1 Simposio Nacional SEOM Simposio Educacional de Temas de Actualidad “Combinaciones de Terapias Antidiana: Desarrollo Futuro” Félix Bonilla Hospital U Puerta de Hierro Majadahonda

Señales mitogénicas 3

Alteraciones del ciclo celular en cánceres humanos Malumbres & Barbacid, 2001 4

Ciclo Celular y dianas modificables 1. Factores que estimulan la entrada en ciclo 2. Bloqueo de los puntos de restriccción 3. Inhibición de la formación de microtúbulos 4. Inhibición de los reguladores de la mitosis 5

Malumbres & Barbacid (2009) Nat. Rev. Cancer 9, 153-166

Pérez de Castro et al. (2008) Curr. Opin. Pharmacol. 8, 375-383

RNAi RNA de interferencia MicroRNAs (miRNAs) are small, RNA molecules encoded in the genomes of plants and animals (Figure 1). These highly conserved, ~21-mer RNAs regulate the expression of genes by binding to the 3'-untranslated regions (3'-UTR) of specific mRNAs. Although the first published description of an miRNA appeared ten years ago (Lee 1993), only in the last two to three years has the breadth and diversity of this class of small, regulatory RNAs been appreciated. A great deal of effort has gone into understanding how, when, and where miRNAs are produced and function in cells, tissues, and organisms. Each miRNA is thought to regulate multiple genes, and since hundreds of miRNA genes are predicted to be present in higher eukaryotes (Lim 2003b) the potential regulatory circuitry afforded by miRNA is enormous. Several research groups have provided evidence that miRNAs may act as key regulators of processes as diverse as early development (Reinhart 2000), cell proliferation and cell death (Brennecke 2003), apoptosis and fat metabolism (Xu 2003), and cell differentiation (Dostie 2003, Chen 2003). Recent studies of miRNA expression implicate miRNAs in brain development (Krichevsky 2003), chronic lymphocytic leukemia (Calin 2002), colonic adenocarcinoma (Michael 2003), Burkitt’s Lymphoma (Metzler 2004), and viral infection (Pfeffer 2004) suggesting possible links between miRNAs and viral disease, neurodevelopment, and cancer. There is speculation that in higher eukaryotes, the role of miRNAs in regulating gene expression could be as important as that of transcription factors. Several hundred miRNAs have been cloned and sequenced from mouse, human, Drosophila, C. elegans, and Arabidopsis (see www.sanger.ac.uk). Estimates suggest that 200–300 unique miRNA genes are present in the genomes of humans and mice (Lim 2003 b). The sequences of many of the miRNAs are homologous among organisms, suggesting that miRNAs represent a relatively old and important regulatory pathway (Grosshans 2002). 8

DNA RNA proteina 9

DNA RNA proteina 10

Inmunidad tumoral

Células Dendríticas Antigenos Asociados a Tumores

Origen Las CD derivan de precursores celulares hematopoyéticos de médula ósea Inicialmente estos precursores se transforman en CD inmaduras Posteriormente se pueden promover a CD maduras como respuesta a estímulos varios

Origen y Transformación

Presentación Ag

Presentación Ag

Células Madre

Células madre y síntesis de anticuerpos time therapeutic protein viral transduction stem/progenitor cell isolation allogenic ex vivo manipulation cell expansion a therapeutic stem cell delivery vehicle (SCDV) b local c free SCDV administration systemic synthetic bioscaffolds bioactive factors matrix-embedded SCDV d semipermeable membrane nutrients oxygen antibodies and immune cells SCDV microencapsulation e Figure 1. Sanz et al. autologous Células madre y síntesis de anticuerpos Compte M. Stem Cells 2009

Células Madre Mesenquimales de Médula Ósea como Vehículos Celulares para Adenovirus Oncolíticos

Características - Selectiva antitumoral. - No tóxica para tejidos sanos. - Autopropagante. - Las cantidades se incrementan tras la inoculación. - Diseminación dentro de la masa tumoral. - Estimulan una respuesta inmune.

Experiencia con la secuenciación completa del genoma de algunos tumores humanos

Alteraciones en Glioblastomas TCGA, Nature 2008

Alteraciones en glioblastomas TCGA, Nature 2008

Alteraciones en adenocarcinoma de páncreas Jones et al., Science 2008

Rutas de señalización implicadas Jones et al., Science 2008

Pleasance et al.,Nature 2010 27

Pleasance et al, Nature 2010 28

Gracias fbonilla.hpth@salud.madrid.org