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MET alterations may provide a potential biomarker to evaluate patients who will benefit from treatment with MET inhibitors. Therefore, the purpose of the present study is to investigate the utility of a liquid biopsy-based strategy to assess MET alterations in cancer patients. We analyzed MET amplification in circulating free DNA (cfDNA) from 174 patients with cancer and 49 healthy controls and demonstrated the accuracy of the analysis to detect its alteration in patients. Importantly, a significant correlation between cfDNA concentration and MET copy number (CN) in cancer patients (r = 0.57, p &lt, 10&minus, 10) was determined. Furthermore, we evaluated two approaches to detect the presence of MET on circulating tumor cells (CTCs), using the CellSearch&reg, and Parsortix systems and monitored patients under anti-EGFR treatment (n = 30) combining both cfDNA and CTCs analyses. This follow-up provides evidence for the potential of MET CN assessment when patients develop resistance to anti-EGFR therapy and a significant association between the presence of CTCs MET+ and the Overall Survival (OS) in head and neck cancer patients (P = 0.05, HR = 6.66). In conclusion, we develop specific and noninvasive assays to monitor MET status in cfDNA/CTCs and demonstrate the utility of plasma MET CN determination as a biomarker for monitoring the appearance of resistance to anti-EGFR therapy.

Trabajo de fin de grado. Grado en Medicina. Curso académico 2019-2020, Los inhibidores de la tirosina cinasa (ITC) constituyen el tratamiento de elección para los pacientes diagnosticados de leucemia mieloide crónica (LMC) en fase crónica, y tras su introducción a principios del siglo XXI se consideraba que el tratamiento había de ser indefinido ya que ensayos realizados in vitro indicaban que estos fármacos no inhibían las células “stem” leucémicas más inmaduras. Hasta el año 2010 no se consideró la posibilidad de poder retirar el tratamiento en los pacientes que conseguían mantener respuesta molecular profunda (RMP) durante un intervalo grande de tiempo. A partir de ese año se comunicaron los datos de los primeros ensayos de discontinuación de ITC en los que alrededor del 50% de pacientes que suspendían estos fármacos tras lograr alcanzar RMP eran capaces de mantener dicha respuesta, lo que evitaba la necesidad de reintroducir el tratamiento. Los factores pronósticos que presentan mayor relevancia a la hora de poder predecir el mantenimiento de respuesta molecular libre de tratamiento difieren según los diferentes ensayos clínicos, por ello, en el presente TFG se realiza un análisis observacional retrospectivo de los pacientes con LMC que han discontinuado el tratamiento con ITC en el Hospital Universitario de Salamanca. De los 152 pacientes con esta hemopatía que han recibido tratamiento con ITC, únicamente en 11 de ellos (7,2%) se ha realizado un intento de discontinuación del tratamiento. En la mayoría de los pacientes (n=8) el motivo de discontinuación fue la toxicidad de bajo grado relacionada con el ITC. Seis pacientes (54,5%) mantienen al menos respuesta molecular mayor (RMM) tras un seguimiento medio de 38,4 meses desde la retirada del ITC y 5 (45,5%) han perdido dicha respuesta, considerada el estándar para la reintroducción del ITC. Todos los pacientes que perdieron la RMM toleraron adecuadamente la reintroducción del mismo ITC que tenían previamente a la discontinuación y el 80% consiguen alcanzar al menos una segunda RMM. Los factores que han demostrado tener más importancia en nuestro estudio para predecir el éxito de la discontinuación han sido la duración del tratamiento con ITC previo a la discontinuación y el tiempo transcurrido desde la introducción del ITC hasta conseguir RMP. Dos pacientes (18,2%) presentaron síntomas del síndrome de retirada de los ITC que se resolvió sin necesidad de tratamiento en un intervalo de 4 meses.

Cancer comprises a collection of related diseases characterized by the existence of altered cellular pathways resulting in an abnormal tendency for uncontrolled growth. A broad spectrum, coordinated, and personalized approach focused on targeting diverse oncogenic pathways with low toxicity and economic natural compounds can provide a real benefit as a chemopreventive and/or treatment of this complex disease. Oleuropein, a bioactive phenolic compound mainly present in olive oil and other natural sources, has been reported to modulate several oncogenic signalling pathways. This review presents and critically discusses the available literature about the anticancer and onco-suppressive activity of oleuropein and the underlying molecular mechanisms implicated in the anticarcinogenic and therapeutic effects. The existence of limitations and the promising perspectives of research on this phenolic compound are also critically analyzed and discussed., This article is the outcome of an in-house financially non-supported study. A. Sureda was partially supported by the Spanish Ministry of Health, Social Services and Equality (CIBEROBN-B12/03/30038). A. Mocan acknowledges funding from UEFISCDI, Romania, project no. PNII-RU-TE-2014-4-1247.

PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitric oxide synthase (eNOS), enhanced levels of reactive oxygen species, and a concomitant increase in oxidized nitric oxide levels, thereby promoting the inhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 loss and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors, and they highlight the importance of PTEN S-nitrosylation in supporting cell survival and proliferation under conditions of energy deprivation., We thank Rodrick Bronson, the entire HMS Rodent Histopathology Core, and the ICR Pathology Core for technical help with the mouse histopathology and discussions concerning the project. We also thank David Carling for the generous gift of the 991 activator, Nick Leslie for the pHR-SIN-PTEN-WT and Tina Yuan for the pLV430G-oFL-T2A-eGFP vectors, Pier Paolo Pandolfi for giving us access to Pten knockout (KO) mice, and Olga Corti and Alexis Brice for providing Park2 KO mice. We thank Susanne Breitkopf and Min Yuan for help with mass spectrometry. This work was supported by grants from the NIH P01-CA120964 (J.M.A. and L.C.C.) and R01-GM041890. A.V. was funded by the Ministry of Education, Culture and Sport under the Program for Promoting and Hiring of Talent and its Employability (Subprogram for Mobility) of the Spanish Government. G.P. is funded by the ICR. Work in the D.A. lab is supported by MRC grant MC_UP_1202/1. L.C.C. owns equity in, receives compensation from, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways in cancer cells and developing drugs to inhibit such enzymes to disrupt tumor cell growth and survival. Finally, we would like to dedicate this work to the memory of Professor Chris Marshall who was an esteemed colleague and mentor, whose scientific discoveries will continue to inspire us and translate basic science into benefits for cancer patients.

BACKGROUND: Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). METHODS: TREATMENT: gefitinib 250 mg day(-1) until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. RESULTS: Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7). CONCLUSION: First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable. Yes