Papel del eje de señalizacion SET/PP2A y su desregulación mediada por microRNAs en el desarrollo del cáncer colorectal : Potencial impacto clínico y terapéutico

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 26-05-201

Activation of MET pathway predicts poor outcome to cetuximab in patients with recurrent or metastatic head and neck cancer

Background: Activation of the MET oncogene promotes tumor growth, invasion and metastasis in several tumor types. Additionally, MET is activated as a compensatory pathway in the presence of EGFR blockade, thus resulting in a mechanism of resistance to EGFR inhibitors. Methods: We have investigated the impact of HGF and MET expression, MET activation (phosphorylation), MET gene status, and MET-activating mutations on cetuximab sensitivity in recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) patients. Results: A single-institution retrospective analysis was performed in 57 patients. MET overexpression was detected in 58 % patients, MET amplification in 39 % and MET activation (p-MET) in 30 %. Amplification was associated with MET overexpression. Log-rank testing showed significantly worse outcomes in recurrent/metastatic, MET overexpressing patients for progression-free survival and overall survival. Activation of MET was correlated with worse PFS and OS. In multivariate logistic regression analysis, p-MET was an independent prognostic factor for PFS. HGF overexpression was observed in 58 % patients and was associated with MET phosphorylation, suggesting a paracrine activation of the receptor. Conclusions: HGF/MET pathway activation correlated with worse outcome in recurrent/metastatic HNSCC patients. When treated with a cetuximab-based regimen, these patients correlated with worse outcome. This supports a dual blocking strategy of HGF/MET and EGFR pathways for the treatment of patients with recurrent/metastatic HNSCCThe present work was supported by grants from the Spanish Ministerio de Economia y Competitividad (MINECO) (AES Program, grant PI12/01552); the Ministerio de Sanidad (Cancer Network); the Comunidad de Madrid (S2010/BMD-2344). The Fundacion Jimenez Diaz Biobank is funded by a grant from the MINECO (Instituto de Salud Carlos III, RETICS Red de Biobancos, with FEDER funds, RD09/0076/00101). S.Z. and C.C. are supported by grants from the same Biobanks initiativ

The role of shared decision-making in personalised medicine: opening the debate

Surgeons and cancer patients are starting to open the debate on how personalised medicine could use shared decision-making (SDM) to balance the personal and clinical components and thus improve the quality and value of care. Personalised precision medicine (PPM) has traditionally focused on the use of genomic information when prescribing treatments, which are usually phar-maceutical. However, the knowledge base is considerably scarcer in terms of how clinicians can individualise the information they provide patients about the consequences of different treatments, and in doing so involve them in the decision-making process. To achieve this, the ethical implications of SDM must be addressed from both sides. This paper explores the medical characteristics, the SDM implications in severe and fragile patients, potential risks, and observed benefits within this healthcare approach through four clinical cases. Findings shed light on current needs for clinician and patient training and tools related to SDM in PPM, and also remarks on the way in which this shift in healthcare settings is taking place to include the human component together with the biological and technological advances when designing care processes in colorectal cancerThis research was funded by the Spanish Ministry of Science and innovation, and Institute of Health Carlos III, grant number PI21/02011 to O.L.-F. The APC was funded by the Quirónsalud Award 2021, category ‘Quality of Care’ for the project ‘Informed Consent 2.0.: study of the impact of shared decision-making mediated by an app between the cancer patient and the surgeon’ developed by the first, second, and last author

Elaboración del curso “Laboratorio de Física Cuántica” en la plataforma iTunes U de la Universidad de Salamanca

Memoria ID-0301. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2014-2015

Functional and clinical impact of circRNas in oral cancer

The increasing number of recently published works regarding the role of circular RNAs (circRNAs) in oral cancer highlights the key contribution of this novel class of endogenous noncoding RNAs as regulators of critical signaling pathways and their clinical value as novel biomarkers. This review summarizes and puts into context the existing literature in order to clarify the relevance of circRNAs as novel mediators of oral cancer pathogenesis as well as their potential usefulness as predictors of clinical outcome and response to therapy in this disease.This research was funded by PI18/00382 and PI16/01468 grants from Instituto de Salud Carlos III FEDE

Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer

The tumor suppressor microRNA-199b (miR-199b) is a negative SET regulator associated with poor outcome in some human cancers. However, its expression levels as well as potential biological and clinical significance in colorectal cancer (CRC) remain completely unexplored. The PP2A inhibitor SET has shown promising therapeutic and clinical implications in metastatic CRC (mCRC) but the molecular mechanisms underlying SET deregulation are currently unknown. We show here miR-199b downregulation in 4 out of 5 CRC SET-overexpressing cell lines and its inverse correlation with SET overexpression in CRC patients. Moreover, miR-199b led to PP2A activation through a direct SET inhibition, impaired cell viability and enhanced oxaliplatin sensitivity in CRC cells. MiR-199b was found downregulated in 25% of cases, and associated with lymph metastasis (p = 0.049), presence of synchronous metastasis at diagnosis (p = 0.026) and SET overexpression (p < 0.001). Furthermore, low miR-199b levels determined shorter overall (p < 0.001), progression-free survival (p = 0.003) and predicted clinical benefit to oxaliplatin treatment. The miR-199b prognostic impact was particularly evident in both younger and KRAS wild-type subgroups. Multivariate analyses confirmed its independent prognostic impact. Altogether, our results show that miR-199b is a tumor suppressor whose downregulation independently determines worse outcome and emerges as a potential contributing mechanism to inhibit PP2A via SET overexpression in a subgroup of mCRC patient

Low microRNA-19b expression shows a promising clinical impact in locally advanced rectal cancer

The standard treatment for patients with locally advanced colorectal cancer (LARC) is neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy (CRT) followed by surgical mesorec-tal excision. However, the lack of response to this preoperative treatment strongly compromises patient outcomes and leads to surgical delays and undesired toxicities in those non-responder cases. Thus, the identification of effective and robust biomarkers to predict response to preoperative CRT represents an urgent need in the current clinical management of LARC. The oncomiR microRNA-19b (miR-19b) has been reported to functionally play oncogenic roles in colorectal cancer (CRC) cells as well as regulate 5-FU sensitivity and determine outcome in CRC patients. However, its clinical impact in LARC has not been previously investigated. Here, we show that miR-19b deregulation is a common event in this disease, and its decreased expression significantly associates with lower tumor size after CRT (p = 0.003), early pathological stage (p = 0.003), and absence of recurrence (p = 0.001) in LARC patients. Interestingly, low miR-19b expression shows a predictive value of better response to neoajuvant CRT (p &lt; 0.001), and the subgroup of LARC patients with low miR-19b levels have a markedly longer overall (p = 0.003) and event-free survival (p = 0.023). Finally, multivariate analyses determined that miR-19b independently predicts both patient outcome and response to preoperative CRT, highlighting its potential clinical usefulness in the management of LARC patientsThis research was funded by PI18/00382 and PI16/01468 grants from “Instituto de Salud Carlos III FEDER”. M.S-A. is supported by “Fundación Cristina Rábago de Jiménez Díaz

Four Decades of COPD Mortality Trends: Analysis of Trends and Multiple Causes of Death

There is little information on chronic obstructive pulmonary disease (COPD) mortality trends, age of death, or male:female ratio. This study therefore sought to analyze time trends in mortality with COPD recorded as the underlying cause of death from 1980 through 2017, and with COPD recorded other than as the underlying cause of death. We conducted an analysis of COPD deaths in Galicia (Spain) from 1980 through 2017, including those in which COPD was recorded other than as the underlying cause of death from 2015 through 2017. We calculated the crude and standardized rates, and analyzed mortality trends using joinpoint regression models. There were 43,234 COPD deaths, with a male:female ratio of 2.4. Median age of death was 82 years. A change point in the mortality trend was detected in 1996 with a significant decrease across the sexes, reflected by an annual percentage change of −3.8%. Taking deaths into account in which COPD participated or contributed without being the underlying cause led to an overall 42% increase in the mortality burden. The most frequent causes of death when COPD was not considered to be the underlying cause were bronchopulmonary neoplasms and cardiovascular diseases. COPD mortality has decreased steadily across the sexes in Galicia since 1996, and age of death has also gradually increased. Multiple-cause death analysis may help prevent the underestimation of COPD mortalityS

Validation of microrna‐199b as a promising predictor of outcome and response to neoadjuvant treatment in locally advanced rectal cancer patients

The absence of established predictive markers with value to anticipate response to neoadjuvant 5‐fluorouracil (5‐FU)‐based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)‐199b has been reported to play a key role determining 5‐FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5‐FU resistant phenotype. Moreover, miR‐199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR‐199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR‐199b expression was quantified by real‐time‐PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size (p= 0.026) and positive lymph node after CRT (p= 0.005), and higher pathological stage (p= 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT (p= 0.004). Moreover, the subgroup of cases with low miR‐199b levels had a markedly shorter overall (p< 001) and event‐free survival (p< 0.001), and multivariate analyses showed that miR‐199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence (p= 0.004). Finally, we compared miR‐199b expression profiles in a set of cases with pre and post‐treatment samples available, observing that only a minimal response leads to miR‐199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.This research was funded by PI18/00382 and PI16/01468 grants from “Instituto de Salud Carlos III FEDER”. M.S-A. is supported by a predoctoral research grant funded by “Fundación Conchita Rábago de Jiménez Díaz”

Material multimedia de apoyo al profesor en el laboratorio de Física

Memoria ID12-0194. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2012-2013