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O-06 CCND2 REARRANGEMENTS ARE THE MOST FREQUENT GENETIC EVENTS IN CYCLIN D1-NEGATIVE MANTLE CELL LYMPHOMA SALAVERRIA I 1 , ROYO C 1 , NAVARRO A 1 , CAMPO E 1 , BEÀ S 1 1 HOSPITAL CLÍNICO, BARCELONA (RD06/0020/0039) Cyclin D1-negative mantle cell lymphomas (MCL) are not well characterized, in part due to the difficulties in their recognition. SOX11 has been recently identified as a reliable biomarker of MCL, also expressed in the cyclin D1-negative variant. We investigated 40 lymphomas with MCL morphology and immunophenotype, negative for cyclin D1 expression/t(11;14) (q13;q32) but SOX11-positive. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and had a poor outcome (5-year overall survival 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18/22 cases, in particular with light chains (10 IGK@, 5 IGL@). No mutations in the phosphorylation motifs of CCND1, CCND2 and CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1-negative SOX11- positive MCL analyzed by copy number arrays were similar to the conventional cyclin D1/ SOX11-positive MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome to the patients. This comprehensive characterization of a large series of cyclin D1-negative MCL indicates that these tumors are clinically and biologically similar to the conventional cyclin D1-positive MCL and provides a basis for the proper identification and clinical management of these patients. O-07 A DOMINANT-NEGATIVE N-TERMINAL FRAGMENT OF HER2 FREQUENTLY EXPRES- SED IN BREAST CANCERS MORANCHO B 1 , PARRA-PALAU JL 1 , IBRAHIM YH 2 , BERNADÓ MORALES C 1 , PEG V 3 , BECH-SERRA JJ 1 , PANDIELLA A 4 , CANALS F 1 , BASELGA J 2, 5 , RUBIO I 6 , ARRIBAS J 1,7,8 1 PRECLINICAL RESEARCH PROGRAM, VALL D’HEBRÓN INSTITUT D’ONCOLOGIA (VHIO), BARCELONA (RD06/0020/0022) 2 PRECLINICAL RESEARCH PROGRAM VALL D’HEBRÓN INSTITUT D’ONCOLOGIA (VHIO), BARCELONA (RD06/0020/0075) 3 PATHOLOGY DEPARTMENT, VALL D’HEBRON UNIVERSITY HOSPITAL AND DEPARTMENT OF MORPHO LOGICAL SCIENCES, UNIVERSITAT AUTONOMA DE BARCELONA, BARCELONA (RD06/0020/0104) 4 CENTRO DE INVESTIGACIÓN DEL CÁNCER DE SALAMANCA (CIC-IBMCC; USAL-CSIC), SALAMANCA (RD06/0020/0041) 5 MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, MASSACHUSETTS GENERAL HOSPITAL, HAR VARD MEDICAL SCHOOL, BOSTON MA (USA) 6 BREAST SURGICAL ONCOLOGY, BREAST CANCER CENTER, VALL D’HEBRON UNIVERSITY HOSPITAL, BARCELONA 7 DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY, UNIVERSITAT AUTONOMA DE BARCELONA, BARCELONA 8 INSTITUCIÓ CATALANA DE RECERCA I ESTUDIS AVANÇATS (ICREA), BARCELONA The transmembrane tyrosine kinase HER2 (ErbB2, neu) is a prototypical biomarker for breast cancers and a therapeutic target. Although anti-HER2 therapies are remarkably effective, HER2-positive tumors are heterogeneous and some subtypes do not respond or develop resistance to these therapies. Here we show that H2NTF, a novel Nterminalfragment of HER2, is expressed at variable levels in 60% of the breast cancer samples analyzed. Despite this high frequency, none of the cell lines analyzed express the fragment at detectable levels, while HER2-derived patient-derived xenografts (PDX)present H2NTF expression. H2NTF was isolated and the C-termini of the fragment was identified by mass spectrometry, being located at the kinase domain. Characterization of H2NTF shows that it is devoid of the tyrosine kinase domain but it readily interacts with full-length HER2 and other HER receptors. As a consequence, H2NTF acts as a dominant negative, attenuating the signaling triggered by full-length HER receptors. Expression of H2NTF results in resistance to the treatment with low concentrations of trastuzumab in vitro. However, cells expressing H2NTF and non-expressing cells have similar sensitivity to trastuzumab in vivo, likely because H2NTF/trastuzumab complexes trigger antibody-dependent cell-mediated cytotoxicity. 22 23
O-08 MITOTIC ARREST DOWN-REGULATES FLIP EXPRESSION AND SENSITIZES TUMOR CELLS TO THE EXTRINSIC PATHWAY OF APOPTOSIS SÁNCHEZ-PÉREZ T 1 , MEDEMA RH 2 , LÓPEZ RIVAS A 1 1 CENTRO ANDALUZ DE BIOLOGÍA MOLECULAR Y MEDICINA REGENERATIVA (CABIMER), SEVILLA (RD06-0020-0068) 2 NETHERLANDS CANCER INSTITUTE, NETHERLANDS Cell cycle deregulation is a feature of tumor cells. Most of the current therapeutic strategies are based on the perturbation of the cell cycle, especially during mitosis. “Anti-mitotic drugs” target different mitotic proteins impeding the proper assembly of the mitotic spindle which triggers mitotic checkpoint activation, mitotic arrest and eventually cell death. However, after several hours of mitotic arrest, cells may exit mitosis by “slippage”. This failure to die during mitotic arrest seems to be the main mechanism of resistance to these treatments. We have observed that mitotic arrest-induced by these treatments causes the down-regulation of the anti-apoptotic protein FLIP and consequently, a sensitization to TRAIL-induced apoptosis in tumor cell resistant to this ligand. Consequently, the combination of TRAIL with either of these anti-mitotic drugs is much more effective in killing tumor cells and preventing the slippage process than either of these treatments alone. Recently, in an attempt to avoid the process of slippage, targeting mitotic exit has been proposed as a better strategy to kill tumor cells. Our results demonstrate that FLIP down-regulation induced by mitotic arrest is independent of checkpoint activation. In this respect, treatments based on combination of mitotic arrestinducing regimes with TRAIL are much more effective against tumor cells. The mechanism underlying FLIP down-regulation seems to involve the CDK1/Cyclin B complex but not other mitotic kinases. Thus, the use of the CDK1 specific inhibitor RO-3306 demonstrates that FLIP levels inversely correlate with CDK1 activity in mitosis. In contrast, the use of a specific inhibitor of Plk-1 does not block FLIP down-regulation during mitotic arrest. Collectively, our results indicate that mitotic arrest sensitizes tumor cells to the extrinsic pathway of apoptosis by down-regulating FLIP expression and highlight the potential therapeutic benefit of the combination of mitotic exit-inhibiting treatments and TRAIL against tumor cells. O-09 MICRORNA-BASED THERAPY FOR HIGH-RISK NEUROBLASTOMA SORIANO A 1 , JUBIERRE L 1 , ROMA J 1 , REVENTÓS J 2 , GALLEGO S 1 , SEGURA MF 1 , SÁNCHEZ DE TOLEDO J 1 1 VALL D’HEBRON INSTITUT DE RECERCA (VHIR), BARCELONA (RD06/0020/1021) 2 VALL D’HEBRON INSTITUT DE RECERCA (VHIR), BARCELONA (RD06/0020/0058) Neuroblastoma (NBL) is a neoplasm of the sympathetic nervous system, and is the most common solid tumor in infants. Furthermore, it accounts for 8% to 10% of all childhood cancers and approximately 15% of cancer deaths in children. Neuroblastomas are very heterogeneous, with prognosis ranging from spontaneous regression to aggressive clinical course, and often become refractory to all current forms of treatment. Patients are assigned to three different risk groups. Overall survival for low-risk patients is excellent. Minimal intervention is required and sometimes only surgery alone suffices. Intermediate-risk patients generally have good prognosis and are treated with surgery and standard chemotherapy. However, high-risk patients have poor prognosis and need intense chemotherapy. Despite the aggressive treatment, only 30-40% of patients will be cured. Acquired drug resistance is often characterized by multiple drug resistance (MDR) defined as coinstantaneous existing resistance to several structurally and functionally different drugs and composed of diverse cellular factors and signal transduction pathways such as the DNA Damage Response process. Owing to the multiple different mechanisms that lead to NBL chemoresistance, targeting single components of a pathway may not suffice to restore chemosensitivity. In this respect, it is desirable to find molecules that can regulate multiple cellular processes, thereby overcoming MDR and improving the therapeutic response. In this project, we intend to use a new type of epigenetic regulators (microRNAs) to target the oncogenic properties of MDR neuroblastomas and render them vulnerable to the currently used chemotherapeutic drugs. We have found a substantial number of genes implicated in the DNA Damage Response deregulated in high-risk NBL. Bioinformatic analysis revealed that most of them can be potentially regulated by microR- NAs. Functional analysis in chemoresistant NBL cell lines identified several microRNAs that regulate proliferation and sensitivity to the chemotherapeutic drug melphalan. These microRNAs are promising candidates for NBL therapy. 24 25
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