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Publicaciones científicas más recientes (desde 2010)

Autores: Erice, O.; Ponz-Sarvise, Mariano; et al.
Revista: CANCERS
ISSN 2072-6694  Vol. 11  Nº 12  2019  págs. 1868
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system.
Autores: Berraondo, Pedro, (Autor de correspondencia); Ochoa, María del Carmen; et al.
Revista: BRITISH JOURNAL OF CANCER
ISSN 0007-0920  Vol. 120  Nº 1  2019  págs. 6 - 15
Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.
Autores: Baraibar, Iosune; Melero, Ignacio Javier; Ponz-Sarvise, Mariano; et al.
Revista: DRUG SAFETY
ISSN 0114-5916  Vol. 42  Nº 2  2019  págs. 281 - 294
Immunotherapy has emerged in recent years and has revolutionized the treatment of cancer. Immune checkpoint inhibitors, including anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) agents, are the first of this new generation of treatments. Anti-PD-1/PD-L1 agents target immune cells by blocking the PD-1/PD-L1 pathway. This blockade leads to enhancement of the immune system and therefore restores the tumour-induced immune deficiency selectively in the tumour microenvironment. However, this shift in the balance of the immune system can also produce adverse effects that involve multiple organs. The pattern of toxicity is different from traditional chemotherapy agents or targeted therapy, and there is still little experience in recognizing and managing it. Thus, toxicity constitutes a real clinical management challenge and any new alteration should be suspected of being treatment-related. The most common toxicities occur in the skin, gastrointestinal tract, lungs, and endocrine, musculoskeletal, renal, nervous, haematologic, cardiovascular and ocular systems. Immune-mediated toxic effects are usually manageable, but toxicities may sometimes lead to treatment withdrawal, and even fulminant and fatal events can occur. Oncologists need to collaborate with internists, clinical immunologists and other specialists to understand, manage and prevent toxicity derived from immunotherapy. This review focuses on the mechanisms of toxicity of anti-PD-1/PD-L1 agents, and its diagnosis and management.
Autores: Forner, A.; Vidili, G.; Rengo, M.; et al.
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 39  Nº Supl. 1  2019  págs. 98 - 107
Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.
Autores: Forner, A.; Vidili, G.; Rengo, M.; et al.
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 39  2019  págs. 98 - 107
Autores: Salas, Diego; Melero, Ignacio Javier; Ponz-Sarvise, Mariano, (Autor de correspondencia)
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 25  Nº 18  2019  págs. 5435 - 5437
No immunotherapy strategy is yet offering consistent results against pancreatic ductal adenocarcinoma. A randomized clinical trial testing repeated immunization with a Listeria monocytogenes-based vaccine encoding for mesothelin in combination with a GM-CSF-transfected allogeneic pancreatic cell vaccine reports no survival benefit for the vaccinated patients.
Autores: Oyaga-Iriarte, E. ; Yu, K. H.; et al.
Revista: CANCERS
ISSN 2072-6694  Vol. 11  Nº 5  2019  págs. 606
Background: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) in resectable PC, and to develop a machine-learning algorithm to predict risk of relapse. Methods: Forty patients with resectable PC treated in our institution with IPCT (based on mFOLFOXIRI, GEMOX or GEMOXEL) followed by CRT (50 Gy and concurrent Capecitabine) were retrospectively analyzed. Additionally, clinical, pathological and analytical data were collected in order to perform a 2-year relapse-risk predictive population model using machine-learning techniques. Results: A RO resection was achieved in 90% of the patients. After a median follow-up of 33.5 months, median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months. The 3 and 5-year actuarial PFS were 43.8% and 32.3%, respectively. The 3 and 5-year actuarial OS were 51.5% and 34.8%, respectively. Forty-percent of grade 3-4 IPCT toxicity, and 29.7% of grade 3 CRT toxicity were reported. Considering the use of granulocyte colony-stimulating factors, the number of resected lymph nodes, the presence of perineural invasion and the surgical margin status, a logistic regression algorithm predicted the individual 2-year relapse-risk with an accuracy of 0.71 (95% confidence interval [CI] 0.56-0.84, p = 0.005). The model-predicted outcome matched 64% of the observed outcomes in an external dataset. Conclusion: An intensified multimodal neoadjuvant approach (IPCT + CRT) in resectable PC is feasible, with an encouraging long-term outcome. Machine-learning algorithms might be a useful tool to predict individual risk of relapse. A small sample size and therapy heterogeneity remain as potential limitations.
Autores: Roman, M.; Guruceaga, Elisabet; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 79  Nº 3  2019  págs. 625 - 638
Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G(2)-M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in down-regulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. Significance: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.
Autores: Rodríguez, María Esperanza, (Autor de correspondencia); Rodriguez, I.; et al.
Revista: MOLECULAR CANCER THERAPEUTICS
ISSN 1535-7163  Vol. 18  Nº 3  2019  págs. 621 - 631
Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGF beta expression or activation increases in irradiated tissues, we tested whether TGF beta blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Indeed, TGF beta blockade with 1D11, a TGF beta-neutralizing mAb, markedly enhanced abscopal effects and overall treatment efficacy against subcutaneous tumors of either 4T1 breast cancer cells or large MC38 colorectal tumors. Increases in CD8 T cells infiltrating the nonirradiated lesion were documented upon combined treatment, which intensely expressed Granzyme-B as an indicator of cytotoxic effector capability. Interestingly, tumor tissue but not healthy tissue irradiation results in the presence of higher concentrations of TGF beta in the nonirradiated contralateral tumor that showed smad2/3 phosphorylation increases in infiltrating CD8 T cells. In conclusion, radiotherapy-induced TGF beta hampers abscopal efficacy even upon combination with a potent immunotherapy regimen. Therefore, TGF beta blockade in combination with radioimmunotherapy results in greater efficacy.
Autores: Ponz-Sarvise, Mariano; Corbo, V.; Tiriac, H.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 25  Nº 22  2019  págs. 6742 - 6755
Purpose: KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. Experimental Design: We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. In addition, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignantspecific vulnerabilities. Results: Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies. Conclusions: Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models, pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT, and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.
Autores: Rodríguez, Javier; Vicent, Silvestre; Chopitea, Ana; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 24  Nº 16  2018  págs. 3787 - 3789
Although molecular subtype-based stratification and genomic signatures of increasing complexity are becoming a new strategy to guide therapeutic decisions in stage II/III colon cancer, several prognostic factors that can be easily obtained from formalin-fixed paraffin-embedded (FFPE) specimens should be considered to create combined models that better define individual patients' needs. (C) 2018 AACR.
Autores: Berraondo, Pedro; Ponz-Sarvise, Mariano; Melero, Ignacio Javier, (Autor de correspondencia)
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 24  Nº 12  2018  págs. 2716 - 2718
IL12 antitumor activities are mediated by the activation of T and natural killer (NK) lymphocytes to produce IFNg. Systemically, recombinant IL12 has a narrow therapeutic window that favors local delivery, for instance, by gene therapy approaches. IL12 is a powerful partner in immunotherapy combinations with checkpoint inhibitors and adoptive T-cell transfer. (C) 2018 AACR.
Autores: Rodríguez, María Esperanza; Pérez, José Luis; Rodríguez, I.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº 5  2018  págs. 1312 - 1319
Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-alpha and IFN-alpha. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m(2) was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre-and posttreatment PBMC from patients achieving durable stable disease (SD) were studied by IFNc ELISPOT-assays responding to tumor-lysate loaded DC and by TCR beta sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-beta and IFN-alpha mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1 beta concentrations, especially in patients presenting SD. IFNc-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
Autores: Rodríguez, Javier; Castañón, Eduardo; Pérez, José Luis; et al.
Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN 2051-1426  Vol. 6  2018  págs. 96
Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1: 1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival -DFS-) 25.26 months, 95% CI 8. 74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32-18.88).
Autores: Rodas, I. M. ; Longo, F.; Rodríguez, María Esperanza; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018  págs. 732 - 732
Autores: Baraibar, Iosune; Martin-Romano, P.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018 
Autores:  et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl.3  2018 
Autores: Baraibar, Iosune; Romano, P. M. ; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 6  2018  págs. 21 - 22
Autores: Alfaro, Carlos; Rodríguez, María Esperanza; et al.
Revista: CANCER TREATMENT REVIEWS
ISSN 0305-7372  Vol. 60  2017  págs. 24 - 31
Interleukin-8 (CXCL8) was originally described asa chemokine whose main function is the attraction of a polymorphonuclear inflammatory leukocyte infiltrate acting on CXCR1/2. Recently, it has been found that tumors very frequently coopt the production of this chemokine, which in this malignant context exerts different pro-tumoral functions. Reportedly, these include angiogenesis, survival signaling for cancer stem cells and attraction of myeloid cells endowed with the ability to immunosuppress and locally provide growth factors. Given the fact that in cancer patients IL-8 is mainly produced by tumor cells themselves, its serum concentration has been shown to correlate with tumor burden. Thus, IL-8 serum concentrations have been shown to be useful asa pharmacodynamic biomarker to early detect response to immunotherapy. Finally, because of the roles that IL-8 plays in favoring tumor progression, several therapeutic strategies are being developed to interfere with its functions. Such interventions hold promise, especially for therapeutic combinations in the field of cancer immunotherapy.
Autores: Rodríguez, María Esperanza; Rodríguez, I.; Barbes, B; et al.
Revista: BRACHYTHERAPY
ISSN 1538-4721  Vol. 16  Nº 6  2017  págs. 1246 - 1251
PURPOSE/OBJECTIVES: Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lesions and on tumors at distant, nonirradiated sites. We have recently reported that external beam radiotherapy achieves abscopal effects when combined with antagonist anti-PD1 mAbs and agonist anti-CD137 (4-1BB) mAbs. The goal of this work is to study the abscopal effects of radiotherapy instigated by brachytherapy techniques. METHODS AND MATERIALS: Mice bearing a subcutaneous colorectal carcinoma, MC38 (colorectal cancer), in both flanks were randomly assigned to receive brachytherapy or not (8 Gy × three fractions) to only one of the two grafted tumors, in combination with intraperitoneal immunostimulatory monoclonal antibodies (anti-PD1, anti-CD137, and/or their respective isotype controls). To study the abscopal effects of brachytherapy, we established an experimental set up that permits irradiation of mouse tumors sparing a distant site resembling metastasis. Such second nonirradiated tumor was used as indicator of abscopal effect. Tumor size was monitored every 2 days. RESULTS: Abscopal effects on distant nonirradiated subcutaneous tumor lesions of transplanted MC38-derived tumors only took place when brachytherapy was combined with immunostimulatory anti-PD1 and/or anti-CD137 mAbs. CONCLUSIONS: Our results demonstrate that immunotherapy-potentiated abscopal effects can be attained by brachytherapy. Accordingly, immunotherapy plus brachytherapy combinations are suitable for clinical translation.
Autores: Ohlund, D.; Handly-Santana, A.; Biffi, G.; et al.
Revista: JOURNAL OF EXPERIMENTAL MEDICINE
ISSN 0022-1007  Vol. 214  Nº 3  2017  págs. 579 - 596
Autores: Vallejo, A.; Guruceaga, Elisabet; et al.
Revista: NATURE COMMUNICATIONS
ISSN 2041-1723  Vol. 21  Nº 8  2017  págs. 14294
KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.
Autores: Marquez Rodas, I.; Rodríguez, María Esperanza; López-Tarruella Cobo, S.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Suppl. 5  2017  págs.  LBA20
Autores: Rodríguez, María Esperanza; Pérez, José Luis; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Supl. 11  2017  págs. 48P
Autores: Etxeberria, I.; Ponz-Sarvise, Mariano; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 22  Nº 17  2016  págs. 4277 - 4279
Autores: Sola, Jesús Javier; Diaz-Gonzalez, JA; et al.
Revista: BRITISH JOURNAL OF CANCER
ISSN 0007-0920  Vol. 115  Nº 6  2016  págs. 655-663
Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.
Autores: Chio, I. I. C.; Jafarnejad, S. M.; Ponz-Sarvise, Mariano; et al.
Revista: CELL
ISSN 0092-8674  Vol. 166  Nº 4  2016  págs. 963 - 976
Autores: Ponz-Sarvise, Mariano; Corbo, V.; Frese, K.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl. 6  2016  págs. 1523P
Autores: Ponz-Sarvise, Mariano; Sun, Y.; Chang, S. S. ; et al.
Revista: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH
ISSN 1943-8141  Vol. 7  Nº 2  2015  págs. 319 - U328
Autores: Boj, S. F. ; Hwang, C. I.; Baker, L. A.; et al.
Revista: CELL
ISSN 0092-8674  Vol. 160  Nº 1 - 2  2015  págs. 324 - 338
Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal-and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.
Autores: Corbo, V., (Autor de correspondencia); Ponz-Sarvise, Mariano; Tuveson, D. A. ;
Revista: EMBO JOURNAL
ISSN 0261-4189  Vol. 33  Nº 21  2014  págs. 2437 - 2438
Autores: Ponz-Sarvise, Mariano; Castañón, Eduardo; et al.
Revista: CLINICAL GENITOURINARY CANCER
ISSN 1558-7673  Vol. 12  Nº 2  2014  págs. 87 - 93
Inhibitor of differentiation-1 (Id1) might constitute a novel prognostic factor able to differentiate indolent from aggressive prostate tumors. In this study, 2 cohorts of 52 and 79 prostate cancer patients were selected for Id1 expression analysis. Higher levels of Id1 protein in advanced poor-prognosis patients and a correlation of higher Id1 mRNA expression levels with a lower survival in stage I to III patients were observed. Background: In the prostate-specific antigen era, potentially indolent prostate tumors are radically treated, causing overtreatment. Molecular prognostic factors might differentiate indolent from aggressive tumors, allowing avoidance of unnecessary treatment. Patients and Methods: Fifty-two prostate cancer patients (20 organ-confined and 32 metastatic) were selected. All formalin-fixed and paraffin-embedded primary biopsies and matched metastases of 15 of them were evaluated for tumor and endothelial cell Id1 protein expression. Seventy-nine additional patients with organ-confined prostate cancer were selected for Id1 mRNA in silico analysis. Results: Among metastatic cancer subjects, 48% of primary tumors and 38% of metastases showed Id1 tumor cell expression, and 79% of primary tumors and 81% of metastases showed endothelial immunoreactivity. In the organ-confined group none of them showed Id1 protein tumor cell expression and 50% displayed endothelial expression. In the metastatic patients group, lower levels of Id1 protein predicted a nonsignificant longer overall survival (13 months vs. 7 months; P = .79). In the in silico analysis, however, lower levels of Id1 mRNA predicted a longer disease-free survival (61 months vs. not-reached; P = .018) and the hazard ratio for progression was 0.451 (P = .022) in favor of patients showing lower levels. Conclusion: In our cohort, it seems to be a differential epithelial expression of Id1 protein according to the prognostic features (metastatic/poor prognosis vs. organ-confined/good prognosis). In localized tumors treated with radical prostatectomy, higher Id1 mRNA expression levels might predict a higher hazard ratio for progression and a shorter disease-free survival. Further validation of these results in larger prospective series is warranted.
Autores: Ponz-Sarvise, Mariano; Nguewa, Paul; Pajares, María Josefa; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 17  Nº 12  2011  págs. 4155 -4166
Autores: Centeno, Carlos; Carvajal Valcarcel, A; et al.
Revista: Journal of Palliative Medicine
ISSN 1096-6218  Vol. 14  Nº 1  2011  págs. 4 - 5
Autores: Zarate, Ruth Noemí; Rodriguez, J.; et al.
Revista: Cancer Research
ISSN 0008-5472  Vol. 102  Nº 6  2010  págs. 987 - 994
Autores: Pajares, María Josefa; Agorreta, J; et al.
Revista: Molecular Cancer
ISSN 1476-4598  Vol. 28  Nº 9  2010  págs. 130