Agullo-Ortuno M.T.,Hospital Universitario 12 Of Octubre |
Lopez-Rios F.,Hospital Universitario Madrid Sanchinarro |
Paz-Ares L.,Hospital Universitario Virgen Del Rocio
Journal of Thoracic Oncology | Year: 2010
Background: Lung cancer (LC) is the dominant cause of death by cancer in the world, being responsible for more than a million deaths annually. It is a highly lethal common tumor that is frequently diagnosed in advanced stages for which effective alternative therapeutics do not exist. In view of this, there is an urgent need to improve the diagnostic, prognostic, and therapeutic classification systems, currently based on clinicopathological criteria that do not adequately translate the enormous biologic complexity of this disease. Methods: The advent of the human genome sequencing project and the concurrent development of many genomic-based technologies have allowed scientists to explore the possibility of using expression profiles to identify homogenous tumor subtypes, new prognostic factors of human cancer, response to a particular treatment, etc. and thereby select the best possible therapies while decreasing the risk of toxicities for the patients. Therefore, it is becoming increasingly important to identify the complete catalog of genes that are altered in cancer and to discriminate tumors accurately on the basis of their genetic background. Results and Discussion: In this article, we present some of the works that has applied high-throughput technologies to LC research. In addition, we will give an overview of recent results in the field of LC genomics, with their effect on patient care, and discuss challenges and the potential future developments of this area. Copyright © 2010 by the International Association for the Study of Lung Cancer.
Rodriguez-Nieto S.,Genes and Cancer Group |
Canada A.,Bioinformatics Unit |
Pros E.,Genes and Cancer Group |
Pinto A.I.,Genes and Cancer Group |
And 6 more authors.
Human Mutation | Year: 2011
The tumor suppressor gene, SMARCA4 (or BRG1), which encodes the ATPase component of the chromatin remodeling complex SWI/SNF, is commonly inactivated by mutations and deletions in lung cancer cell lines. However, SMARCA4 alterations appear to be rare in lung primary tumors. Ultra-deep sequencing technologies provide a promising alternative to achieve a sensitivity superior to that of current sequencing strategies. Here we used ultra-deep pyrosequencing to screen for mutations over the entire SMARCA4 coding region in 12 lung tumors without detectable BRG1 protein. While automatic-fluorescence-based sequencing detected one somatic mutation (p.K586X), the pyrosequencing revealed additional variants, thus increasing the sensitivity. One of the variants, which affected a consensus splice site, was confirmed by individual cloning of PCR products, ruling out the possibility of PCR or pyrosequencing artifacts. This mutation, confirmed to be somatic, was present at a frequency of ten percent, suggesting normal cell contamination in the tumor. Our analysis also allowed us to determine the sensitivity and to identify some limitations of the technology. In conclusion, in addition to cell lines, SMARCA4 is biallelically inactivated in a significant proportion of lung primary tumors, thereby constituting one of the most important genes contributing to the development of this type of cancer. © 2010 Wiley-Liss, Inc.
Marchetti P.,University of Rome La Sapienza |
Voltz R.,University of Cologne |
Rubio C.,Hospital Universitario Madrid Sanchinarro |
Mayeur D.,Mignot Hospital |
Kopf A.,Charite - Medical University of Berlin
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013
Early initiation of palliative care to address pain and other symptoms offers the potential to improve quality of life for patients with cancer. The approaches to implementing and delivering palliative care and pain management services vary depending on patient needs, available resources, provider training, and clinical setting. This article describes the experiences in developing programs in which the need for early palliative care or pain management services for patients with cancer was recognized. In each case, collaborative efforts, careful planning, administrative support, and ample time were needed to implement such services. To tailor services based on the available resources, different approaches were taken, including structuring of services within oncology units; creation of an integrated partnership between oncology and palliative care departments; establishment of a multidisciplinary comprehensive service; and incorporation of nurse-based pain services to address acute, chronic, and cancer pain. These examples offer insights into how to optimize delivery of services in a variety of settings with varying resources. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved.
Castillo S.D.,Bellvitge Biomedical Research Institute IDIBELL |
Matheu A.,UK National Institute for Medical Research |
Mariani N.,Bellvitge Biomedical Research Institute IDIBELL |
Carretero J.,University of Valencia |
And 3 more authors.
Cancer Research | Year: 2012
The HMG box transcription factor SOX4 involved in neuronal development is amplified and overexpressed in a subset of lung cancers, suggesting that it may be a driver oncogene. In this study, we sought to develop this hypothesis including by defining targets of SOX4 that may mediate its involvement in lung cancer. Ablating SOX4 expression in SOX4-amplified lung cancer cells revealed a gene expression signature that included genes involved in neuronal development such as PCDHB, MYB, RBP1, and TEAD2. Direct recruitment of SOX4 to gene promoters was associated with their upregulation upon ectopic overexpression of SOX4. We confirmed upregulation of the SOX4 expression signature in a panel of primary lung tumors, validating their specific response by a comparison using embryonic fibroblasts from Sox4-deficient mice. Interestingly, we found that small cell lung cancer (SCLC), a subtype of lung cancer with neuroendocrine characteristics, was generally characterized by high levels of SOX2, SOX4, and SOX11 along with the SOX4-specific gene expression signature identified. Taken together, our findings identify a functional role for SOX genes in SCLC, particularly for SOX4 and several novel targets defined in this study. ©2011 AACR.
Zimmer L.,University of Duisburg - Essen |
Barlesi F.,Aix - Marseille University |
Martinez-Garcia M.,Hospital del Mar and Cancer Research Program |
Dieras V.,University Pierre and Marie Curie |
And 15 more authors.
Clinical Cancer Research | Year: 2014
Purpose: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. Experimental Design: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. Results: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS /non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. Conclusions: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. © 2014 AACR.