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Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.
Marina Serrano-Maciá; Jorge Simón; Maria J. González-Rellan; Mikel Azkargorta; Naroa Goikoetxea-Usandizaga; Fernando Lopitz-Otsoa; Diego Saenz De Urturi; Rubén Rodríguez-Agudo; Sofia Lachiondo-Ortega; Maria Mercado-Gomez; Virginia Gutiérrez de Juan; Maider Bizkarguenaga; David Fernández-Ramos; Xabier Buque; Guido A. Baselli; Luca V.C. Valenti; Paula Iruzubieta; Javier Crespo; Erica Villa; Jesus M. Banales; Matias A. Avila; Jose J.G. Marin; Patricia Aspichueta; James Sutherland; Rosa Barrio; Ugo Mayor; Félix Elortza; Dimitris P. Xirodimas; Rubén Nogueiras; Teresa C. Delgado; María Luz Martínez-Chantar. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via DEPTOR-mTOR axis. Molecular Metabolism 2021, 53, 101275 .
AMA StyleMarina Serrano-Maciá, Jorge Simón, Maria J. González-Rellan, Mikel Azkargorta, Naroa Goikoetxea-Usandizaga, Fernando Lopitz-Otsoa, Diego Saenz De Urturi, Rubén Rodríguez-Agudo, Sofia Lachiondo-Ortega, Maria Mercado-Gomez, Virginia Gutiérrez de Juan, Maider Bizkarguenaga, David Fernández-Ramos, Xabier Buque, Guido A. Baselli, Luca V.C. Valenti, Paula Iruzubieta, Javier Crespo, Erica Villa, Jesus M. Banales, Matias A. Avila, Jose J.G. Marin, Patricia Aspichueta, James Sutherland, Rosa Barrio, Ugo Mayor, Félix Elortza, Dimitris P. Xirodimas, Rubén Nogueiras, Teresa C. Delgado, María Luz Martínez-Chantar. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via DEPTOR-mTOR axis. Molecular Metabolism. 2021; 53 ():101275.
Chicago/Turabian StyleMarina Serrano-Maciá; Jorge Simón; Maria J. González-Rellan; Mikel Azkargorta; Naroa Goikoetxea-Usandizaga; Fernando Lopitz-Otsoa; Diego Saenz De Urturi; Rubén Rodríguez-Agudo; Sofia Lachiondo-Ortega; Maria Mercado-Gomez; Virginia Gutiérrez de Juan; Maider Bizkarguenaga; David Fernández-Ramos; Xabier Buque; Guido A. Baselli; Luca V.C. Valenti; Paula Iruzubieta; Javier Crespo; Erica Villa; Jesus M. Banales; Matias A. Avila; Jose J.G. Marin; Patricia Aspichueta; James Sutherland; Rosa Barrio; Ugo Mayor; Félix Elortza; Dimitris P. Xirodimas; Rubén Nogueiras; Teresa C. Delgado; María Luz Martínez-Chantar. 2021. "Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via DEPTOR-mTOR axis." Molecular Metabolism 53, no. : 101275.
Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 and n = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient’s overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.
Pablo Fernández-Tussy; Rubén Rodríguez-Agudo; David Fernández-Ramos; Lucía Barbier-Torres; Imanol Zubiete-Franco; Sergio López de Davalillo; Elisa Herraez; Naroa Goikoetxea-Usandizaga; Sofia Lachiondo-Ortega; Jorge Simón; Fernando Lopitz-Otsoa; Virginia Gutiérrez-De Juan; Misti V. McCain; Maria J. Perugorria; Jon Mabe; Nicolás Navasa; Cecilia M. P. Rodrigues; Isabel Fabregat; Loreto Boix; Victor Sapena; Juan Anguita; Shelly C. Lu; José M. Mato; Jesus M. Banales; Erica Villa; Helen L. Reeves; Jordi Bruix; Maria Reig; Jose J. G. Marin; Teresa C. Delgado; María L. Martínez-Chantar. Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity. Cell Death & Disease 2021, 12, 1 -16.
AMA StylePablo Fernández-Tussy, Rubén Rodríguez-Agudo, David Fernández-Ramos, Lucía Barbier-Torres, Imanol Zubiete-Franco, Sergio López de Davalillo, Elisa Herraez, Naroa Goikoetxea-Usandizaga, Sofia Lachiondo-Ortega, Jorge Simón, Fernando Lopitz-Otsoa, Virginia Gutiérrez-De Juan, Misti V. McCain, Maria J. Perugorria, Jon Mabe, Nicolás Navasa, Cecilia M. P. Rodrigues, Isabel Fabregat, Loreto Boix, Victor Sapena, Juan Anguita, Shelly C. Lu, José M. Mato, Jesus M. Banales, Erica Villa, Helen L. Reeves, Jordi Bruix, Maria Reig, Jose J. G. Marin, Teresa C. Delgado, María L. Martínez-Chantar. Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity. Cell Death & Disease. 2021; 12 (6):1-16.
Chicago/Turabian StylePablo Fernández-Tussy; Rubén Rodríguez-Agudo; David Fernández-Ramos; Lucía Barbier-Torres; Imanol Zubiete-Franco; Sergio López de Davalillo; Elisa Herraez; Naroa Goikoetxea-Usandizaga; Sofia Lachiondo-Ortega; Jorge Simón; Fernando Lopitz-Otsoa; Virginia Gutiérrez-De Juan; Misti V. McCain; Maria J. Perugorria; Jon Mabe; Nicolás Navasa; Cecilia M. P. Rodrigues; Isabel Fabregat; Loreto Boix; Victor Sapena; Juan Anguita; Shelly C. Lu; José M. Mato; Jesus M. Banales; Erica Villa; Helen L. Reeves; Jordi Bruix; Maria Reig; Jose J. G. Marin; Teresa C. Delgado; María L. Martínez-Chantar. 2021. "Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity." Cell Death & Disease 12, no. 6: 1-16.
Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent late diagnosis of this form of cancer, which makes surgical removal of the tumor impossible, together with the poor response to standard chemotherapy and targeted therapy with inhibitors of tyrosine kinase receptors. The discovery of genetic alterations with an impact on the malignant characteristics of CCA, such as proliferation, invasiveness, and the ability to generate metastases, has led to envisage to treat these patients with selective inhibitors of mutated proteins. Moreover, the hope of developing new tools to improve the dismal outcome of patients with advanced CCA also includes the use of small molecules and antibodies able to interact with proteins involved in the crosstalk between cancer and immune cells with the aim of enhancing the immune system’s attack against the tumor. The lack of effect of these new therapies in some patients with CCA is associated with the ability of tumor cells to continuously adapt to the pharmacological pressure by developing different mechanisms of resistance. However, the available information about these mechanisms for the new drugs and how they evolve is still limited.
Jose Marin; Paula Sanchon-Sanchez; Candela Cives-Losada; Sofía del Carmen; Jesús González-Santiago; Maria Monte; Rocio Macias. Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance. Cancers 2021, 13, 2358 .
AMA StyleJose Marin, Paula Sanchon-Sanchez, Candela Cives-Losada, Sofía del Carmen, Jesús González-Santiago, Maria Monte, Rocio Macias. Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance. Cancers. 2021; 13 (10):2358.
Chicago/Turabian StyleJose Marin; Paula Sanchon-Sanchez; Candela Cives-Losada; Sofía del Carmen; Jesús González-Santiago; Maria Monte; Rocio Macias. 2021. "Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance." Cancers 13, no. 10: 2358.
PURPOSE About one third of patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) will relapse. Thus, additional therapy is needed. Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor demonstrating efficacy in the metastatic setting. PATIENTS AND METHODS PENELOPE-B ( NCT01864746 ) is a double-blind, placebo‐controlled, phase III study in women with hormone receptor–positive, human epidermal growth factor receptor 2–negative primary breast cancer without a pathological complete response after taxane‐containing NACT and at high risk of relapse (clinical pathological staging-estrogen receptor grading score ≥ 3 or 2 and ypN+). Patients were randomly assigned (1:1) to receive 13 cycles of palbociclib 125 mg once daily or placebo on days 1-21 in a 28-day cycle in addition to endocrine therapy (ET). Primary end point is invasive disease-free survival (iDFS). Final analysis was planned after 290 iDFS events with a two-sided efficacy boundary P < .0463 because of two interim analyses. RESULTS One thousand two hundred fifty patients were randomly assigned. The median age was 49.0 years (range, 19-79), and the majority were ypN+ with Ki-67 ≤ 15%; 59.4% of patients had a clinical pathological staging-estrogen receptor grading score ≥ 3. 50.1% received aromatase inhibitor, and 33% of premenopausal women received a luteinizing hormone releasing hormone analog in addition to either tamoxifen or an aromatase inhibitor. After a median follow-up of 42.8 months (92% complete), 308 events were confirmed. Palbociclib did not improve iDFS versus placebo added to ET-stratified hazard ratio, 0.93 (95% repeated CI, 0.74 to 1.17) and two-sided weighted log-rank test (Cui, Hung, and Wang) P = .525. There was no difference among the subgroups. Most common related serious adverse events were infections and vascular disorders in 113 (9.1%) patients with no difference between the treatment arms. Eight fatal serious adverse events (two palbociclib and six placebo) were reported. CONCLUSION Palbociclib for 1 year in addition to ET did not improve iDFS in women with residual invasive disease after NACT.
Sibylle Loibl; Frederik Marmé; Miguel Martin; Michael Untch; Hervé Bonnefoi; Sung-Bae Kim; Harry Bear; Nicole McCarthy; Mireia Melé Olivé; Karen Gelmon; José García-Sáenz; Catherine M. Kelly; Toralf Reimer; Masakazu Toi; Hope S. Rugo; Carsten Denkert; Michael Gnant; Andreas Makris; Maria Koehler; Cynthia Huang-Bartelett; Maria Jose Lechuga Frean; Marco Colleoni; Gustavo Werutsky; Sabine Seiler; Nicole Burchardi; Valentina Nekljudova; Gunter von Minckwitz. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer—The Penelope-B Trial. Journal of Clinical Oncology 2021, 39, 1518 -1530.
AMA StyleSibylle Loibl, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Mireia Melé Olivé, Karen Gelmon, José García-Sáenz, Catherine M. Kelly, Toralf Reimer, Masakazu Toi, Hope S. Rugo, Carsten Denkert, Michael Gnant, Andreas Makris, Maria Koehler, Cynthia Huang-Bartelett, Maria Jose Lechuga Frean, Marco Colleoni, Gustavo Werutsky, Sabine Seiler, Nicole Burchardi, Valentina Nekljudova, Gunter von Minckwitz. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer—The Penelope-B Trial. Journal of Clinical Oncology. 2021; 39 (14):1518-1530.
Chicago/Turabian StyleSibylle Loibl; Frederik Marmé; Miguel Martin; Michael Untch; Hervé Bonnefoi; Sung-Bae Kim; Harry Bear; Nicole McCarthy; Mireia Melé Olivé; Karen Gelmon; José García-Sáenz; Catherine M. Kelly; Toralf Reimer; Masakazu Toi; Hope S. Rugo; Carsten Denkert; Michael Gnant; Andreas Makris; Maria Koehler; Cynthia Huang-Bartelett; Maria Jose Lechuga Frean; Marco Colleoni; Gustavo Werutsky; Sabine Seiler; Nicole Burchardi; Valentina Nekljudova; Gunter von Minckwitz. 2021. "Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer—The Penelope-B Trial." Journal of Clinical Oncology 39, no. 14: 1518-1530.
Jose Jg Marin; Rocio Ir Macias. Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs. Expert Opinion on Investigational Drugs 2021, 1 -5.
AMA StyleJose Jg Marin, Rocio Ir Macias. Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs. Expert Opinion on Investigational Drugs. 2021; ():1-5.
Chicago/Turabian StyleJose Jg Marin; Rocio Ir Macias. 2021. "Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs." Expert Opinion on Investigational Drugs , no. : 1-5.
Stephen R. D. Johnston; Nadia Harbeck; Masakazu Toi; Miguel Martin; Joyce O'Shaughnessy; Priya Rastogi. Reply to K. Hashimoto and A. Shimomura. Journal of Clinical Oncology 2021, 39, 1507 -1508.
AMA StyleStephen R. D. Johnston, Nadia Harbeck, Masakazu Toi, Miguel Martin, Joyce O'Shaughnessy, Priya Rastogi. Reply to K. Hashimoto and A. Shimomura. Journal of Clinical Oncology. 2021; 39 (13):1507-1508.
Chicago/Turabian StyleStephen R. D. Johnston; Nadia Harbeck; Masakazu Toi; Miguel Martin; Joyce O'Shaughnessy; Priya Rastogi. 2021. "Reply to K. Hashimoto and A. Shimomura." Journal of Clinical Oncology 39, no. 13: 1507-1508.
Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.
Miguel Martin; Rocio Ramos-Medina; Rebeca Bernat; Jose Angel García-Saenz; Maria del Monte-Millan; Enrique Alvarez; Maria Cebollero; Fernando Moreno; Eva Gonzalez-Haba; Oscar Bueno; Paula Romero; Tatiana Massarrah; Isabel Echavarria; Yolanda Jerez; Blanca Herrero; Ricardo Gonzalez del Val; Nerea Lobato; Patricia Rincon; Maria Isabel Palomero; Ivan Marquez-Rodas; Santiago Lizarraga; Fernando Asensio; Sara Lopez-Tarruella. Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts. Scientific Reports 2021, 11, 1 -12.
AMA StyleMiguel Martin, Rocio Ramos-Medina, Rebeca Bernat, Jose Angel García-Saenz, Maria del Monte-Millan, Enrique Alvarez, Maria Cebollero, Fernando Moreno, Eva Gonzalez-Haba, Oscar Bueno, Paula Romero, Tatiana Massarrah, Isabel Echavarria, Yolanda Jerez, Blanca Herrero, Ricardo Gonzalez del Val, Nerea Lobato, Patricia Rincon, Maria Isabel Palomero, Ivan Marquez-Rodas, Santiago Lizarraga, Fernando Asensio, Sara Lopez-Tarruella. Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts. Scientific Reports. 2021; 11 (1):1-12.
Chicago/Turabian StyleMiguel Martin; Rocio Ramos-Medina; Rebeca Bernat; Jose Angel García-Saenz; Maria del Monte-Millan; Enrique Alvarez; Maria Cebollero; Fernando Moreno; Eva Gonzalez-Haba; Oscar Bueno; Paula Romero; Tatiana Massarrah; Isabel Echavarria; Yolanda Jerez; Blanca Herrero; Ricardo Gonzalez del Val; Nerea Lobato; Patricia Rincon; Maria Isabel Palomero; Ivan Marquez-Rodas; Santiago Lizarraga; Fernando Asensio; Sara Lopez-Tarruella. 2021. "Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts." Scientific Reports 11, no. 1: 1-12.
Introduction: Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unraveling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, ‘Mesenchymal’, ‘Proliferation’, ‘Immune’, ‘Metabolic’. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified. Areas covered: We offer insights on perturbed pathways, molecular profiling, and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA. Expert opinion: eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.
Massimiliano Cadamuro; Alberto Lasagni; Angela Lamarca; Laura Fouassier; Maria Guido; Samantha Sarcognato; Enrico Gringeri; Umberto Cillo; Mario Strazzabosco; Jose Jg Marin; Jesus M Banales; Luca Fabris. Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic. Expert Opinion on Investigational Drugs 2021, 30, 377 -388.
AMA StyleMassimiliano Cadamuro, Alberto Lasagni, Angela Lamarca, Laura Fouassier, Maria Guido, Samantha Sarcognato, Enrico Gringeri, Umberto Cillo, Mario Strazzabosco, Jose Jg Marin, Jesus M Banales, Luca Fabris. Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic. Expert Opinion on Investigational Drugs. 2021; 30 (4):377-388.
Chicago/Turabian StyleMassimiliano Cadamuro; Alberto Lasagni; Angela Lamarca; Laura Fouassier; Maria Guido; Samantha Sarcognato; Enrico Gringeri; Umberto Cillo; Mario Strazzabosco; Jose Jg Marin; Jesus M Banales; Luca Fabris. 2021. "Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic." Expert Opinion on Investigational Drugs 30, no. 4: 377-388.
The constitutively active tyrosine-kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine-kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent healthy person. However, since the oncogene stays intact, lifelong oral medication is essential, even though this triggers adverse effects in many patients. Furthermore, leukemic stem cells remain quiescent and resistance is observed in approximately 25% of patients. Thus, new therapeutic alternatives are still needed. In this scenario, the interruption/deletion of the oncogenic sequence might be an effective therapeutic option. The emergence of CRISPR (clustered regularly interspaced short palindromic repeats) technology can offer a definitive treatment based on its capacity to induce a specific DNA double strand break. Besides, it has the advantage of providing complete and permanent oncogene knockout, while tyrosine kinase inhibitors (TKIs) only ensure that BCR-ABL1 oncoprotein is inactivated during treatment. CRISPR/Cas9 cuts DNA in a sequence-specific manner making it possible to turn oncogenes off in a way that was not previously feasible in humans. This review describes chronic myeloid leukemia (CML) disease and the main advances in the genome-editing field by which it may be treated in the future.
Elena Vuelta; Ignacio García-Tuñón; Patricia Hernández-Carabias; Lucía Méndez; Manuel Sánchez-Martín. Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy. Biology 2021, 10, 118 .
AMA StyleElena Vuelta, Ignacio García-Tuñón, Patricia Hernández-Carabias, Lucía Méndez, Manuel Sánchez-Martín. Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy. Biology. 2021; 10 (2):118.
Chicago/Turabian StyleElena Vuelta; Ignacio García-Tuñón; Patricia Hernández-Carabias; Lucía Méndez; Manuel Sánchez-Martín. 2021. "Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy." Biology 10, no. 2: 118.
Over the last decade, regularized regression methods have offered alternatives for performing multi-marker analysis and feature selection in a whole genome context. The process of defining a list of genes that will characterize an expression profile remains unclear. It currently relies upon advanced statistics and can use an agnostic point of view or include some a priori knowledge, but overfitting remains a problem. This paper introduces a methodology to deal with the variable selection and model estimation problems in the high-dimensional set-up, which can be particularly useful in the whole genome context. Results are validated using simulated data and a real dataset from a triple-negative breast cancer study.
Juan C. Laria; M. Carmen Aguilera-Morillo; Enrique Álvarez; Rosa E. Lillo; Sara López-Taruella; María Del Monte-Millán; Antonio C. Picornell; Miguel Martín; Juan Romo. Iterative Variable Selection for High-Dimensional Data: Prediction of Pathological Response in Triple-Negative Breast Cancer. Mathematics 2021, 9, 222 .
AMA StyleJuan C. Laria, M. Carmen Aguilera-Morillo, Enrique Álvarez, Rosa E. Lillo, Sara López-Taruella, María Del Monte-Millán, Antonio C. Picornell, Miguel Martín, Juan Romo. Iterative Variable Selection for High-Dimensional Data: Prediction of Pathological Response in Triple-Negative Breast Cancer. Mathematics. 2021; 9 (3):222.
Chicago/Turabian StyleJuan C. Laria; M. Carmen Aguilera-Morillo; Enrique Álvarez; Rosa E. Lillo; Sara López-Taruella; María Del Monte-Millán; Antonio C. Picornell; Miguel Martín; Juan Romo. 2021. "Iterative Variable Selection for High-Dimensional Data: Prediction of Pathological Response in Triple-Negative Breast Cancer." Mathematics 9, no. 3: 222.
Background Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. Patients and methods PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. Results From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). Conclusions There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.
M. Martin; C. Zielinski; M. Ruiz-Borrego; E. Carrasco; N. Turner; E.M. Ciruelos; M. Muñoz; B. Bermejo; M. Margeli; A. Anton; Z. Kahan; T. Csöszi; M.I. Casas; L. Murillo; S. Morales; E. Alba; E. Gal-Yam; A. Guerrero-Zotano; L. Calvo; J. de la Haba-Rodriguez; M. Ramos; I. Alvarez; A. Garcia-Palomo; C. Huang Bartlett; M. Koehler; R. Caballero; M. Corsaro; X. Huang; J.A. Garcia-Sáenz; J.I. Chacón; C. Swift; C. Thallinger; M. Gil-Gil. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial—PEARL. Annals of Oncology 2020, 32, 488 -499.
AMA StyleM. Martin, C. Zielinski, M. Ruiz-Borrego, E. Carrasco, N. Turner, E.M. Ciruelos, M. Muñoz, B. Bermejo, M. Margeli, A. Anton, Z. Kahan, T. Csöszi, M.I. Casas, L. Murillo, S. Morales, E. Alba, E. Gal-Yam, A. Guerrero-Zotano, L. Calvo, J. de la Haba-Rodriguez, M. Ramos, I. Alvarez, A. Garcia-Palomo, C. Huang Bartlett, M. Koehler, R. Caballero, M. Corsaro, X. Huang, J.A. Garcia-Sáenz, J.I. Chacón, C. Swift, C. Thallinger, M. Gil-Gil. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial—PEARL. Annals of Oncology. 2020; 32 (4):488-499.
Chicago/Turabian StyleM. Martin; C. Zielinski; M. Ruiz-Borrego; E. Carrasco; N. Turner; E.M. Ciruelos; M. Muñoz; B. Bermejo; M. Margeli; A. Anton; Z. Kahan; T. Csöszi; M.I. Casas; L. Murillo; S. Morales; E. Alba; E. Gal-Yam; A. Guerrero-Zotano; L. Calvo; J. de la Haba-Rodriguez; M. Ramos; I. Alvarez; A. Garcia-Palomo; C. Huang Bartlett; M. Koehler; R. Caballero; M. Corsaro; X. Huang; J.A. Garcia-Sáenz; J.I. Chacón; C. Swift; C. Thallinger; M. Gil-Gil. 2020. "Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial—PEARL." Annals of Oncology 32, no. 4: 488-499.
Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.
Alex Claveria-Cabello; Leticia Colyn; Iker Uriarte; Maria Ujue Latasa; Maria Arechederra; Jose M. Herranz; Laura Alvarez; Jesus M. Urman; Maria L. Martinez-Chantar; Jesus M. Banales; Bruno Sangro; Krista Rombouts; Julen Oyarzabal; Jose J. G. Marin; Carmen Berasain; Matias A. Avila; Maite G. Fernandez-Barrena. Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis. Cancers 2020, 12, 3748 .
AMA StyleAlex Claveria-Cabello, Leticia Colyn, Iker Uriarte, Maria Ujue Latasa, Maria Arechederra, Jose M. Herranz, Laura Alvarez, Jesus M. Urman, Maria L. Martinez-Chantar, Jesus M. Banales, Bruno Sangro, Krista Rombouts, Julen Oyarzabal, Jose J. G. Marin, Carmen Berasain, Matias A. Avila, Maite G. Fernandez-Barrena. Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis. Cancers. 2020; 12 (12):3748.
Chicago/Turabian StyleAlex Claveria-Cabello; Leticia Colyn; Iker Uriarte; Maria Ujue Latasa; Maria Arechederra; Jose M. Herranz; Laura Alvarez; Jesus M. Urman; Maria L. Martinez-Chantar; Jesus M. Banales; Bruno Sangro; Krista Rombouts; Julen Oyarzabal; Jose J. G. Marin; Carmen Berasain; Matias A. Avila; Maite G. Fernandez-Barrena. 2020. "Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis." Cancers 12, no. 12: 3748.
Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.
Maria Mercado-Gómez; Fernando Lopitz-Otsoa; Mikel Azkargorta; Marina Serrano-Maciá; Sofia Lachiondo-Ortega; Naroa Goikoetxea-Usandizaga; Rubén Rodríguez-Agudo; David Fernández-Ramos; Maider Bizkarguenaga; Virginia Gutiérrez-De Juan; Benoît Lectez; Kerman Aloria; Jesus M. Arizmendi; Jorge Simon; Cristina Alonso; Juan J. Lozano; Matias A. Avila; Jesus M. Banales; Jose J. G. Marin; Naiara Beraza; José M. Mato; Félix Elortza; Rosa Barrio; James D. Sutherland; Ugo Mayor; María L. Martínez-Chantar; Teresa C. Delgado. Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis. International Journal of Molecular Sciences 2020, 21, 9043 .
AMA StyleMaria Mercado-Gómez, Fernando Lopitz-Otsoa, Mikel Azkargorta, Marina Serrano-Maciá, Sofia Lachiondo-Ortega, Naroa Goikoetxea-Usandizaga, Rubén Rodríguez-Agudo, David Fernández-Ramos, Maider Bizkarguenaga, Virginia Gutiérrez-De Juan, Benoît Lectez, Kerman Aloria, Jesus M. Arizmendi, Jorge Simon, Cristina Alonso, Juan J. Lozano, Matias A. Avila, Jesus M. Banales, Jose J. G. Marin, Naiara Beraza, José M. Mato, Félix Elortza, Rosa Barrio, James D. Sutherland, Ugo Mayor, María L. Martínez-Chantar, Teresa C. Delgado. Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis. International Journal of Molecular Sciences. 2020; 21 (23):9043.
Chicago/Turabian StyleMaria Mercado-Gómez; Fernando Lopitz-Otsoa; Mikel Azkargorta; Marina Serrano-Maciá; Sofia Lachiondo-Ortega; Naroa Goikoetxea-Usandizaga; Rubén Rodríguez-Agudo; David Fernández-Ramos; Maider Bizkarguenaga; Virginia Gutiérrez-De Juan; Benoît Lectez; Kerman Aloria; Jesus M. Arizmendi; Jorge Simon; Cristina Alonso; Juan J. Lozano; Matias A. Avila; Jesus M. Banales; Jose J. G. Marin; Naiara Beraza; José M. Mato; Félix Elortza; Rosa Barrio; James D. Sutherland; Ugo Mayor; María L. Martínez-Chantar; Teresa C. Delgado. 2020. "Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis." International Journal of Molecular Sciences 21, no. 23: 9043.
Background & Aims Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open new therapeutic opportunities. However, modifications such as DNA and histone methylation often co‐exist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a new class of dual G9a histone‐methyltransferase and DNA‐methyltransferase 1 (DNMT1) inhibitors. Approach & Results Expression of G9a, DNMT1 and their molecular adaptor ubiquitin‐like with PHD and RING finger domains‐1 (UHRF1) was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patients‐derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c‐Jun‐N‐terminal‐kinase‐(Jnk) 1/2 and diethyl‐nitrosamine (DEN) plus CCl4 treatment (JnkΔhepa+DEN+CCl4 mice). We found an increased and correlative expression of G9a, DNMT1 and UHRF1 in CCAs. Co‐treatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cells proliferation and synergized with Cisplatin and the ERBB‐targeted inhibitor Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth, and significantly antagonized CCA progression in JnkΔhepa+DEN+CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype towards a differentiated and quiescent status. Conclusions Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential novel strategy to treat CCA and/or to enhance the efficacy of other systemic therapies.
Leticia Colyn; Marina Bárcena‐Varela; Gloria Álvarez‐Sola; M. Ujue Latasa; Iker Uriarte; Eva Santamaría; Jose M. Herranz; Alvaro Santos‐Laso; Maria Arechederra; Mikel Ruiz de Gauna; Patricia Aspichueta; Matteo Canale; Andrea Casadei‐Gardini; Maria Francesconi; Simone Carotti; Sergio Morini; Leonard J. Nelson; Maria J. Iraburu; Chaobo Chen; Bruno Sangro; Jose J.G. Marin; Maria L. Martinez‐Chantar; Jesus M. Banales; Robert Arnes‐Benito; Meritxell Huch; John M. Patino; Altaf A. Dar; Mehdi Nosrati; Julen Oyarzábal; Felipe Prósper; Jesus Urman; Francisco Javier Cubero; Christian Trautwein; Carmen Berasain; Maite G. Fernandez‐Barrena; Matias A. Avila. Dual Targeting of G9a and DNA Methyltransferase‐1 for the Treatment of Experimental Cholangiocarcinoma. Hepatology 2020, 73, 2380 -2396.
AMA StyleLeticia Colyn, Marina Bárcena‐Varela, Gloria Álvarez‐Sola, M. Ujue Latasa, Iker Uriarte, Eva Santamaría, Jose M. Herranz, Alvaro Santos‐Laso, Maria Arechederra, Mikel Ruiz de Gauna, Patricia Aspichueta, Matteo Canale, Andrea Casadei‐Gardini, Maria Francesconi, Simone Carotti, Sergio Morini, Leonard J. Nelson, Maria J. Iraburu, Chaobo Chen, Bruno Sangro, Jose J.G. Marin, Maria L. Martinez‐Chantar, Jesus M. Banales, Robert Arnes‐Benito, Meritxell Huch, John M. Patino, Altaf A. Dar, Mehdi Nosrati, Julen Oyarzábal, Felipe Prósper, Jesus Urman, Francisco Javier Cubero, Christian Trautwein, Carmen Berasain, Maite G. Fernandez‐Barrena, Matias A. Avila. Dual Targeting of G9a and DNA Methyltransferase‐1 for the Treatment of Experimental Cholangiocarcinoma. Hepatology. 2020; 73 (6):2380-2396.
Chicago/Turabian StyleLeticia Colyn; Marina Bárcena‐Varela; Gloria Álvarez‐Sola; M. Ujue Latasa; Iker Uriarte; Eva Santamaría; Jose M. Herranz; Alvaro Santos‐Laso; Maria Arechederra; Mikel Ruiz de Gauna; Patricia Aspichueta; Matteo Canale; Andrea Casadei‐Gardini; Maria Francesconi; Simone Carotti; Sergio Morini; Leonard J. Nelson; Maria J. Iraburu; Chaobo Chen; Bruno Sangro; Jose J.G. Marin; Maria L. Martinez‐Chantar; Jesus M. Banales; Robert Arnes‐Benito; Meritxell Huch; John M. Patino; Altaf A. Dar; Mehdi Nosrati; Julen Oyarzábal; Felipe Prósper; Jesus Urman; Francisco Javier Cubero; Christian Trautwein; Carmen Berasain; Maite G. Fernandez‐Barrena; Matias A. Avila. 2020. "Dual Targeting of G9a and DNA Methyltransferase‐1 for the Treatment of Experimental Cholangiocarcinoma." Hepatology 73, no. 6: 2380-2396.
VertebrateHoxgenes are critical for the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here, we set up to analyze their elusive function in the ectodermal compartment, using the mouse limb bud as a model. We report that theHoxCgene cluster was co-opted to be transcribed in the distal limb ectoderm, where it is activated following the rule of temporal colinearity. These ectodermal cells subsequently produce various keratinized organs such as nails or claws. Accordingly, deletion of theHoxCcluster led to mice lacking nails (anonychia), a condition stronger than the previously reported loss of function ofHoxc13, which is the causative gene of the ectodermal dysplasia 9 (ECTD9) in human patients. We further identified two mammalian-specific ectodermal enhancers located upstream of theHoxCgene cluster, which together regulateHoxcgene expression in the hair and nail ectodermal organs. Deletion of these regulatory elements alone or in combination revealed a strong quantitative component in the regulation ofHoxcgenes in the ectoderm, suggesting that these two enhancers may have evolved along with the mammalian taxon to provide the level of HOXC proteins necessary for the full development of hair and nail.
Marc Fernandez-Guerrero; Nayuta Yakushiji-Kaminatsui; Lucille Lopez-Delisle; Sofía Zdral; Fabrice Darbellay; Rocío Perez-Gomez; Christopher Chase Bolt; Manuel A. Sanchez-Martin; Denis Duboule; Marian A. Ros. Mammalian-specific ectodermal enhancers control the expression ofHoxcgenes in developing nails and hair follicles. Proceedings of the National Academy of Sciences 2020, 117, 30509 -30519.
AMA StyleMarc Fernandez-Guerrero, Nayuta Yakushiji-Kaminatsui, Lucille Lopez-Delisle, Sofía Zdral, Fabrice Darbellay, Rocío Perez-Gomez, Christopher Chase Bolt, Manuel A. Sanchez-Martin, Denis Duboule, Marian A. Ros. Mammalian-specific ectodermal enhancers control the expression ofHoxcgenes in developing nails and hair follicles. Proceedings of the National Academy of Sciences. 2020; 117 (48):30509-30519.
Chicago/Turabian StyleMarc Fernandez-Guerrero; Nayuta Yakushiji-Kaminatsui; Lucille Lopez-Delisle; Sofía Zdral; Fabrice Darbellay; Rocío Perez-Gomez; Christopher Chase Bolt; Manuel A. Sanchez-Martin; Denis Duboule; Marian A. Ros. 2020. "Mammalian-specific ectodermal enhancers control the expression ofHoxcgenes in developing nails and hair follicles." Proceedings of the National Academy of Sciences 117, no. 48: 30509-30519.
The addition of CDK4 and 6 inhibitors (abemaciclib, palbociclib or ribociclib) to endocrine therapy, as first-line treatment or following progression after initial endocrine therapy, significantly increased progression-free survival, objective response rates and in some trials overall survival, compared with endocrine therapy alone in HR+ and HER2- breast metastatic breast cancer. These CDK4 and 6 inhibitors are now approved in this context and have become a new standard of care. A hypothesis-generating exploratory analysis suggested that the addition of abemaciclib to endocrine therapy showed the largest effects in subgroups of women with indicators of poor prognosis, although these data require confirmation. This review provides updated clinical trial data for all three drugs in metastatic breast cancer, focusing on abemaciclib, the most recently approved agent.
Miguel Martin; Jose A Garcia-Saenz; Luis Manso; Antonio Llombart; Alejo Cassinello; Manuel Atienza; Francois Ringeisen; Eva Ciruelos. Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. Future Oncology 2020, 16, 2763 -2778.
AMA StyleMiguel Martin, Jose A Garcia-Saenz, Luis Manso, Antonio Llombart, Alejo Cassinello, Manuel Atienza, Francois Ringeisen, Eva Ciruelos. Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. Future Oncology. 2020; 16 (33):2763-2778.
Chicago/Turabian StyleMiguel Martin; Jose A Garcia-Saenz; Luis Manso; Antonio Llombart; Alejo Cassinello; Manuel Atienza; Francois Ringeisen; Eva Ciruelos. 2020. "Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer." Future Oncology 16, no. 33: 2763-2778.
The chemokine receptor, C‐X‐C chemokine receptor type 4 (CXCR4) and its ligand, C‐X‐C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration‐approved in 2008 for stem cell mobilization). However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P‐001, X4 Pharmaceuticals), motixafortide (BL‐8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol‐Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach. The current status and future directions for radioimaging and treating patients with CXCR4‐expressing hematologic and solid malignancies are reviewed. See related review ‐ At the Bench: Pre‐Clinical Evidence for Multiple Functions of CXCR4 in Cancer. J. Leukoc. Biol. xx: xx–xx; 2020.
Miguel Martin; Ingrid A. Mayer; Annemiek M.E. Walenkamp; Constantin Lapa; Michael Andreeff; Alexandra Bobirca. At the Bedside: Profiling and treating patients with CXCR4‐expressing cancers. Journal of Leukocyte Biology 2020, 109, 953 -967.
AMA StyleMiguel Martin, Ingrid A. Mayer, Annemiek M.E. Walenkamp, Constantin Lapa, Michael Andreeff, Alexandra Bobirca. At the Bedside: Profiling and treating patients with CXCR4‐expressing cancers. Journal of Leukocyte Biology. 2020; 109 (5):953-967.
Chicago/Turabian StyleMiguel Martin; Ingrid A. Mayer; Annemiek M.E. Walenkamp; Constantin Lapa; Michael Andreeff; Alexandra Bobirca. 2020. "At the Bedside: Profiling and treating patients with CXCR4‐expressing cancers." Journal of Leukocyte Biology 109, no. 5: 953-967.
This study evaluates whether serum phospholipids fatty acids (PL-FAs) and markers of their endogenous metabolism are associated with breast cancer (BC) subtypes. EpiGEICAM is a Spanish multicenter matched case-control study. A lifestyle and food frequency questionnaire was completed by 1017 BC cases and healthy women pairs. Serum PL-FA percentages were measured by gas chromatography-mass spectrometry. Conditional and multinomial logistic regression models were used to quantify the association of PL-FA tertiles with BC risk, overall and by pathological subtype (luminal, HER2+ and triple negative). Stratified analyses by body mass index and menopausal status were also performed. Serum PL-FAs were measured in 795 (78%) pairs. Women with high serum levels of stearic acid (odds ratio (OR)T3vsT1 = 0.44; 95% confidence interval (CI) = 0.30–0.66), linoleic acid (ORT3vsT1 = 0.66; 95% CI = 0.49–0.90) and arachidonic to dihomo-γ-linolenic acid ratio (OR T3vsT1 = 0.64; 95% CI = 0.48–0.84) presented lower BC risk. Participants with high concentrations of palmitoleic acid (ORT3vsT1 = 1.65; 95% CI = 1.20–2.26), trans-ruminant palmitelaidic acid (ORT3vsT1 = 1.51; 95% CI = 1.12–2.02), trans-industrial elaidic acid (ORT3vsT1 = 1.52; 95% CI = 1.14–2.03), and high oleic to stearic acid ratio (ORT3vsT1 = 2.04; 95% CI = 1.45–2.87) showed higher risk. These associations were similar in all BC pathological subtypes. Our results emphasize the importance of analyzing fatty acids individually, as well as the desaturase activity indices.
Virginia Lope; Ángel Guerrero-Zotano; Ana Casas; José Manuel Baena-Cañada; Begoña Bermejo; Beatriz Pérez-Gómez; Inmaculada Criado-Navarro; Silvia Antolín; Pedro Sánchez-Rovira; Manuel Ramos-Vázquez; Antonio Antón; Adela Castelló; José Ángel García-Saénz; Montserrat Muñoz; Ana De Juan; Raquel Andrés; Antonio Llombart-Cussac; Blanca Hernando; Rosa María Franquesa; Rosalia Caballero; Feliciano Priego-Capote; Miguel Martín; Marina Pollán. Serum Phospholipids Fatty Acids and Breast Cancer Risk by Pathological Subtype. Nutrients 2020, 12, 3132 .
AMA StyleVirginia Lope, Ángel Guerrero-Zotano, Ana Casas, José Manuel Baena-Cañada, Begoña Bermejo, Beatriz Pérez-Gómez, Inmaculada Criado-Navarro, Silvia Antolín, Pedro Sánchez-Rovira, Manuel Ramos-Vázquez, Antonio Antón, Adela Castelló, José Ángel García-Saénz, Montserrat Muñoz, Ana De Juan, Raquel Andrés, Antonio Llombart-Cussac, Blanca Hernando, Rosa María Franquesa, Rosalia Caballero, Feliciano Priego-Capote, Miguel Martín, Marina Pollán. Serum Phospholipids Fatty Acids and Breast Cancer Risk by Pathological Subtype. Nutrients. 2020; 12 (10):3132.
Chicago/Turabian StyleVirginia Lope; Ángel Guerrero-Zotano; Ana Casas; José Manuel Baena-Cañada; Begoña Bermejo; Beatriz Pérez-Gómez; Inmaculada Criado-Navarro; Silvia Antolín; Pedro Sánchez-Rovira; Manuel Ramos-Vázquez; Antonio Antón; Adela Castelló; José Ángel García-Saénz; Montserrat Muñoz; Ana De Juan; Raquel Andrés; Antonio Llombart-Cussac; Blanca Hernando; Rosa María Franquesa; Rosalia Caballero; Feliciano Priego-Capote; Miguel Martín; Marina Pollán. 2020. "Serum Phospholipids Fatty Acids and Breast Cancer Risk by Pathological Subtype." Nutrients 12, no. 10: 3132.
Structured Abstract Background The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with HER2+ hormone receptor-positive (HR+) early-stage breast cancer (eBC). Patients and methods ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 HER2+ eBC patients after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. Primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤1 year (HR+/≤1-year) and >1 year (HR+/>1-year) post-trastuzumab. Results HR+/≤1-year and HR+/>1-year populations comprised 1334 (neratinib, n=670; placebo, n=664) and 297 (neratinib, n=146; placebo, n=151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤1-year (HR=0.58, 95% CI 0.41‒0.82) and 1.3% in HR+/>1-year (HR=0.74; 95% CI 0.29‒1.84). In HR+/≤1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; HR=0.79, 95% CI 0.55‒1.13). Of 354 HR+/≤1-year patients who received neoadjuvant therapy, 295 had residual disease and results showed absolute benefits of 7.4% at 5-year iDFS (HR=0.60; 95% CI 0.33‒1.07) and 9.1% at 8-year OS (HR=0.47; 95% CI 0.23–0.92). There were fewer CNS events with neratinib. Adverse events were similar to previously reported. Conclusion Neratinib significantly improved iDFS in the HER2+/HR+/≤1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in CNS events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.
Arlene Chan; Beverly Moy; Janine Mansi; Bent Ejlertsen; Frankie Ann Holmes; Stephen Chia; Hiroji Iwata; Michael Gnant; Sibylle Loibl; Carlos H. Barrios; Isil Somali; Snezhana Smichkoska; Noelia Martinez; Mirta Garcia Alonso; John S. Link; Ingrid A. Mayer; Søren Cold; Serafin Morales Murillo; Francis Senecal; Kenichi Inoue; Manuel Ruiz-Borrego; Rina Hui; Neelima Denduluri; Debra Patt; Hope S. Rugo; Stephen R.D. Johnston; Richard Bryce; Bo Zhang; Feng Xu; Alvin Wong; Miguel Martin. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clinical Breast Cancer 2020, 21, 80 -91.e7.
AMA StyleArlene Chan, Beverly Moy, Janine Mansi, Bent Ejlertsen, Frankie Ann Holmes, Stephen Chia, Hiroji Iwata, Michael Gnant, Sibylle Loibl, Carlos H. Barrios, Isil Somali, Snezhana Smichkoska, Noelia Martinez, Mirta Garcia Alonso, John S. Link, Ingrid A. Mayer, Søren Cold, Serafin Morales Murillo, Francis Senecal, Kenichi Inoue, Manuel Ruiz-Borrego, Rina Hui, Neelima Denduluri, Debra Patt, Hope S. Rugo, Stephen R.D. Johnston, Richard Bryce, Bo Zhang, Feng Xu, Alvin Wong, Miguel Martin. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clinical Breast Cancer. 2020; 21 (1):80-91.e7.
Chicago/Turabian StyleArlene Chan; Beverly Moy; Janine Mansi; Bent Ejlertsen; Frankie Ann Holmes; Stephen Chia; Hiroji Iwata; Michael Gnant; Sibylle Loibl; Carlos H. Barrios; Isil Somali; Snezhana Smichkoska; Noelia Martinez; Mirta Garcia Alonso; John S. Link; Ingrid A. Mayer; Søren Cold; Serafin Morales Murillo; Francis Senecal; Kenichi Inoue; Manuel Ruiz-Borrego; Rina Hui; Neelima Denduluri; Debra Patt; Hope S. Rugo; Stephen R.D. Johnston; Richard Bryce; Bo Zhang; Feng Xu; Alvin Wong; Miguel Martin. 2020. "Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial." Clinical Breast Cancer 21, no. 1: 80-91.e7.
Background Abemaciclib is a selective cyclin-dependent kinase 4 & 6 inhibitor administered continuously for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Abemaciclib is associated with dose-dependent early onset diarrhea. nextMONARCH evaluated abemaciclib monotherapy (+/- prophylactic loperamide) and in combination with tamoxifen in endocrine refractory metastatic breast cancer (MBC) following chemotherapy. Patients/Methods nextMONARCH is an open-label, controlled, randomized, phase 2 study in women with endocrine refractory HR+, HER2- MBC previously treated with chemotherapy. Patients received abemaciclib 150 mg + tamoxifen 20 mg (A+T), or abemaciclib 150 mg Q12H (A-150), or abemaciclib 200 mg + prophylactic loperamide (A-200). The primary objective was progression-free survival (PFS). PFS analyses tested superiority of A+T to A-200 and informal noninferiority of A-150 to A-200. Secondary objectives included objective response rate (ORR), safety, and pharmacokinetics (PK). Results Median PFS was 9.1 months for A+T versus 7.4 months for A-200 (HR=.815; 95% CI, .556-1.193; P=.293). A-200 PFS was comparable to A-150 at 6.5 months (HR=1.045; 95% CI, .711-1.535; P=.811). ORR was 34.6%, 24.1%, and 32.5% for A+T, A-150, and A-200, respectively. No new safety signals were identified. Incidence/severity of diarrhea (62.3%, grade 3: 7.8%) in A-200 was similar to A-150 (67.1%, grade 3: 3.8%). PK was comparable to previous observations. Conclusions Addition of tamoxifen to abemaciclib did not significantly improve PFS or ORR compared to abemaciclib monotherapy but confirmed single-agent activity of abemaciclib in heavily pretreated HR+, HER2- MBC. Dose reductions and antidiarrheal medication generally managed diarrhea while maintaining efficacy.
Erika Hamilton; Javier Cortes; Ozgur Ozyilkan; Shin-Cheh Chen; Katarina Petrakova; Aleksey Manikhas; Guy Jerusalem; Roberto Hegg; Jens Huober; Sonya C. Chapman; Yi Lu; Molly C. Hardebeck; Melissa M. Bear; Erica L. Johnston; Miguel Martin. nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer. Clinical Breast Cancer 2020, 21, 181 -190.e2.
AMA StyleErika Hamilton, Javier Cortes, Ozgur Ozyilkan, Shin-Cheh Chen, Katarina Petrakova, Aleksey Manikhas, Guy Jerusalem, Roberto Hegg, Jens Huober, Sonya C. Chapman, Yi Lu, Molly C. Hardebeck, Melissa M. Bear, Erica L. Johnston, Miguel Martin. nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer. Clinical Breast Cancer. 2020; 21 (3):181-190.e2.
Chicago/Turabian StyleErika Hamilton; Javier Cortes; Ozgur Ozyilkan; Shin-Cheh Chen; Katarina Petrakova; Aleksey Manikhas; Guy Jerusalem; Roberto Hegg; Jens Huober; Sonya C. Chapman; Yi Lu; Molly C. Hardebeck; Melissa M. Bear; Erica L. Johnston; Miguel Martin. 2020. "nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer." Clinical Breast Cancer 21, no. 3: 181-190.e2.