00f3xico en lpct, al menos en parte debido a una inhibici\u00f3n de la expresi\u00f3n de genes implicados en la reparaci\u00f3n del adn, aumentando as\u00ed el da\u00f1o en el adn. Cabe destacar que el ipim redujo la viabilidad de c\u00e9lulas t primarias tumorales ex vivo, sin afectar a c\u00e9lulas t normales. Por \u00faltimo, encontramos que la expresi\u00f3n de la prote\u00edna pim2 estaba significativamente asociada con peor pron\u00f3stico en el subtipo linfoma anapl\u00e1sico de c\u00e9lulas grandes (lacg), y la doble inhibici\u00f3n de esta ruta en 2 puntos (alk y pim) era altamente sin\u00e9rgica s\u00f3lo en lacg alk+ y no en otras l\u00edneas de lpct.Como conclusi\u00f3n, estos resultados indican que el estudio de expresi\u00f3n g\u00e9nica en linfomas quimiorresistentes puede identificar posibles dianas terap\u00e9uticas, y podemos considerar que: 1) la combinaci\u00f3n idach + ipim podr\u00eda ser eficaz en los lh resistentes a abvd; 2) la inhibici\u00f3n simult\u00e1nea de pi3k y mek podr\u00eda tener mayor efecto terap\u00e9utico en los lpct sensibles a ipi3k; y 3) la terapia basada en inhibici\u00f3n de pim podr\u00eda ser de utilidad en lpct, y especialmente combinada con inhibidores de alk en lacg alk+.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>New potential therapeutic targets in chemoresistant lymphomas<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 New potential therapeutic targets in chemoresistant lymphomas <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Esperanza Martin Sanchez <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Pa\u00eds vasco\/euskal herriko unibertsitatea<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 18\/06\/2013<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Juan  Fernando Garcia Garcia<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: jeronimo Forteza vila <\/li>\n<li>Javier Le\u00f3n serrano (vocal)<\/li>\n<li>Jos\u00e9 \u00e1ngel Mart\u00ednez climent (vocal)<\/li>\n<li>Mar\u00eda no Provencio pulla (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Esperanza Martin Sanchez Summaryrecent advances in genetics and molecular biology have highly increased the knowledge in the 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