Publications by authors named "Joaquim Bosch-Barrera"

83 Publications

Prognostic model of long-term advanced stage (IIIB-IV) EGFR mutated non-small cell lung cancer (NSCLC) survivors using real-life data.

BMC Cancer 2021 Aug 31;21(1):977. Epub 2021 Aug 31.

Hospital Universitario Puerta de Hierro, 28222 Majadahonda, Madrid, Spain.

Background: There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to predict survival beyond 24 months.

Methods: EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model.

Results: 505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0-1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680).

Conclusions: Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients.
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http://dx.doi.org/10.1186/s12885-021-08713-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406921PMC
August 2021

Silibinin Suppresses Tumor Cell-Intrinsic Resistance to Nintedanib and Enhances Its Clinical Activity in Lung Cancer.

Cancers (Basel) 2021 Aug 19;13(16). Epub 2021 Aug 19.

Girona Biomedical Research Institute (IDIBGI), 17190 (Salt) Girona, Spain.

The anti-angiogenic agent nintedanib has been shown to prolong overall and progression-free survival in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line platinum-based chemotherapy and second-line immunotherapy. Here, we explored the molecular basis and the clinical benefit of incorporating the STAT3 inhibitor silibinin-a flavonolignan extracted from milk thistle-into nintedanib-based schedules in advanced NSCLC. First, we assessed the nature of the tumoricidal interaction between nintedanib and silibinin and the underlying relevance of STAT3 activation in a panel of human NSCLC cell lines. NSCLC cells with poorer cytotoxic responses to nintedanib exhibited a persistent, nintedanib-unresponsive activated STAT3 state, and deactivation by co-treatment with silibinin promoted synergistic cytotoxicity. Second, we tested whether silibinin could impact the lysosomal sequestration of nintedanib, a lung cancer cell-intrinsic mechanism of nintedanib resistance. Silibinin partially, but significantly, reduced the massive lysosomal entrapment of nintedanib occurring in nintedanib-refractory NSCLC cells, augmenting the ability of nintedanib to reach its intracellular targets. Third, we conducted a retrospective, observational multicenter study to determine the efficacy of incorporating an oral nutraceutical product containing silibinin in patients with NSCLC receiving a nintedanib/docetaxel combination in second- and further-line settings ( = 59). Overall response rate, defined as the combined rates of complete and partial responses, was significantly higher in the study cohort receiving silibinin supplementation (55%) than in the control cohort (22%, = 0.011). Silibinin therapy was associated with a significantly longer time to treatment failure in multivariate analysis (hazard ratio 0.43, = 0.013), despite the lack of overall survival benefit (hazard ratio 0.63, = 0.190). Molecular mechanisms dictating the cancer cell-intrinsic responsiveness to nintedanib, such as STAT3 activation and lysosomal trapping, are amenable to pharmacological intervention with silibinin. A prospective, powered clinical trial is warranted to confirm the clinical relevance of these findings in patients with advanced NSCLC.
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http://dx.doi.org/10.3390/cancers13164168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394850PMC
August 2021

Oral vinorelbine and cisplatin as first-line therapy for advanced squamous NSCLC patients: a prospective randomized international phase II study (NAVoTrial 03).

Ther Adv Med Oncol 2021 16;13:17588359211022905. Epub 2021 Jul 16.

Clinical Oncology, ICESP - Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.

Objective: The study investigated the efficacy and safety of oral vinorelbine-cisplatin (OV-CDDP) and gemcitabine-cisplatin (GEM-CDDP) in patients with squamous non-small cell lung cancer (sq-NSCLC).

Patients And Methods: This was an open-label, prospective, multicenter, international phase II study that enrolled untreated patients with advanced sq-NSCLC. Patients were randomized to receive 3-week cycles of either 60-80 mg/m OV days 1 and 8 in combination with 80 mg/m CDDP day 1 (arm A) or 1250 mg/m GEM days 1 and 8 in combination with 75 mg/m CDDP day 1 (arm B). After four cycles, patients without disease progression continued maintenance dose of OV or GEM until progression or unacceptable toxicity. The primary objective was disease control rate (DCR). Secondary objectives included progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), safety, and quality of life (QoL).

Results: A total of 114 patients with sq-NSCLC were randomized, and 113 were treated (57 in arm A and 56 in arm B). DCR was high in both arms: 73.7% (95%CI: 62.4-100.0) in arm A and 75.0% (95%CI: 63.7-100.0) in arm B. Median PFS and TTF were similar in arm A and B 4.2 and 2.8 months, and 4.3 and 3.1 months, respectively. Even though the difference was not significant, the OS was 10.2 for arm A and 8.4 months for arm B. The safety profiles were consistent with the current knowledge of adverse events. QoL results revealed an improvement in patients under OV treatment.

Conclusion: The OV-CDDP combination showed comparable efficacy to GEM-CDDP with acceptable safety profile and enhanced patients' QoL.

Trial Registration: The study was registered under EudraCT number 2012-003531-40.
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http://dx.doi.org/10.1177/17588359211022905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287271PMC
July 2021

LungBEAM: A prospective multicenter study to monitor stage IV NSCLC patients with EGFR mutations using BEAMing technology.

Cancer Med 2021 Sep 23;10(17):5878-5888. Epub 2021 Jul 23.

Medical Oncology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain.

Objectives: The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non-small cell lung cancer (NSCLC) patients treated with first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival.

Methods: Stage IV NSCLC patients with locally confirmed EGFR-TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first- or second-generation EGFR-TKI as first-line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression-free survival (PFS) event or until study completion (72-week follow-up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing.

Results: A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty-six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow-up, preceding radiologic progression with a median of 76 (interquartile ratio: 54-111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48-2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01-7.36; p < 0.001).

Conclusion: Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients.
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http://dx.doi.org/10.1002/cam4.4135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419773PMC
September 2021

Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma.

Clin Transl Oncol 2021 Jul 22. Epub 2021 Jul 22.

Medical Oncology Department, Hospital de La Santa Creu I Sant Pau, Sant Quintí, 89, 08041, Barcelona, Spain.

Background: Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations.

Methods: We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan-Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS).

Results: Median age was 58.9 years (range 42.8-81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2-3 previous treatment lines. Docetaxel was administered at 75 mg/m/3 weeks to 16 patients, at 60 mg/m to 2 patients and at 45 mg/m to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1-38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9-7.3] and the median OS 10.1 months (95% CI 5.9-14.3). The objective response rate (ORR) was 44.4% (23.7-66.8%) and the disease control rate (DCR) 72.2% (49.4-88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1-10.5) versus (vs.) 4.8 (95% CI 3.5-6.1) and a median OS of 12.3 months (95% CI 8.6-16.0) vs. 6.7 months (95% CI 3.9-9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0-6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported.

Conclusions: Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC.
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http://dx.doi.org/10.1007/s12094-021-02661-2DOI Listing
July 2021

Lung Cancer Management with Silibinin: A Historical and Translational Perspective.

Pharmaceuticals (Basel) 2021 Jun 11;14(6). Epub 2021 Jun 11.

Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain.

The flavonolignan silibinin, the major bioactive component of the silymarin extract of (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone to metastasis. First, we summarize the evidence from chemically induced primary lung tumors supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., co-mutant tumors). Forthcoming studies should take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel lung cancer-preventive and therapeutic biomolecules.
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http://dx.doi.org/10.3390/ph14060559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230811PMC
June 2021

Epidemiology, treatment, and survival in small cell lung cancer in Spain: Data from the Thoracic Tumor Registry.

PLoS One 2021 2;16(6):e0251761. Epub 2021 Jun 2.

Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.

Background: Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients retrieved from lung cancer registries is scarce.

Patients And Methods: This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed.

Results: With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8-10.2 months), with an estimated rate of 70.3% (95% CI 67.2-73.4%), 38.9% (95% CI 35.4-42.4%), and 14.8% (95% CI 11.8-17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1-2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis.

Conclusion: This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251761PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171958PMC
June 2021

Challenges and Novel Opportunities of Radiation Therapy for Brain Metastases in Non-Small Cell Lung Cancer.

Cancers (Basel) 2021 Apr 29;13(9). Epub 2021 Apr 29.

Department of Radiation Oncology and Protontherapy Unit, Clinica Universidad de Navarra, 28027 Madrid, Spain.

Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25-50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and screening, as well as the use of new systemic therapies have contributed to a more precise diagnosis and prolonged survival of lung cancer patients with more time for BMs development. In the past, most of the systemic therapies failed intracranially because of the inability to effectively cross the blood brain barrier. Some of the new targeted therapies, especially the group of tyrosine kinase inhibitors (TKIs) have shown durable CNS response. However, the use of ionizing radiation remains vital in the management of metastatic brain disease. Although a decrease in CNS-related deaths has been achieved over the past decade, many challenges arise from the need of multiple and repeated brain radiation treatments, which carry along not insignificant risks and toxicity. The combination of stereotactic radiotherapy and systemic treatments in terms of effectiveness and adverse effects, such as radionecrosis, remains a subject of ongoing investigation. This review discusses the challenges of the use of radiation therapy in NSCLC BMs in view of different systemic treatments such as chemotherapy, TKIs and immunotherapy. It also outlines the future perspectives and strategies for personalized BMs management.
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http://dx.doi.org/10.3390/cancers13092141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124815PMC
April 2021

Analysis of circulating tumour DNA to identify patients with epidermal growth factor receptor-positive non-small cell lung cancer who might benefit from sequential tyrosine kinase inhibitor treatment.

Eur J Cancer 2021 May 5;149:61-72. Epub 2021 Apr 5.

Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain. Electronic address:

Background: Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach.

Patients And Methods: A total of 830 plasma samples from 228 patients with stage IV, EGFR-positive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR).

Results: The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first- or second-generation TKIs (N = 189) with EGFR mutations in plasma at a mutant allele frequency (MAF) <7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF <7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.23-0.64 and HR = 0.22; 95% CI: 0.12-0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first- or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between low-risk or high-responder patients treated upfront with osimertinib (N = 39) and those treated under a sequential approach with osimertinib (N = 60). Median OS was not reached in both cases.

Conclusions: Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.
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http://dx.doi.org/10.1016/j.ejca.2021.02.031DOI Listing
May 2021

Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain: OSIREX-Spanish Lung Cancer Group.

BMC Cancer 2021 Mar 6;21(1):230. Epub 2021 Mar 6.

Medical Oncology Department, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.

Background: AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain.

Methods: Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016-December 2018) from 30 sites.

Primary Objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources.

Results: 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted.

Conclusion: This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events.

Trial Registration: Clinical trial registration number: NCT03790397 .
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http://dx.doi.org/10.1186/s12885-021-07922-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937205PMC
March 2021

Mimetics of extra virgin olive oil phenols with anti-cancer stem cell activity.

Aging (Albany NY) 2020 11 9;12(21):21057-21075. Epub 2020 Nov 9.

Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.

The extra virgin olive oil (EVOO) dihydroxy-phenol oleacein is a natural inhibitor of multiple metabolic and epigenetic enzymes capable of suppressing the functional traits of cancer stem cells (CSC). Here, we used a natural product-inspired drug discovery approach to identify new compounds that phenotypically mimic the anti-CSC activity of oleacein. We coupled 3D quantitative structure-activity relationship-based virtual profiling with phenotypic analysis using 3D tumorsphere formation as a gold standard for assessing the presence of CSC. Among the top 20 computationally-predicted oleacein mimetics, four fulfilled the phenotypic endpoint of specifically suppressing the tumorsphere-initiating capacity of CSC, in the absence of significant cytotoxicity against differentiated cancer cells growing in 2D cultures in the same low micromolar concentration range. Of these, 3,4-dihydrophenetyl butyrate -a lipophilic ester conjugate of the hydroxytyrosol moiety of oleacein- and -allyl-2-((5-nitrofuran-2-yl)methylene)hydrazinecarbothioamide) -an inhibitor of triosephosphate isomerase- were also highly effective at significantly reducing the proportion of aldehyde dehydrogenase (ALDH)-positive CSC-like proliferating cells. Preservation of the mTOR/DNMT binding mode of oleacein was dispensable for suppression of the ALDH-CSC functional phenotype in hydroxytyrosol-unrelated mimetics. The anti-CSC chemistry of complex EVOO phenols such as oleacein can be phenocopied through the use of mimetics capturing its physico-chemical properties.
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http://dx.doi.org/10.18632/aging.202154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695371PMC
November 2020

Comprehensive cross-platform comparison of methods for non-invasive EGFR mutation testing: results of the RING observational trial.

Mol Oncol 2021 01 13;15(1):43-56. Epub 2020 Nov 13.

Liquid Biopsy Laboratory, Biomedical Sciences Research Institute Puerta de Hierro-Majadahonda, Madrid, Spain.

Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next-generation sequencing (NGS)-based methods, three high-sensitivity PCR-based platforms, and two FDA-approved methods were compared using 72 plasma samples, from EGFR-mutant non-small-cell lung cancer (NSCLC) patients progressing on a first-line tyrosine kinase inhibitor (TKI). NGS platforms as well as high-sensitivity PCR-based methodologies showed excellent agreement for EGFR-sensitizing mutations (K = 0.80-0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86-0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false-positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.
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http://dx.doi.org/10.1002/1878-0261.12832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782072PMC
January 2021

Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A multicenter, randomized phase II study (GOAL).

Lung Cancer 2020 12 3;150:62-69. Epub 2020 Oct 3.

Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Spain. Electronic address:

Objectives: Progression-free survival (PFS) and response rate to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) varies in patients with non-small-cell lung cancer (NSCLC) driven byEGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. Low BRCA1 mRNA levels correlate with longer PFS in erlotinib-treated EGFR-mutant NSCLC patients. Since the poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, may attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve outcome in EGFR-mutant advanced NSCLC.

Materials And Methods: GOAL was a multicenter, randomized phase IB/II study performed in two countries, Spain and Mexico. Eligible patients were 18 years or older, treatment-naïve, pathologically confirmed stage IV NSCLC, with centrally confirmed EGFR mutations and measurable disease. Patients were randomly allocated (1:1) to receive gefitinib 250 mg daily or gefitinib 250 mg daily plus olaparib 200 mg three times daily in 28-day cycles. The primary endpoint was PFS. Secondary endpoints included overall survival (OS), response rate, safety and tolerability.

Results: Between September 2013, and July 2016, 182 patients underwent randomization, 91 received gefitinib and 91 received gefitinib plus olaparib. There were no differences in gender, age, smoking status, performance status, presence of bone and brain metastases or type ofEGFR mutation. Median PFS was 10.9 months (95 % CI 9.3-13.3) in the gefitinib arm and 12.8 months (95 % CI 9.1-14.7) in the gefitinib plus olaparib arm (HR 1.38, 95 % CI 1.00-1.92; p = 0.124). The most common adverse events were anemia, 78 % in gefitinib plus olaparib group, 38 % in gefitinib arm, diarrhea, 65 % and 60 %, and fatigue, 40 % and 32 %, respectively.

Conclusions: The gefitinib plus olaparib combination did not provide significant benefit over gefitinib alone. The combination's safety profile showed an increase in hematological and gastrointestinal toxicity, compared to gefitinib alone, however, no relevant adverse events were noted.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.018DOI Listing
December 2020

Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy.

Cancers (Basel) 2020 Jul 2;12(7). Epub 2020 Jul 2.

Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, Spain.

One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system's ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.
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http://dx.doi.org/10.3390/cancers12071757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409312PMC
July 2020

Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients.

J Clin Med 2020 Jun 7;9(6). Epub 2020 Jun 7.

Girona Biomedical Research Institute, 17190 Salt, Girona, Spain.

COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3-a master checkpoint regulator of inflammatory cytokine signaling and immune response-silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)-the central component of the replication/transcription machinery of SARS-CoV-2-silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.
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http://dx.doi.org/10.3390/jcm9061770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356916PMC
June 2020

The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells.

Autophagy 2021 06 25;17(6):1349-1366. Epub 2020 May 25.

Protein Kinases and Signal Transduction Laboratory, Departament De Bioquímica I Biologia Molecular and Institut De Neurociències, Universitat Autònoma De Barcelona (UAB), Barcelona, Spain.

ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increased and mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer. 4-PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATG: autophagy related; ATF4: activating transcription factor 4; Cer: ceramide; DDIT3: DNA damage inducible transcript 3; DEGS1: delta 4-desaturase, sphingolipid 1; dhCer: dihydroceramide; EIF2A: eukaryotic translation initiation factor 2 alpha; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; HSPA5: heat shock protein family A (Hsp70) member 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; NSCLC: non-small cell lung cancer; THC: Δ-tetrahydrocannabinol; TRIB3: tribbles pseudokinase 3; XBP1: X-box binding protein 1; UPR: unfolded protein response.
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http://dx.doi.org/10.1080/15548627.2020.1761651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204958PMC
June 2021

The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes.

Aging (Albany NY) 2020 03 18;12(6):4794-4814. Epub 2020 Mar 18.

Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.

SOX2 is a core pluripotency-associated transcription factor causally related to cancer initiation, aggressiveness, and drug resistance by driving the self-renewal and seeding capacity of cancer stem cells (CSC). Here, we tested the ability of the clinically proven inhibitor of the lysine-specific demethylase 1 (LSD1/KDM1A) iadademstat (ORY-100) to target SOX2-driven CSC in breast cancer. Iadademstat blocked CSC-driven mammosphere formation in breast cancer cell lines that are dependent on SOX2 expression to maintain their CSC phenotype. Iadademstat prevented the activation of an LSD1-targeted stemness-specific SOX2 enhancer in CSC-enriched 3-dimensional spheroids. Using high-throughput transcriptional data available from the METABRIC dataset, high expression of SOX2 was significantly more common in luminal-B and HER2-enriched subtypes according to PAM50 classifier and in IntClust1 (high proliferating luminal-B) and IntClust 5 (luminal-B and HER2-amplified) according to integrative clustering. Iadademstat significantly reduced mammospheres formation by CSC-like cells from a multidrug-resistant luminal-B breast cancer patient-derived xenograft but not of those from a treatment-naïve luminal-A patient. Iadademstat reduced the expression of SOX2 in luminal-B but not in luminal-A mammospheres, likely indicating a selective targeting of SOX2-driven CSC. The therapeutic relevance of targeting SOX2-driven breast CSC suggests the potential clinical use of iadademstat as an epigenetic therapy in luminal-B and HER2-positive subtypes.
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http://dx.doi.org/10.18632/aging.102887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138538PMC
March 2020

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity.

Aging (Albany NY) 2020 01 4;12(1):8-34. Epub 2020 Jan 4.

Program against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.

New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate -linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.
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http://dx.doi.org/10.18632/aging.102646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977679PMC
January 2020

The dark side of immunotherapy: challenges facing the new hope in cancer treatment.

Ann Transl Med 2019 Sep;7(Suppl 6):S183

Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia, Spain.

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http://dx.doi.org/10.21037/atm.2019.07.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789311PMC
September 2019

Hyperprogression after first dose of immunotherapy in a patient with radioresistant metastasis from nonsmall cell lung cancer.

Anticancer Drugs 2019 11;30(10):1067-1070

Girona Biomedical Research Institute (IDIBGI).

Immune checkpoint inhibitors (ICIs) represent a new standard of care for patients with advanced nonsmall cell lung cancer, improving overall survival compared with standard chemotherapy. However, a new pattern of response to ICIs characterized by accelerated tumor growth has been recently described, termed hyperprogressive disease (HPD). We report the case of a 73-year-old patient with advanced lung adenocarcinoma who developed HPD following treatment with a unique dose of atezolizumab for a skin metastasis that was refractory to chemotherapy and radiotherapy. Potential clinical biomarkers related to HPD to ICIs are reviewed.
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http://dx.doi.org/10.1097/CAD.0000000000000837DOI Listing
November 2019

Lung cancer in Spain: information from the Thoracic Tumors Registry (TTR study).

Transl Lung Cancer Res 2019 Aug;8(4):461-475

Hospital Universitario de Salamanca, Salamanca, Spain.

Background: Lung cancer remains a leading cause of cancer incidence and mortality worldwide. Although Spain contributes to global statistics related to cancer, it is difficult to discern aspects linked to clinical presentation of the disease or molecular testing. The Thoracic Tumor Registry (TTR) was created with the aim of filling this gap.

Methods: Observational cohort multicenter study performed in Spain, including patients with lung cancer or other types of thoracic tumors undergoing active treatment or palliative care only. Enrollment took place between August 2016 and December 2018. The evaluation included a review of demographic, epidemiological, clinical and molecular data.

Results: A total of 6,600 patients diagnosed with non-small cell lung cancer (NSCLC) were recruited at 56 Spanish hospitals. The mean age at diagnosis was 64 years. The majority of patients (80%) presented with advanced disease, being adenocarcinoma the most frequent histological type. Up to 86% of patients were current- or ex-smokers, with men starting to smoke earlier than women (average age 17.9 19.2 years). Sixty-seven percent of patients underwent some type of molecular testing. Mutations in and genes were found in 18% and 28% of patients, respectively.

Conclusions: Our findings suggest that the TTR study accurately describes the clinical reality of lung cancer in Spain, including useful information on smoking status as well as molecular profiling and tumor histology, and can therefore be used to drive improvements in health care. Social and political pressure to reduce tobacco consumption among the population should be reinforced, particularly among youth.
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http://dx.doi.org/10.21037/tlcr.2019.08.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749109PMC
August 2019

Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A.

Nutrients 2019 Jul 19;11(7). Epub 2019 Jul 19.

ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, 17007 Girona, Spain.

The lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a central epigenetic regulator of metabolic reprogramming in obesity-associated diseases, neurological disorders, and cancer. Here, we evaluated the ability of oleacein, a biophenol secoiridoid naturally present in extra virgin olive oil (EVOO), to target LSD1. Molecular docking and dynamic simulation approaches revealed that oleacein could target the binding site of the LSD1 cofactor flavin adenosine dinucleotide with high affinity and at low concentrations. At higher concentrations, oleacein was predicted to target the interaction of LSD1 with histone H3 and the LSD1 co-repressor (RCOR1/CoREST), likely disturbing the anchorage of LSD1 to chromatin. AlphaScreen-based in vitro assays confirmed the ability of oleacein to act as a direct inhibitor of recombinant LSD1, with an IC as low as 2.5 μmol/L. Further, oleacein fully suppressed the expression of the transcription factor SOX2 (SEX determining Region Y-box 2) in cancer stem-like and induced pluripotent stem (iPS) cells, which specifically occurs under the control of an LSD1-targeted distal enhancer. Conversely, oleacein failed to modify ectopic SOX2 overexpression driven by a constitutive promoter. Overall, our findings provide the first evidence that EVOO contains a naturally occurring phenolic inhibitor of LSD1, and support the use of oleacein as a template to design new secoiridoid-based LSD1 inhibitors.
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http://dx.doi.org/10.3390/nu11071656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683035PMC
July 2019

Revisiting silibinin as a novobiocin-like Hsp90 C-terminal inhibitor: Computational modeling and experimental validation.

Food Chem Toxicol 2019 Oct 26;132:110645. Epub 2019 Jun 26.

ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain; Girona Biomedical Research Institute (IDIBGI), Girona, Spain. Electronic address:

The flavonolignan silibinin is the major component of the extract isolated from the seeds of the milk thistle (Silybum marianum). Herein, we performed an in silico analysis focusing on the molecular docking of the putative atomic interactions between silibinin and heat shock protein 90 (Hsp90), an adenosine triphosphate-dependent molecular chaperone differentially expressed in response to microenvironmental stress. Time-resolved fluorescence resonance energy transfer was employed to measure the capacity of silibinin to inhibit Hsp90 binding to other co-chaperones with enzymatic activity. Whereas silibinin is predicted to interact with several pockets in the C-terminal domain (CTD) of Hsp90α and β, its highest-ranking docked poses significantly overlap with those of novobiocin, a well-characterized Hsp90 CTD-targeting inhibitor. The net biochemical effect of silibinin was to inhibit the efficiency of Hsp90α/β CTD binding to its co-chaperone PPID/cyclophilin D in the low millimolar range, equivalent to that observed for novobiocin. The hepatotoxicant behavior of silibinin solely occurred at concentrations several thousand times higher than those of the Hsp90 N-terminal inhibitor geldanamycin. Silibinin might be viewed as a non-hepatotoxic, novobiocin-like Hsp90 inhibitor that binds the CTD to induce changes in Hsp90 conformation and alter Hsp90-co-chaperone-client interactions, thereby providing new paths to developing safe and efficacious Hsp90 inhibitors.
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http://dx.doi.org/10.1016/j.fct.2019.110645DOI Listing
October 2019

Computational de-orphanization of the olive oil biophenol oleacein: Discovery of new metabolic and epigenetic targets.

Food Chem Toxicol 2019 Sep 29;131:110529. Epub 2019 May 29.

ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Spain; Girona Biomedical Research Institute (IDIBGI), Girona, Spain. Electronic address:

The health promoting effects of extra virgin olive oil (EVOO) relate to its unique repertoire of phenolic compounds. Here, we used a chemoinformatics approach to computationally identify endogenous ligands and assign putative biomolecular targets to oleacein, one of the most abundant secoiridoids in EVOO. Using a structure-based virtual profiling software tool and reference databases containing more than 9000 binding sites protein cavities, we identified 996 putative oleacein targets involving more than 700 proteins. We subsequently identified the high-level functions of oleacein in terms of biomolecular interactions, signaling pathways, and protein-protein interaction (PPI) networks. Delineation of the oleacein target landscape revealed that the most significant modules affected by oleacein were associated with metabolic processes (e.g., glucose and lipid metabolism) and chromatin-modifying enzymatic activities (i.e., histone post-translational modifications). We experimentally confirmed that, in a low-micromolar physiological range (<20 μmol/l), oleacein was capable of inhibiting the catalytic activities of predicted metabolic and epigenetic targets including nicotinamide N-methyltransferase, ATP-citrate lyase, lysine-specific demethylase 6A, and N-methyltransferase 4. Our computational de-orphanization of oleacein provides new mechanisms through which EVOO biophenols might operate as chemical prototypes capable of modulating the biologic machinery of healthy aging.
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http://dx.doi.org/10.1016/j.fct.2019.05.037DOI Listing
September 2019

Correction: Monitoring -T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer.

Oncotarget 2019 04 2;10(26):2576. Epub 2019 Apr 2.

Molecular Biology Laboratory of Cancer Dr. Rosell, Can Ruti Campus: Institute Germans Trias i Pujol (IGTP), Catalan Institute of Oncology, Badalona, Spain.

[This corrects the article DOI: 10.18632/oncotarget.25478.].
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http://dx.doi.org/10.18632/oncotarget.26855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493461PMC
April 2019

The extra virgin olive oil phenolic oleacein is a dual substrate-inhibitor of catechol-O-methyltransferase.

Food Chem Toxicol 2019 Jun 29;128:35-45. Epub 2019 Mar 29.

ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Spain; Girona Biomedical Research Institute (IDIBGI), Girona, Spain. Electronic address:

Catechol-containing polyphenols present in coffee and tea, while serving as excellent substrates for catechol-O-methyltransferase (COMT)-catalyzed O-methylation, can also operate as COMT inhibitors. However, little is known about the relationship between COMT and the characteristic phenolics present in extra virgin olive oil (EVOO). We here selected the EVOO dihydroxy-phenol oleacein for a computational study of COMT-driven methylation using classic molecular docking/molecular dynamics simulations and hybrid quantum mechanical/molecular mechanics, which were supported by in vitro activity studies using human COMT. Oleacein could be superimposed onto the catechol-binding site of COMT, maintaining the interactions with the atomic positions involved in methyl transfer from the S-adenosyl-L-methionine cofactor. The transition state structure for the meta-methylation in the O5 position of the oleacein benzenediol moiety was predicted to occur preferentially. Enzyme analysis of the conversion ratio of catechol to O-alkylated guaiacol confirmed the inhibitory effect of oleacein on human COMT, which remained unaltered when tested against the protein version encoded by the functional ValMet polymorphism of the COMT gene. Our study provides a theoretical determination of how EVOO dihydroxy-phenols can be metabolized via COMT. The ability of oleacein to inhibit COMT adds a new dimension to the physiological and therapeutic utility of EVOO secoiridoids.
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http://dx.doi.org/10.1016/j.fct.2019.03.049DOI Listing
June 2019

Intestinal Permeability Study of Clinically Relevant Formulations of Silibinin in Caco-2 Cell Monolayers.

Int J Mol Sci 2019 Mar 31;20(7). Epub 2019 Mar 31.

Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, Spain.

An ever-growing number of preclinical studies have investigated the tumoricidal activity of the milk thistle flavonolignan silibinin. The clinical value of silibinin as a bona fide anti-cancer therapy, however, remains uncertain with respect to its bioavailability and blood⁻brain barrier (BBB) permeability. To shed some light on the absorption and bioavailability of silibinin, we utilized the Caco-2 cell monolayer model of human intestinal absorption to evaluate the permeation properties of three different formulations of silibinin: silibinin-meglumine, a water-soluble form of silibinin complexed with the amino-sugar meglumine; silibinin-phosphatidylcholine, the phytolipid delivery system Siliphos; and Eurosil/Euromed, a milk thistle extract that is the active component of the nutraceutical Legasil with enhanced bioavailability. Our approach predicted differential mechanisms of transport and blood⁻brain barrier permeabilities between the silibinin formulations tested. Our assessment might provide valuable information about an idoneous silibinin formulation capable of reaching target cancer tissues and accounting for the observed clinical effects of silibinin, including a recently reported meaningful central nervous system activity against brain metastases.
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http://dx.doi.org/10.3390/ijms20071606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480586PMC
March 2019

Next-generation Sequencing for ALK and ROS1 Rearrangement Detection in Patients With Non-small-cell Lung Cancer: Implications of FISH-positive Patterns.

Clin Lung Cancer 2019 07 26;20(4):e421-e429. Epub 2019 Feb 26.

Pathology Department, Hospital del Mar, Barcelona, Spain; Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. Electronic address:

Background: Detection of ALK and ROS1 gene rearrangements in non-small-cell lung cancer is required for directing patient care. Although fluorescence in situ hybridization (FISH) and immunohistochemistry have been established as gold standard methods, next-generation sequencing (NGS) platforms are called to be at least equally successful. Comparison of these methods for translation into daily use is currently under investigation.

Patients And Methods: Forty non-small-cell lung cancer paraffin-embedded samples with previous ALK (n = 33) and ROS1 (n = 7) FISH results were examined with the Oncomine Focus Assay and tested for ALK and ROS1 immunoreactivity. Clinical implications of concurrent molecular alterations and concordance between methods were evaluated.

Results: NGS was successful in 32 (80%) cases: 25 ALK and 7 ROS1. Few concomitant alterations were detected: 1 ALK rearranged case had an ALK p.L1196M-resistant mutation, 4 had CDK4, MYC, and/or ALK amplifications, and 1 ROS1 rearranged case showed a FGFR4 amplification. Comparison between techniques revealed 5 (16%) discordant cases that had lower progression-free survival than concordant cases: 7.6 (95% confidence interval, 2.2-13) versus 19.4 (95% confidence interval, 10.1-28.6). Remarkably, 4 of these cases had isolated 3' signal FISH pattern (P = .026).

Conclusion: Our data support that the identification of 3' isolated signal FISH pattern in ALK and ROS1 cases might suggest a false-positive result. NGS seems a reliable technique to assess ALK and ROS1 rearrangements, offering the advantage over immunohistochemistry of detecting other molecular alterations with potential therapeutic implications.
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http://dx.doi.org/10.1016/j.cllc.2019.02.008DOI Listing
July 2019

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation.

Front Endocrinol (Lausanne) 2018 6;9:657. Epub 2018 Nov 6.

ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.

Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD hydrolysis product ADP-ribose, a "C-pocket"-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD . Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits maintenance of SIRT1 activity during the aging process when NAD levels decline.
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http://dx.doi.org/10.3389/fendo.2018.00657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232372PMC
November 2018

An olive oil phenolic is a new chemotype of mutant isocitrate dehydrogenase 1 (IDH1) inhibitors.

Carcinogenesis 2019 03;40(1):27-40

Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain.

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene confer an oncogenic gain-of-function activity that allows the conversion of α-ketoglutarate (α-KG) to the oncometabolite R-2-hydroxyglutarate (2HG). The accumulation of 2HG inhibits α-KG-dependent histone and DNA demethylases, thereby generating genome-wide hypermethylation phenotypes with cancer-initiating properties. Several chemotypes of mutant IDH1/2-targeted inhibitors have been reported, and some of them are under evaluation in clinical trials. However, the recognition of acquired resistance to such inhibitors within a few years of clinical use raises an urgent need to discover new mutant IDH1 antagonists. Here, we report that a naturally occurring phenolic compound in extra-virgin olive oil (EVOO) selectively inhibits the production of 2HG by neomorphic IDH1 mutations. In silico docking, molecular dynamics, including steered simulations, predicted the ability of the oleoside decarboxymethyl oleuropein aglycone (DOA) to preferentially occupy the allosteric pocket of mutant IDH1. DOA inhibited the enzymatic activity of recombinant mutant IDH1 (R132H) protein in the low micromolar range, whereas >10-fold higher concentrations were required to inhibit the activity of wild-type (WT) IDH1. DOA suppressed 2HG overproduction in engineered human cells expressing a heterozygous IDH1-R132H mutation. DOA restored the 2HG-suppressed activity of histone demethylases as it fully reversed the hypermethylation of H3K9me3 in IDH1-mutant cells. DOA epigenetically restored the expression of PD-L1, an immunosuppressive gene silenced in IDH1 mutant cells via 2HG-driven DNA hypermethylation. DOA selectively blocked colony formation of IDH1 mutant cells while sparing WT IDH1 isogenic counterparts. In sum, the EVOO-derived oleoside DOA is a new, naturally occurring chemotype of mutant IDH1 inhibitors.
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http://dx.doi.org/10.1093/carcin/bgy159DOI Listing
March 2019
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