Oncological translational research in the Spanish national health system: the INTRO study

Under the auspices of the Foundation for Excellence and Quality in Oncology (ECO), the Translational Research in Oncology Medical Services Study (INTRO) was conducted with the aim of describing the current state of, and future expectations for translational cancer research in Spanish medical centres. The first step in the investigation was intended to analyse the current condition of the national Medical Oncology Services network by examining different aspects of the oncology research field. A descriptive and observational multicentre study was performed at a statewide level; information was collected by surveying a cross-section of all those responsible for Medical Oncology Services in Spain. The survey was completed by key informants, who were selected independently by each service, between September 2010 and April 2011. We were able to gather comprehensive data from a total of 27 Spanish hospitals. These data enabled us to describe the allocation of human and material resources devoted to clinical and translational research across the Medical Oncology Services and to describe the organisational and functional components of these services and units. These data included information pertaining to the activities developed, their funding sources, and their functional dependence on other internal or external bodies. Finally, we explored the degree of dissemination and use of some specific techniques used for the genetic diagnosis of cancer, which have recently been introduced in Medical Oncology within the Spanish healthcare system. A wide range of variability exists between different oncology services in Spanish hospitals. Time should be spent reflecting on the need and opportunities for improvement in the development of translational research within the field of oncology.Caballero, C.; Jantus-Lewintre, E.; Carrato, A.; García Foncillas, J.; Gascon, P.; Blasco, A.; Moreno Nogueira, JA.... (2014). Oncological translational research in the Spanish national health system: the INTRO study. Clinical and Translational Oncology. 16(8):686-695. doi:10.1007/s12094-013-1138-6S686695168Díaz-Rubio E. Translational research in clinical oncology: challenges and opportunities. Farm Hosp. 2010;34(Supl.1):1–7.Marincola FM. Translational medicine: a two-way road. J Transl Med. 2003;1(1):1.Ablin RJ, Marincola FM, Natali PG. The “excellence in translational medicine” and “bedside-to-bench” awards 2008–09. J Transl Med. 2010;13(8):95.García-Sáenz JA, Bueno C, SanPedro T, Díaz-Rubio E. La nueva oncología médica: aportación de la biología molecular al diagnóstico y tratamiento del cáncer. In: Díaz-Rubio E, editor. Tomo IV. Madrid: You and Us; 2006. p. 1–24.ORDEN SCO/709/2002, Boletín Oficial del Estado, 3 de abril de 2003, núm. 80, pp. 12742–12746. http://www.boe.es/boe/dias/2002/04/03/pdfs/A12742-12746.pdf . Accessed 30 sept 2013.Soto-Martínez JL, Baselga-Torres J, Carrato-Mena A. La investigación Translacional en Oncología Médica. En Primer Libro blanco de la Oncología Médica en España. Dosier 2006. Madrid: Editorial Dispublic SL; 2007. p. 177–99.Ministerio de Sanidad y Consumo. Agencia de Calidad del Sistema Nacional de Salud. Estrategia en Cáncer del Sistema Nacional de Salud. 2006. http://www.msc.es/organizacion/ sns/planCalidadSNS/docs/estratCancerSNS.pdf. Accessed 30 sept 2013.Lenfant C. Shattuck lecture–clinical research to clinical practice-lost in translation? N Engl J Med. 2003;349(9):868–74.Laurence J. Translating translational research. Transl Res. 2006;148(1):1–3.Lemieux-Charles L, McGuire WL. What do we know about health care team effectiveness? A review of the literature. Med Care Res Rev. 2006;63(3):263–300.Oandasan I, Baker RG, Barker K, Bosco C, D’Amour D, Jones L, et al. Teamwork in health care: promoting effective teamwork in healthcare in Canada; policy synthesis and recommendations. June 2006. http://www.chsrf.ca/Migrated/PDF/teamwork-synthesis-report_e.pdf . Accessed 30 Sep 2013.Mankoff SP, Brander C, Ferrone S, Marincola FM. Lost in Translation: obstacles to translational medicine. J Transl Med. 2004;2(1):14.Curran T. Lost in translation: the future of cancer research? Clin Cancer Res. 2005;11(13):4644.Valladares Y. Memoria y actas del primer congreso de investigación sobre el cáncer en España. Madrid; 1983.Vicente J. Apuntes para una historia de la Oncología en España. Los orígenes. Oncología. 2000;23(7):310–7.Legido-Quigley H, Otero L, la Parra D, Alvarez-Dardet C, Martin-Moreno JM, McKee M. Will austerity cuts dismantle the Spanish healthcare system? BMJ. 2013;13(346):f2363

Identification of novel synthetic lethal vulnerability in non small cell lung cancer by co targeting TMPRSS4 and DDR1

Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4

Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas

Abstract: Background: Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. Nevertheless, the molecular consequences of numerous genetic alterations still remain unclear. Methods: To identify novel genes implicated in HNSCC pathogenesis, we analyzed the genomic alterations present in five HNSCC-derived cell lines by array CGH, and compared high level focal gene amplifications with gene expression levels to identify genes whose expression is directly impacted by these genetic events. Next, we knocked down TRPC6, one of the most highly amplified and over-expressed genes, to characterize the biological roles of TRPC6 in carcinogenesis. Finally, real time PCR was performed to determine TRPC6 gene dosage and mRNA levels in normal mucosa and human HNSCC tissues. Results: The data showed that the HNSCC-derived cell lines carry most of the recurrent genomic abnormalities previously described in primary tumors. High-level genomic amplifications were found at four chromosomal sites (11q21-q22.2, 18p11.31-p11.21, 19p13.2-p13.13, and 21q11) with associated gene expression changes in selective candidate genes suggesting that they may play an important role in the malignant behavior of HNSCC. One of the most dramatic alterations of gene transcription involved the TRPC6 gene (located at 11q21-q22.2) which has been recently implicated in tumour invasiveness. siRNA-induced knockdown of TRPC6 expression in HNSCC-derived cells dramatically inhibited HNSCC-cell invasion but did not significantly alter cell proliferation. Importantly, amplification and concomitant overexpression of TRPC6 was also found in HNSCC tumour samples. Conclusions: Altogether, these data show that TRPC6 is likely to be a target for 11q21-22.2 amplification that confers enhanced invasive behavior to HNSCC cells. Therefore, TRPC6 may be a promising therapeutic target in the treatment of HNSCC.This work was supported by Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria [FIS PI11/929 to M.-D.C and C. S.]; Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0015] Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF); and Obra Social CajAstur-Instituto Universitario de Oncologia del Principado de Asturias.Bernaldo De Quirós, S.; Merlo, A.; Secades, P.; Zambrano, I.; Saenz De Santa María, I.; Ugidos, N.; Jantus Lewintre, E.... (2013). Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas. 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Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB)

Precision medicine was born with the development of new diagnostic techniques and targeted drugs, yielding better outcomes in cancer care. With the evolution and increasing sensitivity for detecting oncogenic drivers, liquid biopsies (LBs), specifically cell-free DNA (cfDNA) analysis, have been proposed as a minimally-invasive technique for genomic profiling. Ranging from sequencing techniques to PCR-based methods and other more complex strategies, this approach, currently applicable in some solid tumors with robust evidence, is showing promising opportunities in other cancers. However, difficulties in validating their clinical utility exist within limitation at different levels among several techniques, reporting of the results, lack of appropriate clinical trial designs, and unknown economic impact. One of the aims of the ISLB is to create recommendations to develop reliable and sustainable diagnostic, prognostic and predictive tools using LBs. This paper is addressing these objectives, helping the healthcare providers and scientific community to understand the potential of LB

Challenges and opportunities of cfDNA analysis implementation in clinical practice : perspective of the International Society of Liquid Biopsy (ISLB)

Precision medicine was born with the development of new diagnostic techniques and targeted drugs, yielding better outcomes in cancer care. With the evolution and increasing sensitivity for detecting oncogenic drivers, liquid biopsies (LBs), specifically cell-free DNA (cfDNA) analysis, have been proposed as a minimally-invasive technique for genomic profiling. Ranging from sequencing techniques to PCR-based methods and other more complex strategies, this approach, currently applicable in some solid tumors with robust evidence, is showing promising opportunities in other cancers. However, difficulties in validating their clinical utility exist within limitation at different levels among several techniques, reporting of the results, lack of appropriate clinical trial designs, and unknown economic impact. One of the aims of the ISLB is to create recommendations to develop reliable and sustainable diagnostic, prognostic and predictive tools using LBs. This paper is addressing these objectives, helping the healthcare providers and scientific community to understand the potential of LB

TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients

Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification of NSCLC patients and their associated prognosis, but molecular biomarkers could improve the heterogeneous outcomes found within each stage. Here, using two independent cohorts (MDA and CIMA-CUN) and the eighth TNM classification, we show that TMPRSS4 protein expression is an independent prognostic factor in NSCLC, particularly for patients at stage I: relapse-free survival (RFS) HR, 2.42 (95% CI, 1.47–3.99), p < 0.001; overall survival (OS) HR, 1.99 (95% CI, 1.25–3.16), p = 0.004). In stage IA, high levels of this protein remained associated with worse prognosis (p = 0.002 for RFS and p = 0.001 for OS). As TMPRSS4 expression is epigenetically regulated, methylation status could be used in circulating tumor DNA from liquid biopsies to monitor patients. We developed a digital droplet PCR (ddPCR) method to quantify absolute copy numbers of methylated and unmethylated CpGs within the TMPRSS4 and SHOX2 (as control) promoters in plasma and bronchoalveolar lavage (BAL) samples. In case-control studies, we demonstrated that TMPRSS4 hypomethylation can be used as a diagnostic tool in early stages, with an AUROC of 0.72 (p = 0.008; 91% specificity and 52% sensitivity) for BAL and 0.73 (p = 0.015; 65% specificity and 90% sensitivity) for plasma, in early stages. In conclusion, TMPRSS4 protein expression can be used to stratify patients at high risk of relapse/death in very early stages NSCLC patients. Moreover, analysis of TMPRSS4 methylation status by ddPCR in blood and BAL is feasible and could serve as a non-invasive biomarker to monitor surgically resected patients

Cancer epigenetic biomarkers in liquid biopsy for high incidence malignancies

Simple Summary Apart from genetic changes, cancer is characterized by epigenetic alterations, which indicate modifications in the DNA (such as DNA methylation) and histones (such as methylation and acetylation), as well as gene expression regulation by non-coding (nc)RNAs. These changes can be used in biological fluids (liquid biopsies) for diagnosis, prognosis and prediction of cancer drug response. Although these alterations are not widely used as biomarkers in the clinical practice yet, increasing number of commercial kits and clinical trials are expected to prove that epigenetic changes are able to offer valuable information for cancer patients. Early alterations in cancer include the deregulation of epigenetic events such as changes in DNA methylation and abnormal levels of non-coding (nc)RNAs. Although these changes can be identified in tumors, alternative sources of samples may offer advantages over tissue biopsies. Because tumors shed DNA, RNA, and proteins, biological fluids containing these molecules can accurately reflect alterations found in cancer cells, not only coming from the primary tumor, but also from metastasis and from the tumor microenvironment (TME). Depending on the type of cancer, biological fluids encompass blood, urine, cerebrospinal fluid, and saliva, among others. Such samples are named with the general term "liquid biopsy" (LB)

Cancer epigenetic biomarkers in liquid biopsy for high incidence malignancies

Simple Summary Apart from genetic changes, cancer is characterized by epigenetic alterations, which indicate modifications in the DNA (such as DNA methylation) and histones (such as methylation and acetylation), as well as gene expression regulation by non-coding (nc)RNAs. These changes can be used in biological fluids (liquid biopsies) for diagnosis, prognosis and prediction of cancer drug response. Although these alterations are not widely used as biomarkers in the clinical practice yet, increasing number of commercial kits and clinical trials are expected to prove that epigenetic changes are able to offer valuable information for cancer patients. Early alterations in cancer include the deregulation of epigenetic events such as changes in DNA methylation and abnormal levels of non-coding (nc)RNAs. Although these changes can be identified in tumors, alternative sources of samples may offer advantages over tissue biopsies. Because tumors shed DNA, RNA, and proteins, biological fluids containing these molecules can accurately reflect alterations found in cancer cells, not only coming from the primary tumor, but also from metastasis and from the tumor microenvironment (TME). Depending on the type of cancer, biological fluids encompass blood, urine, cerebrospinal fluid, and saliva, among others. Such samples are named with the general term "liquid biopsy" (LB)