| Jueves
/ Thursday / 16 |
| 08:15 |
Recogida
de Acreditaciones / Registration |
| 08:30 |
Bienvenida / Opening and welcome addresses
Porqué este Simposio / Why this Symposium
Mariano Barbacid. CNIO; Madrid, Spain
José A. Gutiérrez-Fuentes. Fundación Lilly; Spain |
| 08:45 |
CONFERENCIA DE APERTURA / KEYNOTE
ADDRESS
Moderador / Chairperson : Mariano Barbacid |
|
Paul A. Marks. Memorial Sloan-Kette
ring Cancer Center; New York, USA. |
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Los inhibidores de las deacetilasas
de histonas: mecanismo de acción y desarrollo de
fármacos anticáncer / Histone Deacetylase
Inhibitors: Mechanisms of Action and Development as Anti-Cancer
Agents.
Among the most studied epigenetic mechanisms of regulation
of gene expression is the acetylation-deacetylation of histone
proteins controlled by histone deacetylase (HDAC0 and histone
acetyltransferase (HAT) activities. In addition to histones,
HDAC targets include transcription factors, proteins regulating
cell growth and death pathways and proteins regulating cell
migration, angiogenesis and cell adhesion. The mechanisms
of action of the HDAC inhibitor (HDACi), SAHA, and related
compound discovered in our laboratory. SAHA has been in Phase
I/II clinical trials and shown significant anti-cancer activity
in patients with hematologic and solid malignancies at well
tolerated doses. |
| Session 1 |
METILACIÓN DEL ADN, CÉLULAS TUMORALES Y EL METILOMA HUMANO / DNA METHYLATION, CANCER CELLS AND THE HUMAN METHYLOME
Moderador / Chairperson: Juan
Carlos Lacal. Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain |
| 09:30 |
Peter A. Jones. USC/Norris Comprehensive Cancer Center; Los Angeles, USA |
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Alteración del epigenoma en cáncer / How the
epigenome gets altered in cancer.
The covalent modification of DNA cytosine residues and associated histone proteins play a major role in the stability and heritability of epigenetic states. These covalent modifications of DNA and proteins interact with the chromatin remodeling apparatus to regulate the interaction of transcription factors with DNA thus contributing to stable patterns of gene expression. CpG islands are usually unmethylated in normal tissues except for genes located on the inactive X-chromosome, imprinted genes and some tissue specific genes. Histones are marked by covalent modifications and we have found that active marks are highly localized to the start sites of human genes. These patterns of modification are altered during the formation of human cancer so that CpG islands become abnormally methylated, histones become modified with repressive marks and we have recently discovered that nucleosomal remodeling occurs, resulting in the silencing of genes. Focal changes such as these often occur in the presence of genomic cytosine hypomethylation and histone hyperacetylation showing a major imbalance in epigenetic programming. Epigenetic silencing can serve as a therapeutic target for epigenetic therapies which seek to reverse silencing and restore more normal gene expression patterns to cancer cells. To date, the focus has mainly been on the reactivation of protein coding genes yet we have found that micro RNAs can also become abnormally silenced in human cancer cells by such chromatin modifications. Reactivating micro RNAs could potentially yield a novel therapeutic strategy in the treatment of cancer. |
| 10:15 |
Stephen B. Baylin. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Baltimore, USA |
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El papel clave del silenciamiento
genético en las etapas más tempranas del cáncer /The
key role for epigenetic gene silencing in the earliest stages
of neoplasia.
In this presentation, I will express the concept that epigenetic changes, and especially aberrant DNA hypermethylation of key gene promoters, play a critical role in the earliest stages of neoplastic evolution. These changes may, actually, drive such stages even before critical gene mutations emerge through addicting cells to signal pathway abnormalities which foster abnormal clonal cell expansion. A key to understanding why these epigenetic changes arise is to consider the concept of the cancer DNA hypermethylome , including the numbers of genes involved, and programs which might underlie the silencing of such genes. In turn, a key to this understanding relates to defining the chromatin construction of involved gene promoters and the association of these chromatin patterns with the associated DNA methylation. Current data concerning these issues will be discussed |
| 11:00 |
Café/Coffee
Sesión de Paneles I / Poster Session I |
| 11:30 |
Manel Esteller.
CNIO; Madrid, Spain. |
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Epigenética del cáncer:
desde el conocimiento al tratamiento / Cancer epigenetics:
From knowledge to therapy.
The recognition of epigenetic defects in all types of cancer has represented a revolutionary achievement in cancer research in recent years. DNA methylation aberrant changes (global hypomethylation and CpG island hypermethylation) were among the first events to be recognized. Over recent years, a better understanding of the machinery that connects DNA methylation, chromatin and transcriptional activity, in which histone modifications stand in a key position, has been achieved. The identification of these connections has contributed to developing novel therapies that can reverse epigenetic defects in cancer cells |
| 12:15 |
Andrew P. Feinberg. Johns Hopkins
University School of Medicine; Baltimore, USA. |
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La epigenética en la
etiología del cáncer / The epigenetics of cancer
etiology.
Cancer epigenetics has been limited by questions of cause and effect, since epigenetic changes can arise secondary to the cancer process and its associated widespread changes in gene expression. We have focused on identifying epigenetic changes in normal cells that predispose to cancer. One line of investigation has been on the disorder Beckwith-Wiedemann syndrome (BWS). We have also developed an animal model for the role of loss of imprinting (LOI) of IGF2 in cancer, showing that it cooperates with Apc mutations to increase cancer frequency, consistent with human data suggesting a several fold increased cancer risk for this common epigenetic variant in the adult population. These data suggest that a major component of cancer risk involves epigenetic changes in normal cells that increase the probability of cancer after genetic mutation. |
| 13:00 |
Christoph Plass. The Comprehensive Cancer Center,
The Ohio State University; Columbus, USA. |
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La metilación del ADN
y el genoma del cáncer / DNA methylation and the
cancer genome.
The cancer genome is characterized bi genetic and epigenetic alterations. DNA methylation is one of the epigenetic modifications that is modified in the cancer genome. Both the loss of global DNA methylation levels and as well as the gain of aberrant DNA methylation in regulatory sequences has been described. Here we will discuss our current knowledge on CpG Island methylation and provide evidence for fine tuned “micro” patterns of altered DNA methylation that modulate gene expression. |
| 13:45 |
Almuerzo
/ Lunch |
| Sesión
2 |
TRATAMIENTO DE LOS
PACIENTES ONCOLÓGICOS MEDIANTE FÁRMACOS DESMETILANTES DEL
ADN / CLINICAL TREATMENT OF CANCER PATIENTS BY
DNA DEMETHYLATING AGENTS.
Moderador / Chairperson: Hernán Cortés Funes.
Servicio de Oncología, Hospital 12 de Octubre; Madrid, Spain. |
| 15:00 |
Robert Brown. Cancer Research UK Beatson Laboratories;
Glasgow, UK. |
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Modulación de la resistencia a los fármacos
mediante tratamientos epigenéticos / Modulation
of drug resistance by epigenetic therapies.
The acquisition of drug resistance is a major problem in the successful treatment of cancer. There is increasing evidence for a role for aberrant epigenetic regulation of gene expression during the acquisition of resistance to cytotoxic chemotherapies. I will describe preclinical models and clinical trials that examine the potential of DNMT and HDAC inhibitors to chemosensitise solid tumours. Central to these studies is the use of biomarkers, both as pharmacodynamic markers of drug efficacy and for enrichment of patients who may benefit from these epigenetic therapies. |
| 15:45 |
Michael Lubbert. University of Freiburg Medical
Center; Freiburg, Germany. |
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Agentes desmetilantes
a dosis bajas: Una opción de tratamiento no intensivo para
pacientes mayores con neoplasia mieloide / Low-dose
demethylating agents: A non-intensive treatment option for
older patients with myeloid neoplasia.
The large majority of myeloid neoplasias do not carry the bcr-abl rearrangement or another activated tyrosine kinase presently amenable to pharmacological inhibition. Thus no targetted therapy is established for the these often elderly patients with inherent poor tolerance to aggressive chemotherapy (due to reduced performance status, comorbid conditions etc.). Demethylating agents have been developed at schedules allowing non-intensive treatment, with very limited non-hematological toxicity, of myelodysplasia (5-azacytidine/Vidaza, Decitabine) and AML (Decitabine). Agents with demethylating activity have be shown by systematic cytogenetic analyses to be at least partially selective for the abnormal, clonal hematopoetic cells of MDS, while myelosuppressive effects upon normal hematopoiesis, at least at the doses studied so far, are much less marked. Thus both the response rates and favorable toxicity profile are very encouraging and further development of these drugs includes combinations e.g. with histone deacetylase inhibitors. |
| 16:30 |
Café
/ Coffee
Sesión de Paneles I / Poster Session I |
| 17:00 |
Jean-Pierre
J. Issa.
University of Texas, MD Anderson Cancer Center; Houston, USA |
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¡La hipometilación funciona como terapia! / Hypomethylation therapy works!
The FDA approval of 5-azacytidine for the treatment of MDS and the favorable clinical results obtained with 5-aza-2’-deoxycytidine
(DAC) in various hematologic malignancies transform hypomethylation
therapy of cancer from concept to clinical reality. Mechanism-based
optimization of dose and schedule led to a substantial improvement
in the clinical results, such that more than half the patients
with myeloid malignancies show dramatic responses to this
agent. Responses require hypomethylation and are associated
with induction of P15 expression. Genetic markers suggest
that responses relate to early differentiation and late clearing
of the malignant clone, all suggestive of an epigenetic mechanism
of action. Histone deacetylase inhibitors are also showing
clinical activity, albeit lower than that of hypomethylating
drugs. The future of epigenetic therapy will clearly entail
combinations of drugs to (i) enhance gene reactivation and
(ii) exploit gene reactivation, and clinical trials of such
approaches are ongoing. |
| 17:45 |
Pere
Gascón. Servicio de Oncología, Hospital
Clinic; Barcelona, Spain |
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La epigenética y el microambiente tumoral / Epigenetics
and the tumoral microenvironment.
There is a growing body of evidence that normal cells effectively restrict malignant behaviour, and that such forces must be controlled in order to establish a tumour. Persistent disruption of the microenvironment such in inflammation or pathological tissue states may compromise its ability to suppress carcinogenesis. Recent publications have shown that stromal cells and their products can cause the transformation of adjacent cells through transient signalling that leads to the disruption of tissue homeostatic regulation. It is now well established that tumour progression requires a continually evolving network of interactions between neoplastic cells and tissue microenvironment (stromal cells and extracellular matrix-ECM).It is postulated, that only when the disruption of tissue homeostasis becomes chronic such as in persistent inflammatory conditions, continual up regulation of enzymes such as matrix metalloproteases by stromal fibroblasts can disrupt the ECM, and invading immune cells, such as macrophages, can overproduce factors that promote abnormal proliferation. These abnormal interactions might lead to genomic instability within normal tissue cells and the acquisition of tumorigenic potential. At this point, the tumour has become its own organ. However, some cells with tumorigenic genotype can become phenotypically normal if the context is appropriately manipulated. In other words, the phenotype can override the genotype. Under these premises, one can contemplate therapeutic strategies where the new agents will target the tumour microenvironment.
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|
| Viernes
/ Friday 17 |
| Sesión
3 |
MODIFICACIÓN DE LAS HISTONAS
Y LA CROMATINA Y SUS MODIFICADORES / HISTONE AND
CHROMATIN MODIFICATIONS AND THEIR MODIFIERS.
Moderador
/ Chairperson: Juan Angel Velasco (Lilly Research Labs., Alcobendas, Spain). |
| 09:00 |
Tony Kouzarides . Wellcome Trust
/ Cancer Research, Gurdon Institute; London, UK. |
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Las modificaciones de la cromatina y
sus funciones /Chromatin modifications and their
functions.
Chromatin modifications play an important role
in many biological processes and their pathways are
disrupted in cancer. We are trying to identify and
characterize new modifications that affect chromatin.
One such new pathway is the isomerisation of proline
residues within histone H3. Analysis of this new pathway
reveals that it regulates transcription by offering
the methylation of histone H3 at lysine 36. |
| 09:45 |
Rob Martienssen. Cold Spring
Harbor Laboratory; Cold Spring Harbor, New York, USA. |
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Dando sentido al ARN heterocromático / Making
sense of heterochromatic RNA.
Heterochromatic
(junk) RNA is widespread and processed by RNAi, especially
from tandem repeats. In fission yeast, PolII and a putative
3'end processing complex are required for silencing and
RNAi. In Arabidopsis, the SWI/SNF remodeler DDM1 targets
DNA methylation and histone H3 K9 methylation to transposons,
via siRNA. DDM1, HDAC and MET1 (dnmt1) can silence transposons
independently of RNAi, but re-silencing requires siRNA
in cis. Transposons and heterochromatic repeats can regulate
neighboring genes. |
| 10:30 |
Thomas Jenuwein.
Research Institute of Molecular Pathology –IMP-;
Vienna, Austria. |
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Control epigenético mediante
la metilación de las histonas /Epigenetic
control by histone methylation.
Epigenetic mechanisms control eukaryotic development beyond
DNA-stored information. DNA methylation, histone modifications
and variants, nucleosome remodelling and non-coding RNAs
all contribute to the dynamic 'make-up' of chromatin under
distinct developmental options. In particular, the great
diversity of covalent histone tail modifications has been
proposed to be ideally suited for imparting epigenetic information.
While most of the histone tail modifications represent transient
marks at transcriptionally permissive chromatin, some modifications
appear more robust at silent chromatin regions where they
index repressive epigenetic states with functions also outside
transcriptional regulation. Under-representation of repressive
histone marks could be indicative of epigenetic plasticity
in stem, young and tumor cells, while committed and senescent
(old) cells often display increased levels of these more
stable modifications. We analyzed profiles of normal and
aberrant histone lysine methylation patterns, as they occur
during the transition of an embryonic to a differentiated
cell or in controlled self-renewal vs. pro-neoplastic or
metastatic conditions. Elucidating these histone modification
patterns promises to have important implications for novel
advances in stem cell research, nuclear reprogramming and
cancer, and may offer novel targets for the combat of tumor
cells, potentially leading to new diagnostic and therapeutic
avenues in human biology and disease. |
| 11:15 |
Café
/ Coffee
Sesión de Paneles II / Poster Session II |
11:45
|
Yi Zhang. University of North Carolina at Chapel
Hill; North Carolina, USA. |
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La metilación de las histonas
en la regulación de la transcripción y el
cáncer / Histone methylation in transcription
regulation and cancer.
Chromosomal translocation is a common cause
of leukemia. However, the underlying mechanism for most
leukemias involving chromosomal translocation is not clear.
We demonstrate that the H3K79 methyltransferase hDOT1L
contributes to leukemogenesis of several fusion proteins
by mis-targeted to different Hox genes. |
| 12:30 |
Yang Shi. Harvard
Medical School; Boston, USA. |
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Regulación
de la metilación de las histonas mediante desmetilasas
/ Regulation of histone methylation by demethylases.
Histone methylation was considered a “permanent” modification
until the discovery of LSD1. Together with the recent finding
of JHDM1, these results suggest that demethylases are likely
to represent a general mechanism that provides dynamic regulation
of histone methylation. In this presentation, I will discuss
our investigation of LSD1 in S. pombe and our efforts of
identifying new histone demethylases. |
| 13:15 |
Almuerzo |
| Sesión
3 (cont.) |
MODIFICACIÓN
DE LAS HISTONAS Y LA CROMATINA Y SUS MODIFICADORES / HISTONE
AND CHROMATIN MODIFICATIONS AND THEIR MODIFIERS.
Moderador / Chairperson: Eugenio Santos. Instituto de Biología Molecular y Celular del Cáncer; Salamanca, Spain.
|
| 15:00 |
Peter B. Becker.
Adolf-Butenandt Institut; Munich, Germany |
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Remodelación
del nucleosoma en el desarrollo temprano de Drosophila
melanogaster /Nucleosome
remodeling during early development of Drosophila melanogaster.
ATP-dependent nucleosome remodeling emerges as a principal
mechanism underlying all dynamic transitions of chromatin
structure. The considerable number of nucleosome remodeling
ATPases and their association with regulatory subunits leads
to enzymes with cell-type specificity and functional diversification.
Studies in the Drosophila model reveals crucial functions
for ISWI-containing remodeling complex during the earliest
embryonic developmental stages. |
| 15:45 |
Genevieve Almouzni . CNRS / Institut
Curie; Paris, France |
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Propagación del estado epigenético
durante el ensamblaje de la cromatina / Propagation
of epigenetics states at the level of chromatin assembly.
Heterochromatin
is thought to play a critical role for centromeric function
and gene silencing. In mouse cells, we found that centric
and pericentric repeats on the chromosomes (corresponding
to minor and major satellites) have distinct heterochromatic
properties in the nucleus. These domains display specific
higher order organisation and replicate asynchronously. Furthermore,
chromatid cohesion is sustained for a longer time in major
satellites compared to minor satellites. We thus define functionally
independent centromeric subdomains, which spatio-temporal
isolation is proposed to be important for centromeric cohesion
and dissociation during chromosome segregation.
We then investigated how the complex organization of HP1-rich
pericentric domains is reproduced at each replication cycle
in mouse cells. We find that replication occurs mainly at the
surface of these domains where both PCNA and CAF-1 are located.
Pulse-chase experiments combined with high resolution analysis
and 3D modeling show that within 90 minutes newly replicated
DNA become internalized inside the domain. Remarkably, during
this time period, a specific subset of HP1 molecules ( a and
g ) coinciding with CAF-1 and replicative sites is resistant
to RNAse treatment. This replicative pool of HP1 molecules
disappears completely following p150CAF-1 siRNA treatment.
We conclude that during replication, the interaction of HP1
with p150CAF-1 is essential to promote delivery of HP1 molecules
to heterochromatic sites. We will discuss our recent data on
this topic. |
| 16:30 |
Maarten van Lohuizen. The Netherlands
Cancer Institute; Amsterdam, The Netherlands. |
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Represores de Polycomb que controlan
el devenir de las células madre: Implicaciones en
el cáncer y el desarrollo / Polycomb repressors
controlling stem cell fate: Implications for cancer and
development.
Repressive Polycomb-group protein complexes
are involved in the dynamic maintenance of proper gene
expression patterns during development, acting at the level
of chromatin structure. As such, they are important controllers
of cell fate. In particular, recent experiments have demonstrated
a crucial role for Polycomb repressors in controlling the
self-renewal capacity of stem cells and cancer stem cells.
When deregulated, these master switches of gene expression
are strongly implicated in formation of a diverse set of
cancers. I will discuss recent examples highlighting the
emerging molecular mechanisms by which Polycomb repressors
regulate stem cell fate and may contribute to cancer formation. |
| 17:15 |
Café / Coffee
Sesión
de Paneles II / Poster Session II |
| 17:45 |
Carlos Caldas. Cancer Genomics Program,
University of Cambridge; Cambridge, UK. |
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Expresión diferencial de los genes
modificadores de histonas en tumores humanos sólidos:
Dianas para el diagnóstico y la terapia / Differential
expression of histone modifier genes in human solid tumors:
Targets for diagnosis and therapy.
Histone modifier enzymes are responsible for modulating
histone tail modifications and regulate gene expression at
the chromatin level. The characterization of patterns of
expression of genes encoding histone modifiers (using QRT-PCR
and expression arrays) is an essential first step in the
understanding of their biology and in their development as
diagnostic and therapeutic targets. |
| 18:30 |
Eric Miska. Wellcome / CRC Institute,
University of Cambridge; Cambridge, UK. |
(+ info)
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Papel de los microARNs en el desarrollo
de C. elegans y en el cáncer
humano / Roles of microRNAs in C. elegans development
and human cancer.
In the last five years microRNAs (miRNAs) have emerged from
the obscurity of C. elegans heterochronic heterochronic
pathway to a new paradigm of gene regulation in plants an
animals. Currently, microRNAs represent 2% of all known human
genes. Very little is known about their biological function.We
have taken a functional genomics approach to study the roles
of microRNAs in C. elegans development. We
have generated deletion strains corresponding to 96 microRNAs,
covering the majority of known microRNA genes. We will present
an overview of the classes of mutant phenotypes we have observed.
One focus will be the issue of redundancy within families
of microRNA genes. This study represents the first comprehensive
analysis of microRNA function. We are also interested in
the roles of short RNAs in the control of gene expression
at the transcriptional level. We will present our work on
how these short RNAs work together with a set of argonaute
proteins to control germline development in C. elegans. |
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Sábado
/ Saturday 18 |
| Sesión 4 |
TRATAMIENTO DEL CÁNCER CON INHIBIDORES
DE LAS DEACETILASAS DE HISTONAS Y OTRAS TERAPIAS TRANSCRIPCIONALES
/ CLINICAL TREATMENT OF CANCER BY INHIBITORS OF
HISTONE DEACETYLASES AND OTHER TRANSCRIPTIONAL THERAPIES.
Moderador
/ Chairperson: Alfredo Carrato Mena .
Hospital Universitario de Elche; Alicante, Spain. |
| 09:00 |
Francesco Lo Coco. Universita Tor
Vergata; Rome, Italy. |
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Datos preliminares del tratamiento de
leucemia mieloide aguda avanzada con ácido valpróico
/ Preliminary experience on treatment of advanced acute
myeloid leukemia with valproic acid.
A pilot study was carried out in 8 high-risk AML patients
not eligible for intensive therapy to asses the biological
and therapeutic activities of the HDAC inhibitor VPA used
to remodel chromatin, followed by the addition of ATRA, to
activate gene transcription and differentiation in leukemic
cells. We found that VPA/ATRA treatment is well tolerated
and induces phenotypic changes of AML blasts through chromatin
remodelling. Further studies are needed to evaluate whether
VPA-ATRA treatment by reprogramming differentiation of the
leukemic clone might improve the response to chemotherapeutic
agents in leukemia patients. |
| 09:45 |
Miguel Ángel Sanz . Hospital
Universitario La Fe; Valencia, Spain. |
(+ info)
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Tratamiento de las neoplasias mieloides
con terapias transcripcionales / Treatment of myeloid
malignancies by transcriptional therapies.
Understanding
the basic cellular and molecular biology of leukemia is
crucial to the development of targeted therapies. Epigenetic
mechanisms underlying leukemogenesis have recently received
much attention as potential therapeutic targets. Two major
mechanisms of aberrant gene silencing have been implicated
in acute myeloid leukemia (AML) and myelodysplasia (MDS).
These include transcriptional repression by mutated or
aberrantly expressed transcription factors, and aberrant
epigenetic silencing by hypermethylation of tumor suppressor
or DNA repair–related genes. To target these mechanisms,
several drugs are currently under clinical trials. In this
presentation, we will discuss the potential impact of this
new therapeutic approach in AML and MDS. |
| 10:30 |
Pier Giuseppe Pelicci. European Institute
of Oncology; Milan, Italy. |
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Epigenética de la leucemia
promielocítica y sus fármacos /Epigenetics
of acute promyelocitic leukemia and their drugs.
Molecular investigations on Acute Promyelocytic Leukemia
(APL) have opened the way to modern concepts of anti-cancer
treatment. APL has been the first example of a neoplastic
disease that can be specifically treated by targeting therapy
to the transforming protein (molecular treatment) and represents
a unique model for differentiation therapy. Indeed, the APL
oncogene (PML-RAR) is responsible for the high sensitivity
of the blasts to the differentiative action of retinoic acid
(RA) both in vivo and in vitro. The dissection of the molecular
mechanisms underlying PML-RAR activities (chromatin recruitment
of histone deacetylases, histone and DNA methyltransferases)
has demonstrated that epigenetic modifications of DNA (methylation)
and chromatin (acetylation and methylation of histones) may
contribute to cancer. This has allowed the concept of epigenetic
treatment of cancer to be introduced and validated. Recent
work from our lab has demonstrated that HDAC-i induce apoptosis
of leukemic blasts, that apoptosis is p53-independent and
depends upon activation of the death receptor pathway (TRAIL
and Fas signalling pathway). The effects of HDAC-I treatment
on RA-target genes in PML-RAR cells was negligible, thus
suggesting that HDACi might target alternative mechanisms
of PML-RAR activity. Indeed, members of the TRAIL and Fas
pathway are not direct RA-targets. We are currently investigating
whether PML-RAR regulates transcription of genes which do
not possess RA-responsive elements (RARE). Many genes regulated
by RA and/or PML/RARa do not contain a RARE. However, these
genes are clustered in long stretches of co-regulation spanning
regions up to 1 Megabase in length.These clusters are found
within regions particularly enriched with RARE consensus
sequences that, surprisingly, are included within Alu repeats.
Such a striking co-localization of RAR- and/or PML/RARa-
regulated genes, RARE consensuses and Alu sequences suggests
that the insertion of potentially thousands of Alu repeats
containing binding sites for NHRs throughout the primate
genome is likely to have played a functionally important
role in the evolution of regulation of the primate gene expression. |
| 11:15 |
Café / Coffee |
| 11:45 |
James E. Bradner. Dana–Farber Cancer
Institute; Boston, USA |
(+ info)
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Inhibición selectiva de HDAC6
en la terapia oncológica /Selective inhibition
of HDAC6 in cancer therapy.
Histone deacetylase enzymes represent credentialed targets
for cancer therapy. Early phase clinical studies assessing
the activity of non-selective inhibitors in the treatment
of hematologic malignancies have been encouraging, though
the toxic liabilities of these agents may ultimately limit
their clinical development. Consequently, targeted strategies
are needed. Our recent chemical biologic exploration of this
class of enzymes has realized selective inhibition of HDAC6
and the utility of such a strategy in multiple myeloma. Additional
strategies have realized small molecule HDAC inhibitors with
appealing ADME properties for therapeutic application. |
| 12:30 |
Roberto Pili. Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins; Baltimore, USA. |
(+ info)
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Ensayos clínicos en Fase I de
inhibidores de HDAC, aislados y en combinación / Phase
I trials of HDAC inhibitors, alone and in combination.
This presentation will review the HDAC inhibitors currently
in clinical testing as well as, describe the rationale for
combination strategies. It will outline the clinical issues
related to the drug development of this novel class of agents. |
| 13:15 |
CONFERENCIA DE CLAUSURA / CLOSURE
KEYNOTE
Joe Shih. Discovery Chemistry Research & Technology,
LRL-Eli Lilly; Indianapolis, USA. |
|
El Caso de estudio del descubrimiento
y desarrollo de Alimta, un nuevo antifolato multidiana
para el mesotieloma pleural maligno y el cáncer
de pulmón de células no pequeña / A
Case Study of the discovery and development of Alimta,
a novel multitargeted antifolate for malignanat pleural
mesothieloma and non-small cell lung cancer.
ALIMTA Ò (Pemetrexed Disodium) is a new pyrrolopyrimidne-based
antifolate that was recently approved by FDA as the first line
treatment (in combination with cisplatin) for the malignant
pleural mesothelioma (MPM) and as the 2 nd line treatment (single
agent) for non-small cell lung carcinoma (NSCLC). ALIMTA Ò acts
through a novel mechanism of action by inhibiting several key
folate-requiring enzymes (TS, DHFR and GARFT) of the folate
metabolism. This unique multi-targeted MOA together with the
vitamins (folic acid and B-12) supplementation have made ALIMTA Ò a
highly effective and well tolerated chemotherapeutic agent.
The history of the discovery, the preclinical pharmacology
and some key clinical trial results (for MPM and NSCLC) of
ALIMTA Ò will be presented in this lecture. |
| 14:00 |
Despedida y Cierre / Farewell & Closure. |
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| INFORMACIÓN
GENERAL |
Tel: + 34 91 732 80 00 