Nuestros investigadores

Marc García Moure

Publicaciones científicas más recientes (desde 2010)

Autores: Puigdelloses Vallcorba, Montserrat; González Huarriz, María Soledad; García Moure, Marc; et al.
Revista: NEURO-ONCOLOGY ADVANCES
ISSN 2632-2498  Vol. 2  Nº 1  2020  págs. vdaa010
Background: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. Methods: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. Results: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). Conclusions: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.
Autores: García Moure, Marc; Martínez Velez, Naiara; González Huarriz, María Soledad; et al.
Revista: SCIENTIFIC REPORTS
ISSN 2045-2322  Vol. 9  Nº 1  2019  págs. 14368
Last advances in the treatment of pediatric tumors has led to an increase of survival rates of children affected by primitive neuroectodermal tumors, however, still a significant amount of the patients do not overcome the disease. In addition, the survivors might suffer from severe side effects caused by the current standard treatments. Oncolytic virotherapy has emerged in the last years as a promising alternative for the treatment of solid tumors. In this work, we study the anti-tumor effect mediated by the oncolytic adenovirus VCN-01 in CNS-PNET models. VCN-01 is able to infect and replicate in PNET cell cultures, leading to a cytotoxicity and immunogenic cell death. In vivo, VCN-01 increased significantly the median survival of mice and led to long-term survivors in two orthotopic models of PNETs. In summary, these results underscore the therapeutic effect ofVCN-01 for rare pediatric cancers such as PNETs, and warrants further exploration on the use of this virus to treat them.
Autores: Gonzalez-Morales, A.; Zabaleta Azpiroz, Aintzane; García Moure, Marc; et al.
Revista: JOURNAL OF PROTEOMICS
ISSN 1874-3919  Vol. 194  2019  págs. 168 - 178
Adenovirus Delta-24-RGD has shown a remarkable efficacy in a phase I clinical trial for glioblastoma. Delta-24-RGD induces autophagy in glioma cells, however, the molecular derangements associated with Delta-24-RGD infection remains poorly understood. Here, proteomics was applied to characterize the glioma metabolic disturbances soon after Delta-24-RGD internalization and late in infection. Minutes post-infection, a rapid survival reprogramming of glioma cells was evidenced by an early c-Jun activation and a time-dependent dephosphorylation of multiple survival kinases. At 48 h post-infection (hpi), a severe intracellular proteostasis impairment was characterized, detecting differentially expressed proteins related to mRNA splicing, cytoskeletal organization, oxidative response, and inflammation. Specific kinase-regulated protein interactomes for Delta-24-RGD-modulated proteome revealed interferences with the activation dynamics of protein kinases C and A (PKC, PKA), tyrosine-protein kinase Src (c-Src), glycogen synthase kinase-3 (GSK-3) as well as serine/threonine-protein phosphatases 1 and 2A (PP1, PP2A) at 48hpi, in parallel with adenoviral protein overproduction. Moreover, the late activation of the nuclear factor kappa B (NF-kappa B) correlates with the extracellular increment of specific cytokines involved in migration, and activation of different inflammatory cells. Taken together, our integrative analysis provides further insights into the effects triggered by Delta-24-RGD in the modulation of tumor suppression and immune response against glioma. Significance: The current study provides new insights regarding the molecular mechanisms governing the glioma metabolism during Delta-24-RGD oncolytic adenoviral therapy. The compilation and analysis of intracellular and extracellular proteomics have led us to characterize: i) the cell survival reprogramming during Delta-24-RGD internalization, ii) the proteostatic disarrangement induced by Delta-24-RGD during the autophagic stage, iii) the protein interactomes for Delta-24-RGD-modulated proteome, iv) the regulatory effects on kinase dynamics induced by Delta-24-RGD late in infection, and v) the overproduction of multitasking cytokines upon Delta-24-RGD treatment. We consider that the quantitative molecular maps generated in this study may establish the foundations for the development of complementary adenoviral based-vectors to increase the potency against glioma.
Autores: Martínez Velez, Naiara; García Moure, Marc; Marigil Sánchez, Miguel; et al.
Revista: NATURE COMMUNICATIONS
ISSN 2041-1723  Vol. 10  Nº 1  2019  págs. 2235
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
Autores: Martínez Velez, Naiara; Marigil Sánchez, Miguel; García Moure, Marc; et al.
Revista: ACTA NEUROPATHOLOGICA
ISSN 1432-0533  Vol. 7  2019  págs. 64
Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.
Autores: García Moure, Marc; González Huarriz, María Soledad; Laspidea Ustés, Virginia; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  Nº Supl. 6  2019  págs. 192 - 192
Autores: García Moure, Marc; González Huarriz, María Soledad; Marrodán Fernández, Lucía; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  Nº Supl. 2  2019  págs. 63
Autores: Laspidea Ustés, Virginia; Puigdelloses Vallcorba, Montserrat; García Moure, Marc; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  2019  págs. 36 - 36
Autores: Martínez Velez, Naiara; García Moure, Marc; Laspidea Ustés, Virginia; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 79  Nº Supl. 13  2019 
Autores: Laspidea Ustés, Virginia; Varela Guruceaga, Maider; García Moure, Marc; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  Nº Supl. 2  2019  págs. 119
Autores: Martínez Velez, Naiara; García Moure, Marc; Laspidea Ustés, Virginia; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  2019  págs. 68 - 69
Autores: Laspidea Ustés, Virginia; Puigdelloses Vallcorba, Montserrat; Íñigo Marco, Ignacio; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  Nº Supl. 6  2019  págs. 122
Autores: García Moure, Marc; González Huarriz, María Soledad; Marrodán Fernández, Lucía; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  Nº Supl. 3  2019  págs. 47
Autores: Íñigo Marco, Ignacio; Diez Valle, Ricardo; García Moure, Marc; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  Nº Supl. 6  2019  págs. 283 - 284
Autores: Puigdelloses Vallcorba, Montserrat; Martínez Velez, Naiara; García Moure, Marc; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 21  2019  págs. 56 - 56
Autores: Aldave, G.; González Huarriz, María Soledad; Rubio Díaz-Cordoves, Ángel; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 20  Nº 7  2018  págs. 930 - 941
Background: Glioblastoma, the most aggressive primary brain tumor, is genetically heterogeneous. Alternative splicing (AS) plays a key role in numerous pathologies, including cancer. The objectives of our study were to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation. Methods: We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma. Results: BAF45d is part of the switch/sucrose nonfermentable complex and plays a key role in the development of the CNS. The BAF45d/6A isoform is present in 85% of over 200 glioma samples that have been analyzed and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription. Conclusions: Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.
Autores: Varela Guruceaga, Maider; Tejada Solís, Sonia; García Moure, Marc; et al.
Revista: CANCERS
ISSN 2072-6694  Vol. 10  Nº 7  2018  págs.  E226.
Autores: Martínez Velez, Naiara; Marigil, M. ; Aristu Mendioroz, José Javier; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 78  Nº 13 Supl.  2018 
Autores: Marigil Sánchez, Miguel; Martinez-Velez, N.; Domínguez Echávarri, Pablo Daniel; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 12  Nº 1  2017  págs. e0170501
Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1 mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.
Autores: Puigdelloses Vallcorba, Montserrat; González Huarriz, María Soledad; García Moure, Marc; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  Nº Supl 6  2017  págs. 34
Autores: García Moure, Marc; Martinez-Velez, N.; Gonzalez-Huarriz, M.; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  Nº Supl. 4  2017  págs. 42
Primitive Neuroectodermal Tumors (PNETs) are very rare aggressive pediatric tumors characterized by the presence of poorly differentiated tumor cells. Despite formidable advances in targeted therapies and in the knowledge of the molecular make-up of these tumors, the development of curative therapies is still lagging. Therefore, the outcome for children affected with PNETs still remains dismal. Thus, it is critical to propel alternative therapeutic approaches to improve the survival and quality of life of these children. Delta-24-RGD is an oncolytic adenovirus engineered to have a tumor restricted replication and an expanded tropism to cancer cells. Altogether, these modifications result in a potent antitumor and lack of toxicity as shown by preclinical and clinical studies. In this work we describe the antitumor effect mediated by Delta-24-RGD in PNETs (PFSK-1 and SK-PN-DW cells), as well as a in a new unpublished cell line (PBT-25) that we have generated from a tumor biopsy. First, we demonstrated in vitro that Delta-24-RGD transduces efficiently PNET cells leading to an effective replication yielding high titers of new infectious particles when compared with other type of brain tumors such as glioma. Treatment with the virus in vitro resulted in an effective cell killing effect, obtaining IC50 values ranging from 7 to 18 MOIs. In vivo, Delta-24-RGD showed a safety profile since no signs of toxicity were observed upon its administration. Finally, the antitumor effect of Delta-24-RGD was assessed in vivo in two orthotopic models of sPNET. Delta-24-RGD treatment resulted in a significant increase in overall survival of the animals (19 and 21 days for PFSK-1 and SK-PN-DW, respectively) compared to vehicle treated animals (14 days) and led to long-term survivors free of disease. In vivo antitumor effect in PBT-25 is on-going. In summary, these results demonstrate the potential therapeutic benefit of Delta-24-RGD for the treatment of PNETs.
Autores: García Moure, Marc; Martínez-Velez, N; Patiño García, Ana; et al.
Revista: JOURNL OF BONE ONCOLOGY
ISSN 2212-1366  Vol. 9  2016  págs. 41-47
Osteosarcoma is the most common bone cancer among those with non-hematological origin and affects mainly pediatric patients. In the last 50 years, refinements in surgical procedures, as well as the introduction of aggressive neoadjuvant and adjuvant chemotherapeutic cocktails, have increased to nearly 70% the survival rate of these patients. Despite the initial therapeutic progress the fight against osteosarcoma has not substantially improved during the last three decades, and almost 30% of the patients do not respond or recur after the standard treatment. For this group there is an urgent need to implement new therapeutic approaches. Oncolytic adenoviruses are conditionally replicative viruses engineered to selectively replicate in and kill tumor cells, while remaining quiescent in healthy cells. In the last years there have been multiple preclinical and clinical studies using these viruses as therapeutic agents in the treatment of a broad range of cancers, including osteosarcoma. In this review, we summarize some of the most relevant published literature about the use of oncolytic adenoviruses to treat human osteosarcoma tumors in subcutaneous, orthotopic and metastatic mouse models. In conclusion, up to date the preclinical studies with oncolytic adenoviruses have demonstrated that are safe and efficacious against local and metastatic osteosarcoma. Knowledge arising from phase I/II clinical trials with oncolytic adenoviruses in other tumors have shown the potential of viruses to awake the patient¿s own immune system generating a response against the tumor. Generating osteosarcoma immune-competent adenoviruses friendly models will allow to better understand this potential. Future clinical trials with oncolytic adenoviruses for osteosarcoma tumors are warranted.