| Friday
25 |
| 08:30
– 09:00 |
Recogida
de Acreditaciones / Registration |
| 09:00 |
Opening and welcome addresses:
Autoridades
Mariano Barbacid (Chairman).
José A. Gutiérrez Fuentes (Fundación Lilly. Madrid, Spain):
Why this symposium. |
| OPENING |
KEYNOTE ADDRESS
Moderador / Chairperson:
Mariano Barbacid. CNIO. Madrid, Spain. |
| 09:20 |
Julio Celis
Institute of Cancer Biology; The Danish Cancer Society.
Copenhagen, Denmark. |
 |
Proteomics and Functional Genomics in Translational
Cancer Research: towards an integrated approach /Proteómica
y genómica funcional en la investigación translacional
del cáncer: hacia una aproximación integrada.
Today, the application of novel technologies from proteomics
and functional genomics to the study of cancer is slowly
shifting to the analysis of clinically relevant samples
such as fresh biopsy specimens and fluids, as the ultimate
aim of translational research is to bring basic discoveries
closer to the bedside. The implementation of discovery
driven translational research, however, will not only
require co-ordination of basic research activities, facilities
and infrastructures, but also the creation of an integrated
and multidisciplinary environment with the participation
of a dedicated team of clinicians, oncologists, pathologists,
epidemiologists as well as industrial partners. Issues
related to sample collection, handling and storage, number
of patients, availability of normal controls, tissue banks,
quality of the clinical information, follow-up studies
are critical and must be carefully considered.
Here I will describe our experience in establishing translational
research programs in bladder and breast cancer. |
| MESA
/ SESSION 1 |
SIGNALLING I
Moderador / Chairperson:
Rafael Rosell. Hospital Ramón Trias i Pujol.
Barcelona, Spain.
|
| 10:00 |
Julian Downward
ICRF. London, UK. |
|
Signalling cell survival by PI 3-kinase
and Raf / Supervivencia celular: función de PI 3-kinasa
y Raf.
Two signalling pathways are activated by most growth factors
and the Ras oncogenes: phosphatidylinositol 3-kinase and
Raf/MAP kinase. These pathways both impact on the ability
of cells to resist programmed cell death in a number of
ways. We have used a variety of approaches to characterise
these mechanisms in an attempt to understand how tumour
cells acquire resistance to apoptotic stimuli.
|
| 10:30 |
Discussion. |
| 10:45
– 11:15 |
Café / Coffee |
| 11:15 |
Manuel Hidalgo
The Johns Hopkins Univ. Baltimore, USA. |
 |
mTOR inhibitors in cancer treatment / Inhibidores
mTOR en el tratamiento del cáncer.
The mammalian target of rapamycin (mTOR) is a serine-threonine
kinase involved in the PI3K/AKt signaling pathway that
participates in the regulation of multiple biological
phenomena such as control of transcription and translation
of certain proteins. Rapamycin and analog compounds are
natural occurring inhibitor of mTOR that have demonstrated
antitumor effects in preclinical cancer models. Currently,
two rapamacyn analogs, CCI-779 and Rad001 are in clinical
development. CCI-779 demonstrated significant antitumor
affects in phase I and Phase II studies and is currently
in Phase III trials. The development of mTOR inhibitors
present some unique difficulties given the lack of significant
toxicities encountered in Phase I studies, the observation
of clinical responses at doses different from the maximum
tolerated dose, and the preclinical data suggesting that
these drugs are more effective in tumors with hyperactivated
PI3/Akt signaling pathway. Ongoing efforts include the
integration of pharmacodiagnostic tests to define the
population of patients more likely to respond to these
drugs and the use of pharmacodynamic endpoints to guide
dose and schedule selections. |
| 11:45 |
Discussion. |
| MESA
/ SESSION 2 |
TRANSDUCCIÓN DE SEÑALES / SIGNALLING II
Moderador / Chairperson:
Juan A. Velasco. Lilly Research Labs. Alcobendas,Madrid, Spain. |
| 12:00 |
Mariano Barbacid
CNIO. Madrid, Spain. |
 |
Animal models for cancer / Modelos animales en
cáncer.
Today we know of a number of genes that are mutated in
human cancer. It is accepted that these genes might be
valid targets for the development of specific anti-tumour
drugs. The success of STI-571 in CML attests to this assumption.
Yet, treatment of solid tumours that, unlike leukaemias,
may harbour several mutations, has not been equally successful.
Our laboratory is using gene-targeted mice to test whether
ablation of certain targets will affect tumour development.
These results should provide valuable information to validate
targets before embarking in costly drug discovery programmes.
Specifically, I will present our current results using
conditional strains of knock out mice for farnesyl transferase
and Cdk2. |
| 12:30 |
Discussion. |
| 12:45 |
Said Sebti
MRC-DRDIS. Tampa, Florida, USA. |
 |
FT inhibitors: from molecular pharmacology to hypothesis-driven
clinical trials / Inhibidores de la Farnesiltransferasa:
desde la farmacología molecular a los ensayos clínicos
basados en hipótesis.
This talk will focus on discussing important issues relating
to the mechanism by which farnesyltransferase inhibitors
(FTIs) inhibit tumor growth and induce apoptosis. Potential
biochemical targets as well as signaling pathway targets
for FTIs will be discussed. The talk will conclude with
how some of the laboratory bench findings are being translated
in the patient bed side. Results from 2 hypothesis-driven
clinical trials we have conducted will be discussed. |
| 13:15 |
Discussion. |
| 14:00 |
Almuerzo /Lunch |
| MESA
/ SESSION 3 |
ONCOGENIC PATHWAYS I
Moderador / Chairperson:
Carlos Martínez CNB. Madrid, Spain. |
| 16:00 |
Jonathan Yingling
LRL. Indianapolis, USA. |
 |
Targeting the TGF? Signal Transduction Pathway for
Cancer Therapy / La ruta de transducción de señales
TGFßcomo diana terapéutica en cáncer.
The transforming growth factor beta pathway plays diverse
roles in tumor biology. Early in the evolution of many
tumors, the TGF? growth inhibitory pathway is disrupted
leading to increased cell proliferation. Paradoxically,
enhanced expression of TGF? contributes to creation of
a microenvironment conducive to tumor growth by promoting
angiogenesis and epithelial-to-mesenchymal transition,
remodeling of the extracellular matrix, and immunosuppression.
Identification of potent, selective, orally bioavailable
TGF? receptor inhibitors has led to an effective anti-tumor
therapy in preclinical models. |
| 16:30 |
Discussion. |
| 16:45 |
Moshe Oren
The Weizmann Institute of Science. Rehovot, Israel. |
|
|
Wild type p53 loss of function and mutant
p53 gain of function in cancer/ Pérdida de función
y mutaciones de p53 en cáncer.
Half of all human cancers carry p53 gene mutations. Mutant
p53 can downregulate CD95 expression and protect against
CD95-induced apoptosis. In tumors that retain a wild type
p53 gene, p53 function is nevertheless defective. In some
cases, the defect is due to expression of dominant negative
p63. Elimination of DNp63 triggers p53-mediated apoptosis.
|
| 17:15 |
Discussion. |
| 17:30
– 18:00 |
Café / Coffee |
| MESA
/ SESSION 4 |
ONCOGENIC PATHWAYS II
Moderado / Chairperson:
Eugenio Santos CIC. Salamanca, Spain. |
| 18:00 |
Richard Gaynor
LRL. Indianapolis, USA. |
|
Regulation of the NF-?B Pathway / Regulación
de la via NF-kB.
This talk will be focused on the role of the I?B kinases
on regulating the NF-?B pathway in response to cytokine
activation. Novel functions of these kinases in NF-?B
activation will be discussed. |
| 18:30 |
Discussion. |
| 18:45 |
Hans Clevers
Hubrecht Laboratorium. Utrecht, The Netherlands. |
 |
The beta-catenin/TCF complex imposes a crypt progenitor
phenotype on colorectal cancer cells / El complejo
beta-catenina/TCF determina un fenotipo progenitor oculto
en las células cancerosas colorectales.
Mutations in the Wnt pathway components APC, beta-catenin
and conductin all induce sustained complex formation of
the co-activator beta-catenin with TCF transcription factors.
The resulting transactivation of TCF target genes is believed
to represent the primary transforming event in colorectal
cancer (CRC). Yet, the consequence of the presence of
mutationally activated beta-catenin/TCF in fully transformed
CRC cells is unknown. We have constructed CRC cell lines
carrying inducible dominant-negative TCF constructs. Inhibition
of beta-catenin/TCF resulted in a rapid G1 arrest. DNA
array analysis revealed the downregulation of a small
set of transcripts. These genes were expressed in polyps,
but also, physiologically, in the crypt progenitor compartments
of the colon. By contrast, we observed the induction of
multiple marker genes of intestinal differentiation upon
inhibing beta-catenin/TCF in CRC cells. We provide evidence
that p21 is responsible for this phenomenon. We conclude
that beta-catenin/TCF inhibits differentiation and imposes
a crypt progenitor phenotype on CRC cells. Moreover, inhibition
of beta-catenin/TCF activity restores the differentiation
program, despite the presence of multiple other mutations
in CRC. |
| 19:15 |
Discussion. |
| Saturday
26 |
| MESA
/ SESSION 5 |
CANCER GENOMICS
Moderador / Chairperson:
Eduardo Díaz-Rubio. Hospital Clínico. Madrid, Spain.
|
| 09:15 |
Marc Van de Vijver
Netherlands Cancer Institute. Amsterdam, The Netherlands. |
 |
Microarrays and Breast cancer / Microarrays y
cáncer de mama.
We have used gene expression profiling to identify a gene
expression profile that is associated with a high risk
to develop distant metastases within five years in lymph
node negative patients younger than 55 years. This “prognosis
signature” consists of 70 genes; this includes genes that
play a role in cell cycle control, invasion and angiogenesis.
More recently, we have found that this “prognosis signature”
is also associated with poor outcome in lymph node positive
patients. An important use of the “prognosis signature”
is to guide systemic adjuvant treatment of patients with
operable breast cancer. |
| 09:45 |
Discussion. |
| 10:00 |
Miguel Angel Piris
CNIO. Madrid, Spain. |
 |
Building outcome predictors in lymphoma / Elaboración
de predictores de resultados en linfomas.
Molecular massive techniques have been now applied to
the analysis of different types of lymphoid malignancies.
Essentially the results are showing that human tumours
carry on a huge constellation of molecular alterations
in genes and pathways regulating cell cycle, apoptosis,
signal transduction and other critical pathways.
The identification of this myriad of alterations in the
level of expression of multiple genes allows to integrate
this information into predictive systems, this permitting
to stratify patients into different levels of risk to
treatment-failure, with an unprecedented accuracy. A further
step in this pathway has been the identification of molecular
signatures which allow to differentiate conditions such
as malignant and inflammatory diseases. Molecular signatures
permit also to deconstruct the pathogenesis of common
tumours, such as it’s being doing for the elucidation
of the role of key genes in the pathogenesis of the most
common lymphoma types. |
| 10:30 |
Discussion. |
| 10:45
– 11:15 |
Café / Coffee |
| MESA
/ SESSION 6 |
NOVEL THERAPIES
Moderador / Chairperson:
Hernán Cortés. Hospital 12 de Octubre, Madrid,
Spain.
|
| 11:15 |
Axel Ullrich
Max Planck Institute of Biochemistry. Martinsried, Germany. |
|
|
From gene to cancer therapy / Desde
el gen al tratamiento del cáncer.
Gene technology methods have opened new ways towardsthe
elucidation of aberrant processes in cancer cells that
are causally connected to the development and progression
of tumors. The first gene-based cancer therapeutic confirming
the validity of this paradigm is “HERCEPTIN”.
Which targets the oncoprotein HER2/neu in breat cancer.
Other examples including anti-angiogenic strategies will
be presented. |
| 11:45 |
Discusssion. |
| 12:00 |
José Baselga
Hospital Vall d´Hebron. Barcelona, Spain. |
 |
Tyrosine kinase inhibitors / Inhibidores de tirosin
quinasa.
The epidermal growth factor receptor (EGF receptor) is
a tyrosine kinase receptor of the ErbB family that is
abnormally activated in many epithelial tumors. Receptor
activation leads to recruitment and phosphorylation of
several downstream intracellular substrates, leading to
mitogenic signaling and other tumor-promoting cellular
activities. In human tumors, receptor ovexpression correlates
with a more agressive clinical course. Monoclonal antibodies
directed at the ligand-binding extracellular domain and
low molecular weight (MW) inhibitors of the receptor’s
tyrosine kinase are currently in advanced stages of clinical
development. These agents prevent ligand-induced receptor
activation and downstream signaling, which results in
cell cycle arrest, promotion of apoptosis, and inhibition
of angiogenesis. In patients, single agent activity has
been observed in colon carcinoma, non-small-cell-lung
cancer, head and neck cancer, and ovarian carcinoma. |
| 12:30 |
Discussion. |
| 12:45 |
Robert Pinedo
Head, Free University of Amsterdam. Amsterdam, Netherlands |
 |
Cancer Clinical Trials in the next decade / Ensayos
clínicos en cáncer en la próxima década
Cancer therapy is changing dramatically. While most cytotoxic
therapies were far from being tumor specific, we are experiencing
an increasing number of targeted treatments entering the
clinic. This will require a change of mind of clinical
oncologists. In the next 10 years clinical protocols will
require a ‘translational section’ based on the type of
targeted treatment under study. Such targeted therapies
differ widely, including specific types of anti-angiogenic
treatments, proteosome inhibitors, monoclonal antibodies
to specific receptors/antigens and specific immunotherapeutic
approaches. Patients will need to be stratified based
on biologic parameters of the tumor, which can be assessed
through genomics and proteonomic approaches. Treatment
results will be assessed through surrogate markers, including
new imaging procedures.
|
| 13:25 |
Discussion.. |
| FAREWELL |
Mariano Barbacid
José A. Gutiérrez Fuentes |
|
|
