Simposio Internacional: Terapias oncológicas avanzadas
Internatinal Symposium: Advance oncological thrrapies
Madrid, 15 y 16 de octubre de 2014
Madrid, October 15-16, 2014
I
 Integrating personalized cancer medicine into drug discovery and development,
Carlos Garcia Echeverria
 Targetting telomeres in cáncer, María Blasco
 A path to clinical development of nanomedical applications, Gabriel LopezBerenstein
 Biomaterial-based therapeutic cancer vaccines, David Mooney
 Mieloid derived supresor cells as targets for cancer immunomodulation, Vicenzo
Bronte
 Cross-communication between immune and endothelial cells: Implications for
cancer therapy, Santos Mañes
 Investigación translacional dirigida al desarrollo de estrategias de inmunoterapia del
cáncer, Ignacio Melero
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Terapias oncológicas avanzadas
Internatinal Symposium: Advance oncological thrrapies
Madrid, 15 y 16 de octubre de 2014
Madrid, October 15-16, 2014
Integrating personalized cancer medicine into drug discovery and development,
Carlos Garcia Echeverria
Oncology has become one of the major focus areas for public research institutions and
pharmaceutical companies. This interest stems from the existence of high unmet need for
improved and safe treatments of multiple types of hematological malignancies and solid
tumors. Thus, and despite the availability of new targeted cancer therapies, cancer is still
one of the leading causes of mortality worldwide. Additionally, for indications for which new
therapies have provided clinical benefit over the past few years, the high mutation potential
of tumor cells and original heterogeneity in genetic alterations mean that patients may
relapse following initial treatment success, which creates a pressing need for alternative
agents that could be used as later lines of therapy.
This oral communication will cover representative examples of drug discovery projects and
modalities directed to the advancement of targeted therapies illustrating current challenges
in the identification and validation of target engagement, patient stratification and safety
biomarkers. All these preclinical translational efforts are settings the stage for increased
use of molecular diagnostics that could help oncologists and health providers choose the
most effective treatment options for cancer patients. The possibility to increase the clinical
benefit of emerging therapies by identifying optimal combination partners will also be
illustrated.
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Targetting telomeres in cáncer, María Blasco
Cancer is one of the leading causes of death worldwide. In spite of some success of
targeted therapies, new therapeutic strategies are needed. Telomeres are considered anticancer targets, as telomere maintenance above a minimum length is necessary for cancer
cell growth. Inhibition of telomerase is being currently tested in cancer clinical trials.
Telomerase deficiency in a K-RasG12V lung carcinogenesis mouse model, however, only
decreased tumor growth after five mouse generations when telomeres reach a critically
short length, and this tumor suppressive effect was lost upon p53 mutation. Here, we set
to address whether induction of acute telomere uncapping owing to abrogation of the Trf1
shelterin protein could be an alternative strategy to effectively kill cancer cells
independently of telomere length. We show here that Trf1 abrogation impairs K-RasG12Vinduced lung tumorigenesis both in the presence and absence of p53, concomitant with
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Terapias oncológicas avanzadas
Internatinal Symposium: Advance oncological thrrapies
Madrid, 15 y 16 de octubre de 2014
Madrid, October 15-16, 2014
increased mouse survival. The anti-tumorigenic effect of Trf1 deletion is accompanied by
induction of telomeric DNA damage, apoptosis, decreased proliferation, G2-arrest, and
endoreduplication, independently of p53. Downregulation of Trf1 in cell lines derived from
already established p53-deficient K-RasG12V lung carcinomas also impaired tumor growth
and metastasis in allograft models, as well as in xenograph models of human lung cancer
cell lines. Importantly, conditional whole-body Trf1 deletion in adult mice during more than
1.5 months did not impact on mouse survival and viability. Together, these results
demonstrate that Trf1 deletion effectively impairs the growth and progression of lung
cancer without severe effects in tissue homeostasis. Thus, induction of acute telomere
uncapping emerges as a potential new therapeutic target for lung cancer.
VOLVER/RETURN
A path to clinical development of nanomedical applications, Gabriel LopezBerenstein
The presentation will cover three aspects of therapeutic development in Cancer; 1)
discovery phase
2) preclinical studies and
3) protocol development.
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Biomaterial-based therapeutic cancer vaccines, David Mooney
Therapeutic cancer vaccines typically depend on extensive manipulation of cells in the
laboratory, but subsequent cell infusion typically leads to large-scale cell death and limited
efficacy. We are instead developing biomaterials that provide sustained, localized delivery
of immunomodulatory factors, in certain ways mimicking aspects of microbial infection, to
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Terapias oncológicas avanzadas
Internatinal Symposium: Advance oncological thrrapies
Madrid, 15 y 16 de octubre de 2014
Madrid, October 15-16, 2014
target immune cells in the body and bypass the need to manipulate cells in the laboratory.
These material strategies allow control over immune cell trafficking and activation, promote
potent responses to cancer antigens, and cause tumor regression in preclinical models.
VOLVER/RETURN
Mieloid derived supresor cells as targets for cancer immunomodulation, Vicenzo
Bronte
We are facing an unprecedented interest and confidence in cancer immunotherapy,
sustained by recent clinical success of checkpoint blockade by monoclonal antibodies and
adoptive cell therapy. However, the number of patients who can benefit from this novel
approaches is still limited. The clinical inefficiency of cancer immunotherapy is, in part, due
to the presence of an immunosuppressive network that favors tumor progression; in fact,
by producing soluble molecules such as cytokines, interleukins and growth factors, tumors
induce an alternative hematopoiesis, which modifies the normal myeloid cell differentiation,
pushing proliferation and expansion of cells with immunosuppressive activity called
myeloid-derived suppressor cells (MDSCs). The MDSC presence and frequency in blood
of tumor patients is often reported as a prognostic marker that correlates with the clinical
outcome and response to therapies, both conventional and immune-based. These cells
use distinctive and redundant pathways to suppress the proliferation and function of
antigen-stimulated T lymphocytes. Although MDSCs are heterogeneous, it appears that
three main immunosuppressive cell subsets have been identified: granulocytic, monocytic
and more immature cells, which might be able to originate the other two subpopulations. In
last years, we have gathered information about mechanisms used by MDSCs to restrain
adaptive and innate immunity, the possibility to generate MDSCs by in vitro culture of bone
marrow precursors, the definition of transcription factors and microRNAs regulating their in
vivo expansion and maturation. This knowledge allow us to hypothesize and design novel
strategies not only to interfere with MDSC inhibitory activity in cancer but also to hijack
MDSCs for the regulation of disorders characterized by excessive or uncontrolled
stimulation of the immune response, such as transplant rejection and autoimmune
diseases.
VOLVER/RETURN
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Terapias oncológicas avanzadas
Internatinal Symposium: Advance oncological thrrapies
Madrid, 15 y 16 de octubre de 2014
Madrid, October 15-16, 2014
Cross-communication between immune and endothelial cells: Implications for
cancer therapy, Santos Mañes
Tumors are able to evade the immune system in the early stages of the carcinogenic
process, and to shape the inflammatory microenvironment to suppress immunity. Immune
cells thus become allied with transformed cells, aiding their expansion. Specific conditions
of chronic immune system activation might promote the initiation and/or development of
certain tumor types. The immune system is nonetheless able to identify and delete
neoplastic cells, and clinical practice now indicates that immune cell reprogramming is a
therapeutically relevant strategy for certain tumors. Harnessing the maximum therapeutic
potential of the immune system requires, on the one hand, correct activation of immune
effector cells and on the other, infiltration of those activated cells into the tumor
parenchyma. This presentation will highlight the role of a specific chemokine receptor in T
lymphocyte costimulation and show how an anti-oxidant enzyme differentially regulates the
transendothelial migration of lymphoid and myeloid cells into tumors. Finally, evidence will
be shown that suggests crosscommunication between the immune infiltrate and the tumorassociated endothelium.
VOLVER/RETURN
Investigación translacional dirigida al desarrollo de estrategias de inmunoterapia
del cáncer, Ignacio Melero
La inmunoterapia del cáncer se está convirtiendo en nuevo pilar fundamental en el
tratamiento de las enfermedades malignas. Fruto del trabajo de las últimas décadas
hemos descubierto muchos mecanismos celulares y moleculares que determinan la
eficacia de la respuesta inmunitaria frente al cáncer, que ahora están siendo explotados
con éxito en algunos casos. Para ello disponemos de modelos de tumores transplantables
en ratones singénicos y de ratones transgénicos de desarrollan tumores de forma
espontánea. En ellos ha sido posible poner de manifiesto mecanismos susceptibles de
inmunomodulación y estrategias de tratamiento que se han podido llevar a la
experimentación clínica. El campo está en revolución gracias a los resultados de eficacia
terapéutica con anticuerpos monoclonales inmunoestimulantes que actúan como
herramientas para desreprimir o de estimular la intensidad de respuesta inmunitaria, así
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Terapias oncológicas avanzadas
Internatinal Symposium: Advance oncological thrrapies
Madrid, 15 y 16 de octubre de 2014
Madrid, October 15-16, 2014
como mediante la transferencia adoptiva de linfocitos T ingenierizados genéticamente
para reconocer y eliminar células tumorales. En nuestra línea de trabajo expondremos
experimentación sobre anticuerpos inmunoestimulantes dirigidos frente a los receptores
PD-1 y CD137 utilizados en el contexto de estrategias de tratamiento combinadas y
terapia celular adoptiva. Mostraremos y discutiremos datos sobre la utilidad de ratones
“inmunoavatar” (ratones inmunodeficientes reconstituidos con linfocitos humanos y
xenoinjertados con tumores de pacientes).
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