43 results on '"Nicola Candia A"'
Search Results
2. Targeting FOXP3 Tumor-Intrinsic Effects Using Adenoviral Vectors in Experimental Breast Cancer
- Author
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Alejandro J. Nicola Candia, Matías Garcia Fallit, Jorge A. Peña Agudelo, Melanie Pérez Küper, Nazareno Gonzalez, Mariela A. Moreno Ayala, Emilio De Simone, Carla Giampaoli, Noelia Casares, Adriana Seilicovich, Juan José Lasarte, Flavia A. Zanetti, and Marianela Candolfi
- Subjects
Foxp3 ,cell penetrating peptide ,gene therapy ,breast cancer ,chemosensitivity ,Microbiology ,QR1-502 - Abstract
The regulatory T cell master transcription factor, Forkhead box P3 (Foxp3), has been detected in cancer cells; however, its role in breast tumor pathogenesis remains controversial. Here we assessed Foxp3 tumor intrinsic effects in experimental breast cancer using a Foxp3 binder peptide (P60) that impairs Foxp3 nuclear translocation. Cisplatin upregulated Foxp3 expression in HER2+ and triple-negative breast cancer (TNBC) cells. Foxp3 inhibition with P60 enhanced chemosensitivity and reduced cell survival and migration in human and murine breast tumor cells. We also developed an adenoviral vector encoding P60 (Ad.P60) that efficiently transduced breast tumor cells, reduced cell viability and migration, and improved the cytotoxic response to cisplatin. Conditioned medium from transduced breast tumor cells contained lower levels of IL-10 and improved the activation of splenic lymphocytes. Intratumoral administration of Ad.P60 in breast-tumor-bearing mice significantly reduced tumor infiltration of Tregs, delayed tumor growth, and inhibited the development of spontaneous lung metastases. Our results suggest that Foxp3 exerts protumoral intrinsic effects in breast cancer cells and that gene-therapy-mediated blockade of Foxp3 could constitute a therapeutic strategy to improve the response of these tumors to standard treatment.
- Published
- 2023
- Full Text
- View/download PDF
3. In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer
- Author
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Ana Alfano, Eduardo G. A. Cafferata, Mariela Gangemi, Alejandro Nicola Candia, Cristian M. Malnero, Ismael Bermudez, Mauricio Vargas Lopez, Gregorio David Ríos, Cecilia Rotondaro, Nicasio Cuneo, David T. Curiel, Osvaldo L. Podhajcer, and Maria Veronica Lopez
- Subjects
gynecologic neoplasms ,cytokines ,ovarian cancer ,gene therapy ,adenovirus ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.
- Published
- 2023
- Full Text
- View/download PDF
4. Evaluation of Baculoviruses as Gene Therapy Vectors for Brain Cancer
- Author
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Matías Garcia Fallit, Matías L. Pidre, Antonela S. Asad, Jorge A. Peña Agudelo, Mariana B. Vera, Alejandro J. Nicola Candia, Sofia B. Sagripanti, Melanie Pérez Kuper, Leslie C. Amorós Morales, Abril Marchesini, Nazareno Gonzalez, Carla M. Caruso, Víctor Romanowski, Adriana Seilicovich, Guillermo A. Videla-Richardson, Flavia A. Zanetti, and Marianela Candolfi
- Subjects
baculoviruses ,glioblastoma ,astrocytes ,gene therapy ,brain ,Microbiology ,QR1-502 - Abstract
We aimed to assess the potential of baculoviral vectors (BV) for brain cancer gene therapy. We compared them with adenoviral vectors (AdV), which are used in neuro-oncology, but for which there is pre-existing immunity. We constructed BVs and AdVs encoding fluorescent reporter proteins and evaluated their transduction efficiency in glioma cells and astrocytes. Naïve and glioma-bearing mice were intracranially injected with BVs to assess transduction and neuropathology. Transgene expression was also assessed in the brain of BV-preimmunized mice. While the expression of BVs was weaker than AdVs in murine and human glioma cell lines, BV-mediated transgene expression in patient-derived glioma cells was similar to AdV-mediated transduction and showed strong correlation with clathrin expression, a protein that interacts with the baculovirus glycoprotein GP64, mediating BV endocytosis. BVs efficiently transduced normal and neoplastic astrocytes in vivo, without apparent neurotoxicity. BV-mediated transgene expression was stable for at least 21 days in the brain of naïve mice, but it was significantly reduced after 7 days in mice systemically preimmunized with BVs. Our findings indicate that BVs efficiently transduce glioma cells and astrocytes without apparent neurotoxicity. Since humans do not present pre-existing immunity against BVs, these vectors may constitute a valuable tool for the delivery of therapeutic genes into the brain.
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- 2023
- Full Text
- View/download PDF
5. Targeting FOXP3 Tumor-Intrinsic Effects Using Adenoviral Vectors in Experimental Breast Cancer
- Author
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Nicola Candia, Alejandro J., primary, Garcia Fallit, Matías, additional, Peña Agudelo, Jorge A., additional, Pérez Küper, Melanie, additional, Gonzalez, Nazareno, additional, Moreno Ayala, Mariela A., additional, De Simone, Emilio, additional, Giampaoli, Carla, additional, Casares, Noelia, additional, Seilicovich, Adriana, additional, Lasarte, Juan José, additional, Zanetti, Flavia A., additional, and Candolfi, Marianela, additional
- Published
- 2023
- Full Text
- View/download PDF
6. Mitochondrial Peptide Humanin Facilitates Chemoresistance in Glioblastoma Cells
- Author
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Peña Agudelo, Jorge A., primary, Pidre, Matías L., additional, Garcia Fallit, Matias, additional, Pérez Küper, Melanie, additional, Zuccato, Camila, additional, Nicola Candia, Alejandro J., additional, Marchesini, Abril, additional, Vera, Mariana B., additional, De Simone, Emilio, additional, Giampaoli, Carla, additional, Amorós Morales, Leslie C., additional, Gonzalez, Nazareno, additional, Romanowski, Víctor, additional, Videla-Richardson, Guillermo A., additional, Seilicovich, Adriana, additional, and Candolfi, Marianela, additional
- Published
- 2023
- Full Text
- View/download PDF
7. Targeting Foxp3 Tumor Intrinsic Effects Using Adenoviral Vectors in Experimental Breast Cancer
- Author
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Nicola Candia, Alejandro Javier, primary, Garcia Fallit, Matias, additional, Peña Agudelo, Jorge Armando, additional, Perez Kuper, Melanie, additional, Gonzalez, Nazareno, additional, Moreno Ayala, Mariela Alejandra, additional, De Simone, Emilio, additional, Giampaoli, Carla, additional, Casares, Noelia, additional, Seilicovich, Adriana, additional, Lasarte, Juan José, additional, Zanetti, Flavia Adriana, additional, and Candolfi, Marianela, additional
- Published
- 2023
- Full Text
- View/download PDF
8. Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración
- Author
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Antonela Sofía Asad, Camila Florencia Zuccato, Alejandro Javier Nicola Candia, María Florencia Gottardo, Mariela Alejandra Moreno Ayala, María Susana Theas, Adriana Seilicovich, and Marianela Candolfi
- Subjects
humanina ,péptido mitocondrial ,cáncer ,enfermedades neurodegenerativas ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
La humanina es un péptido derivado de la mitocondria con efectos protectores robustos contra una gran variedad de estímulos citotóxicos en diversos tipos celulares. Esto la convierte en un blanco terapéutico interesante para muchas enfermedades, como el cáncer y enfermedades neurodegenerativas, entre otras. Además, este péptido podría utilizarse como un biomarcador en estas enfermedades. Durante la última década, han sido desarrollados análogos y péptido-miméticos de la humanina que muestran resultados prometedores en modelos preclínicos. A su vez, también se está explorando el potencial terapéutico de vectores de terapia génica que puedan sobreexpresar o silenciar la humanina endógena. Varios puntos importantes a considerar antes de trasladar estas estrategias terapéuticas a la clínica son su posible papel en la progresión del cáncer y la eventual generación de quimiorresistencia. Todos estos temas serán abordados en este artículo de revisión.
- Published
- 2019
- Full Text
- View/download PDF
9. Current Approaches for Glioma Gene Therapy and Virotherapy
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Kaushik Banerjee, Felipe J. Núñez, Santiago Haase, Brandon L. McClellan, Syed M. Faisal, Stephen V. Carney, Jin Yu, Mahmoud S. Alghamri, Antonela S. Asad, Alejandro J. Nicola Candia, Maria Luisa Varela, Marianela Candolfi, Pedro R. Lowenstein, and Maria G. Castro
- Subjects
gene therapy ,glioma ,viral vectors ,non-viral vectors ,HSV1-TK ,mutant IDH1 3 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
- Published
- 2021
- Full Text
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10. In Vitro and In Vivo Efficacy of a Stroma Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer
- Author
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Alfano, Ana, primary, Cafferata, Eduardo G. A, additional, Gangemi, Mariela, additional, Nicola Candia, Alejandro, additional, Malnero, Cristian M, additional, Bermudez, Ismael, additional, Rios, Gregorio David, additional, Rotondaro, Cecilia, additional, Cuneo, Nicasio, additional, Curiel, David T, additional, Podhajcer, Osvaldo L, additional, and Lopez, Maria Veronica, additional
- Published
- 2023
- Full Text
- View/download PDF
11. Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer
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Moreno Ayala, Mariela A., Gottardo, María Florencia, Zuccato, Camila Florencia, Pidre, Matías Luis, Nicola Candia, Alejandro Javier, Asad, Antonela Sofia, Imsen, Mercedes, Romanowski, Víctor, Creton, Aldo, Isla Larrain, Marina, Seilicovich, Adriana, and Candolfi, Marianela
- Published
- 2020
- Full Text
- View/download PDF
12. Prolactin and its receptor as therapeutic targets in glioblastoma multiforme
- Author
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Asad, Antonela Sofía, Nicola Candia, Alejandro Javier, Gonzalez, Nazareno, Zuccato, Camila Florencia, Abt, Araceli, Orrillo, Santiago Jordi, Lastra, Yael, De Simone, Emilio, Boutillon, Florence, Goffin, Vincent, Seilicovich, Adriana, Pisera, Daniel Alberto, Ferraris, María Jimena, and Candolfi, Marianela
- Published
- 2019
- Full Text
- View/download PDF
13. H3.3-G34R Mutation-Mediated Epigenetic Reprogramming Leads to Enhanced Efficacy of Immune Stimulatory Gene Therapy in Pediatric High-Grade Gliomas
- Author
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Garcia-Fabiani, Maria B., Haase, Santiago, Banerjee, Kaushik, McClellan, Brandon, Zhu, Ziwen, Mujeeb, Anzar, Li, Yingxiang, Yu, Jin, Kadiyala, Padma, Taher, Ayman, Núñez, Felipe J., Alghamri, Mahmoud S., Comba, Andrea, Mendez, Flor M., Nicola Candia, Alejandro J., Salazar, Brittany, Koschmann, Carl, Nunez, Fernando M., Edwards, Marta, Qin, Tingting, Sartor, Maureen A., Lowenstein, Pedro R., and Castro, Maria G.
- Subjects
Article - Abstract
Pediatric high-grade gliomas (pHGGs) are diffuse and highly aggressive CNS tumors which remain incurable, with a 5-year overall survival of less than 20%. Within glioma, mutations in the genes encoding the histones H3.1 and H3.3 have been discovered to be age-restricted and specific of pHGGs. This work focuses on the study of pHGGs harboring the H3.3-G34R mutation. H3.3-G34R tumors represent the 9-15% of pHGGs, are restricted to the cerebral hemispheres, and are found predominantly in the adolescent population (median 15.0 years). We have utilized a genetically engineered immunocompetent mouse model for this subtype of pHGG generated via the Sleeping Beauty-transposon system. The analysis of H3.3-G34R genetically engineered brain tumors by RNA-Sequencing and ChIP-Sequencing revealed alterations in the molecular landscape associated to H3.3-G34R expression. In particular, the expression of H3.3-G34R modifies the histone marks deposited at the regulatory elements of genes belonging to the JAK/STAT pathway, leading to an increased activation of this pathway. This histone G34R-mediated epigenetic modifications lead to changes in the tumor immune microenvironment of these tumors, towards an immune-permissive phenotype, making these gliomas susceptible to TK/Flt3L immune-stimulatory gene therapy. The application of this therapeutic approach increased median survival of H3.3-G34R tumor bearing animals, while stimulating the development of anti-tumor immune response and immunological memory. Our data suggests that the proposed immune-mediated gene therapy has potential for clinical translation for the treatment of patients harboring H3.3-G34R high grade gliomas.
- Published
- 2023
14. In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer
- Author
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Lopez, Ana Alfano, Eduardo G. A. Cafferata, Mariela Gangemi, Alejandro Nicola Candia, Cristian M. Malnero, Ismael Bermudez, Mauricio Vargas Lopez, Gregorio David Ríos, Cecilia Rotondaro, Nicasio Cuneo, David T. Curiel, Osvaldo L. Podhajcer, and Maria Veronica
- Subjects
gynecologic neoplasms ,cytokines ,ovarian cancer ,gene therapy ,adenovirus - Abstract
More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.
- Published
- 2023
- Full Text
- View/download PDF
15. Oncolytic Adenovirus-Loaded Menstrual Blood Stem Cells Overcome the Blockade of Viral Activity Exerted by Ovarian Cancer Ascites
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Ana Laura Alfano, Alejandro Nicola Candia, Nicasio Cuneo, Leandro N. Guttlein, Alejandro Soderini, Cecilia Rotondaro, Leonardo Sganga, Osvaldo L. Podhajcer, and M. Veronica Lopez
- Subjects
CRAd ,ovarian cancer ,MSC ,peritoneal carcinosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Patients with ovarian cancer present peritoneal ascites at recurrence as a marker of disseminated disease and dismal prognosis. Oncolytic immunotherapy is an emerging approach for the treatment of disseminated cancer. In the present work, we constructed a novel oncolytic adenovirus, AR2011, to target malignant ovarian tumors. AR2011 exhibited a clear lytic effect in vitro in human ovarian cancer cell lines and malignant cells obtained from ascitic fluids (AFs) of patients with ovarian cancer. AR2011 activity was neutralized by antibodies present in 31 samples of patient-derived AFs. However, this blockade was overridden by preloading menstrual blood stem cells (MenSCs) with AR2011 (MenSC-AR), since AFs exerted no in vitro inhibitory effect on viral lytic activity under these conditions. Moreover, soluble factors present in AFs act as MenSC chemoattractants. MenSC-AR treatment of nude mice carrying established peritoneal carcinomatosis following administration of human ovarian cancer cells was able to inhibit tumor growth at levels similar to those observed with AR2011 alone. This study demonstrates that MenSCs can be used to override the blockade that AFs exert on viral oncolytic effects.
- Published
- 2017
- Full Text
- View/download PDF
16. Evaluation of Baculoviruses as Gene Therapy Vectors for Brain Cancer
- Author
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Garcia Fallit, Matías, primary, Pidre, Matías L., additional, Asad, Antonela S., additional, Peña Agudelo, Jorge A., additional, Vera, Mariana B., additional, Nicola Candia, Alejandro J., additional, Sagripanti, Sofia B., additional, Pérez Kuper, Melanie, additional, Amorós Morales, Leslie C., additional, Marchesini, Abril, additional, Gonzalez, Nazareno, additional, Caruso, Carla M., additional, Romanowski, Víctor, additional, Seilicovich, Adriana, additional, Videla-Richardson, Guillermo A., additional, Zanetti, Flavia A., additional, and Candolfi, Marianela, additional
- Published
- 2023
- Full Text
- View/download PDF
17. Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer
- Author
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Moreno Ayala, Mariela A., Gottardo, María Florencia, Gori, María Soledad, Nicola Candia, Alejandro Javier, Caruso, Carla, De Laurentiis, Andrea, Imsen, Mercedes, Klein, Slobodanka, Bal de Kier Joffé, Elisa, Salamone, Gabriela, Castro, Maria G., Seilicovich, Adriana, and Candolfi, Marianela
- Published
- 2017
- Full Text
- View/download PDF
18. Potential of IDH mutations as immunotherapeutic targets in gliomas: a review and meta-analysis
- Author
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Nazareno Gonzalez, Antonela S. Asad, José Gómez Escalante, Jorge A. Peña Agudelo, Alejandro J. Nicola Candia, Matías García Fallit, Adriana Seilicovich, and Marianela Candolfi
- Subjects
Pharmacology ,Brain Neoplasms ,Mutation ,Clinical Biochemistry ,Drug Discovery ,Tumor Microenvironment ,Humans ,Molecular Medicine ,Glioma ,Immunotherapy ,Isocitrate Dehydrogenase - Abstract
Gliomas are stratified by the presence of a hotspot mutation in the enzyme isocitrate dehydrogenase genes (IDH1/2). While mutated IDH (mIDH) correlates with better prognosis, the role of this mutation in antitumor immunity and the response to immunotherapy is not completely understood. Understanding the relationship between the genetic features of these tumors and the tumor immune microenvironment (TIME) may help to develop appropriate therapeutic strategies.In this review we discussed the available literature related to the potential role of IDH mutations as an immunotherapeutic target in gliomas and profiled the immune transcriptome of glioma biopsies. We aimed to shed light on the role of mIDH on the immunological landscape of the different subtypes of gliomas, taking into account the most recent WHO classification of tumors of the central nervous system (CNS). We also discussed different immunotherapeutic approaches to target mIDH tumors and to overcome their immunosuppressive microenvironment.Data presented here indicates that the TIME not only differs in association with IDH mutation status, but also within glioma subtypes, suggesting that the cellular context affects the overall effect of this genetic lesion. Thus, specific therapeutic combinations may help patients diagnosed with different glioma subtypes.
- Published
- 2021
19. Current Non-viral Gene Therapy Strategies for the Treatment of Glioblastoma
- Author
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Alejandro Javier Nicola Candia, Camila Florencia Zuccato, Adriana Seilicovich, Antonela Sofía Asad, Marianela Candolfi, and Nazareno González
- Subjects
Pharmacology ,Tumor microenvironment ,Brain Neoplasms ,business.industry ,Transgene ,Genetic enhancement ,Organic Chemistry ,Genetic Therapy ,Glioma ,Gene delivery ,medicine.disease ,Bioinformatics ,Biochemistry ,Viral gene ,Viral vector ,Clinical trial ,Blood-Brain Barrier ,Drug Discovery ,Tumor Microenvironment ,medicine ,Humans ,Molecular Medicine ,Glioblastoma ,business - Abstract
Background: Glioblastoma constitutes the most frequent and aggressive primary malignant brain tumor in adults. Despite the advances in its treatment, its prognosis remains very poor. Gene therapy has been proposed as a complementary treatment since it may overcome the problem of the blood-brain barrier for systemic therapies, allowing to target tumor cells and their tumor microenvironment locally, without affecting the normal brain parenchyma. In comparison with viral vectors, non-viral vectors became an attractive tool due to their reduced potential of biosafety risks, lower cost, higher availability, and easy storage. Objective: In this article, we aimed to outline the current preclinical and clinical developments of non-viral delivery systems for therapeutic transgene delivery in malignant gliomas. Conclusion: Non-viral vectors are efficient tools for gene delivery since they exhibit reduced non-specific cytotoxicity and can go through several modifications in order to achieve high tumor tropism and the ability to cross the blood-brain barrier to access the tumor mass. However, further evaluations in preclinical models and clinical trials are required in order to translate it into the neuro-oncology clinic.
- Published
- 2021
20. Breast cancer progression and kynurenine pathway enzymes are induced by hexachlorobenzene exposure in a Her2-positive model
- Author
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Lorena V. Zárate, Noelia V. Miret, Alejandro J. Nicola Candia, C. Daniel Zappia, Carolina A. Pontillo, Florencia A. Chiappini, Federico Monczor, Marianela Candolfi, and Andrea S. Randi
- Subjects
General Medicine ,Toxicology ,Food Science - Published
- 2023
21. In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer.
- Author
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Alfano, Ana, Cafferata, Eduardo G. A., Gangemi, Mariela, Nicola Candia, Alejandro, Malnero, Cristian M., Bermudez, Ismael, Lopez, Mauricio Vargas, Ríos, Gregorio David, Rotondaro, Cecilia, Cuneo, Nicasio, Curiel, David T., Podhajcer, Osvaldo L., and Lopez, Maria Veronica
- Subjects
ADENOVIRUSES ,TUMOR microenvironment ,ANIMAL models in research ,OVARIAN cancer ,UTERINE cancer ,NEOADJUVANT chemotherapy - Abstract
More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
22. Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración
- Author
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Alejandro Javier Nicola-Candia, Adriana Seilicovich, María Florencia Gottardo, Mariela Alejandra Moreno-Ayala, Camila Florencia Zuccato, Marianela Candolfi, Antonela Sofía Asad, and María Susana Theas
- Subjects
Humanina ,lcsh:R5-920 ,lcsh:Biology (General) ,cáncer ,enfermedades neurodegenerativas ,humanina ,cancer ,neurodegenerative diseases ,péptido mitocondrial ,mitochondrial-derived peptide ,lcsh:Medicine (General) ,lcsh:QH301-705.5 ,Humanin - Abstract
Resumen La humanina es un péptido derivado de la mitocondria con efectos protectores robustos contra una gran variedad de estímulos citotóxicos en diversos tipos celulares. Esto la convierte en un blanco terapéutico interesante para muchas enfermedades, como el cáncer y enfermedades neurodegenerativas, entre otras. Además, este péptido podría utilizarse como un biomarcador en estas enfermedades. Durante la última década, han sido desarrollados análogos y péptido-miméticos de la humanina que muestran resultados prometedores en modelos preclínicos. A su vez, también se está explorando el potencial terapéutico de vectores de terapia génica que puedan sobreexpresar o silenciar la humanina endógena. Varios puntos importantes a considerar antes de trasladar estas estrategias terapéuticas a la clínica son su posible papel en la progresión del cáncer y la eventual generación de quimiorresistencia. Todos estos temas serán abordados en este artículo de revisión. Abstract Humanin is a mitochondrial-derived peptide which shows robust protective effects against large series of cytotoxic stimuli in many cell types. This makes it an interesting therapeutic target for many diseases, including cancer and neurodegenerative diseases, among others. Furthermore, this peptide could be used as a biomarker for such diseases. Over the last decade, humanin analogs and peptide mimetics have been developed, which exert highly promising results in preclinical models. Besides, the therapeutic potential of gene therapy vectors that overexpress or silence endogenous humanin is under evaluation. Nonetheless, its possible role in cancer progression and chemoresistance are critical issues to be addressed before translating these therapeutic approaches to the clinic. All these matters will be covered in this review.
- Published
- 2019
23. Potential of IDH mutations as immunotherapeutic targets in gliomas: a review and meta-analysis
- Author
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Gonzalez, Nazareno, primary, Asad, Antonela S., additional, Gómez Escalante, José, additional, Peña Agudelo, Jorge A., additional, Nicola Candia, Alejandro J., additional, García Fallit, Matías, additional, Seilicovich, Adriana, additional, and Candolfi, Marianela, additional
- Published
- 2021
- Full Text
- View/download PDF
24. Humanin promotes tumor progression in experimental triple negative breast cancer
- Author
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Marina Teresita Isla Larrain, Mariela A. Moreno Ayala, Matías Luis Pidre, Mercedes Imsen, Alejandro Javier Nicola Candia, Adriana Seilicovich, Antonela Sofía Asad, María Florencia Gottardo, Marianela Candolfi, Víctor Romanowski, Camila Florencia Zuccato, and Aldo Creton
- Subjects
Lung Neoplasms ,medicine.medical_treatment ,Mammary gland ,lcsh:Medicine ,Apoptosis ,Triple Negative Breast Neoplasms ,Mice ,Breast cancer ,Tumor Cells, Cultured ,Medicine ,lcsh:Science ,Triple-negative breast cancer ,Aged, 80 and over ,Mice, Inbred BALB C ,Multidisciplinary ,Intracellular Signaling Peptides and Proteins ,Patología ,purl.org/becyt/ford/3.1 [https] ,Middle Aged ,Prognosis ,Tumor progression ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Medicina Básica ,medicine.anatomical_structure ,Systemic administration ,Disease Progression ,Female ,purl.org/becyt/ford/3 [https] ,Adult ,CIENCIAS MÉDICAS Y DE LA SALUD ,Adolescent ,Mice, Nude ,Article ,Young Adult ,BREAST CANCER ,Biomarkers, Tumor ,Animals ,Humans ,Cancer models ,Ciencias Exactas ,Humanin ,Aged ,Cell Proliferation ,Chemotherapy ,business.industry ,lcsh:R ,medicine.disease ,Xenograft Model Antitumor Assays ,HUMANIN ,Ciencias Médicas ,Cancer research ,lcsh:Q ,business - Abstract
Humanin (HN) is a mitochondrial-derived peptide with cytoprotective efect in many tissues. Administration of HN analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the efect of HN on the progression of experimental triple negative breast cancer (TNBC). The meta-analysis of transcriptomic data from The Cancer Genome Atlas indicated that HN and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of HN in TNBC biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous HN protected TNBC cells from apoptotic stimuli whereas shRNA-mediated HN silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic efect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These fndings suggest that HN may exert pro-tumoral efects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efcacy of chemotherapy in breast cancer., Instituto de Biotecnologia y Biologia Molecular
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- 2020
25. Current Approaches for Glioma Gene Therapy and Virotherapy
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Kaushik Banerjee, Felipe J. Núñez, Santiago Haase, Brandon L. McClellan, Syed M. Faisal, Stephen V. Carney, Jin Yu, Mahmoud S. Alghamri, Antonela S. Asad, Alejandro J. Nicola Candia, Maria Luisa Varela, Marianela Candolfi, Pedro R. Lowenstein, and Maria G. Castro
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0301 basic medicine ,viral vectors ,Genetic enhancement ,medicine.medical_treatment ,mutant IDH1 3 ,Review ,Viral vector ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,HSV1-TK ,Glioma ,glioma ,non-viral vectors ,Medicine ,Virotherapy ,Molecular Biology ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,FMS-like tyrosine kinase 3 ligand ,Tumor microenvironment ,business.industry ,Immunotherapy ,medicine.disease ,gene therapy ,Oncolytic virus ,030104 developmental biology ,030220 oncology & carcinogenesis ,Drug delivery ,Cancer research ,immunotherapy ,business ,Neuroscience - Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
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- 2020
26. The role of the prolactin receptor pathway in the pathogenesis of glioblastoma: what do we know so far?
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Antonela Sofía Asad, Adriana Seilicovich, Alejandro Javier Nicola Candia, Marianela Candolfi, Nazareno González, and Camila Florencia Zuccato
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0301 basic medicine ,Adult ,Male ,Receptors, Prolactin ,Genetic enhancement ,Clinical Biochemistry ,Brain tumor ,Disease ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Molecular Targeted Therapy ,Receptor ,Pharmacology ,business.industry ,Brain Neoplasms ,Prolactin receptor ,Genetic Therapy ,medicine.disease ,Prognosis ,Prolactin ,nervous system diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Female ,business ,Glioblastoma ,Hormone - Abstract
Introduction: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies. GBM is the most common and aggressive primary brain tumor in adults and the prognosis for patients is dismal; hence researchers are exploring the PRLR pathway as a therapeutic target in this disease. Areas covered: This paper explores the effects of PRLR activation on the biology of GBM, the correlation between PRL and PRLR expression and GBM progression and survival in male and female patients. Finally, we discuss how a better understanding of the PRLR pathway may allow the development of novel treatments for GBM. Expert opinion: We propose PRL and PRLR as potential prognosis biomarkers and therapeutic targets in GBM. Local administration of PRLR inhibitors using gene therapy may offer a beneficial strategy for targeting GBM cells disseminated in the non-neoplastic brain; however, efficacy and safety require careful and extensive evaluation. The data depicted herein underline the need to (i) improve our understanding of sexual dimorphism in GBM, and (ii) develop accurate preclinical models that take into consideration different hormonal contexts, specific genetic alterations, and tumor grades.
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- 2020
27. Immunotherapy for gliomas: shedding light on progress in preclinical and clinical development
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Stephen Carney, Andrea Comba, Maria B. Garcia-Fabiani, Alejandro Javier Nicola Candia, Ava Mauser, Anna Schwendeman, Maria Ventosa, Marianela Candolfi, Lindsay Scheetz, Pedro R. Lowenstein, Mahmoud S. Alghamri, Padma Kadiyala, James J. Moon, Joerg Lahann, Maria G. Castro, and Syed M Faisal
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0301 basic medicine ,Oncology ,Surgical resection ,medicine.medical_specialty ,CIENCIAS MÉDICAS Y DE LA SALUD ,Standard of care ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Ciencias de la Salud ,DENDRITIC CELLS ,CHECKPOINT INHIBITOR ,03 medical and health sciences ,High morbidity ,purl.org/becyt/ford/3.3 [https] ,0302 clinical medicine ,Internal medicine ,Glioma ,VACCINES ,parasitic diseases ,medicine ,Tumor Microenvironment ,NANOPARTICLES ,Animals ,Humans ,Pharmacology (medical) ,IMMUNOTHERAPY ,CAR T-CELL ,Pharmacology ,Chemotherapy ,IMMUNOSUPPRESSION ,business.industry ,Brain Neoplasms ,Immunosuppression ,General Medicine ,Immunotherapy ,medicine.disease ,Otras Ciencias de la Salud ,Survival Rate ,030104 developmental biology ,ANTIBODY ,030220 oncology & carcinogenesis ,GLIOMA ,VIRUS ,purl.org/becyt/ford/3 [https] ,business - Abstract
Gliomas are infiltrating brain tumors associated with high morbidity and mortality. Current standard of care includes radiation, chemotherapy and surgical resection. Today, survival rates for malignant glioma patients remain dismal and unchanged for decades. The glioma microenvironment is highly immunosuppressive and consequently this has motivated the development of immunotherapies for counteracting this condition, enabling the immune cells within the tumor microenvironment to react against this tumor.Areas covered: The authors discuss immunotherapeutic strategies for glioma in phase-I/II clinical trials and illuminate their mechanisms of action, limitations and key challenges. They also examine promising approaches under preclinical development.Expert opinion: In the last decade there has been an expansion in immune-mediated anti-cancer therapies. In the glioma field, sophisticated strategies have been successfully implemented in preclinical models. Unfortunately, clinical trials have not yet yielded consistent results for glioma patients. This could be attributed to our limited understanding of the complex immune cell infiltration and its interaction with the tumor cells, the selected time for treatment, the combination with other therapies and the route of administration of the agent. Applying these modalities to treat malignant glioma is challenging, but many new alternatives are emerging to by-pass these hurdles. Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ventosa, Maria. University of Michigan; Estados Unidos Fil: Comba, Andrea. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Alghamri, Mahmoud S.. University of Michigan; Estados Unidos Fil: Kadiyala, Padma. University of Michigan; Estados Unidos Fil: Carney, Stephen. University of Michigan; Estados Unidos Fil: Faisal, Syed M.. University of Michigan; Estados Unidos Fil: Schwendeman, Anna. University of Michigan; Estados Unidos Fil: Moon, James J.. University of Michigan; Estados Unidos Fil: Scheetz, Lindsay. University of Michigan; Estados Unidos Fil: Lahann, Joerg. University of Michigan; Estados Unidos Fil: Mauser, Ava. University of Michigan; Estados Unidos Fil: Lowenstein, Pedro R.. University of Michigan; Estados Unidos Fil: Castro, Maria Gabriela. University of Michigan; Estados Unidos
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- 2020
28. Prospects of Biological and Synthetic Pharmacotherapies for Glioblastoma
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Marianela Candolfi, Mahmoud S. Alghamri, David B. Altshuler, Maria G. Castro, Felipe J Nunez, Padma Kadiyala, Antonela Sofía Asad, Stephen Carney, Anna Schwendeman, Joerg Lahann, Alejandro Javier Nicola Candia, Fernando M. Nunez, Pedro R. Lowenstein, James J. Moon, and Maria B. Garcia-Fabiani
- Subjects
0301 basic medicine ,CIENCIAS MÉDICAS Y DE LA SALUD ,Genetic enhancement ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Clinical Biochemistry ,GENE THERAPY ,Cancer Vaccines ,Immunotherapy, Adoptive ,Article ,03 medical and health sciences ,0302 clinical medicine ,Glioma ,IDH1 Mutation ,Drug Discovery ,Medicine ,Humans ,IMMUNE CHECKPOINT INHIBITORS ,IMMUNOTHERAPY ,Immune Checkpoint Inhibitors ,Pharmacology ,Oncolytic Virotherapy ,IDH1 MUTATION ,business.industry ,Brain Neoplasms ,Immunotherapy ,Genetic Therapy ,medicine.disease ,Isocitrate Dehydrogenase ,Otras Ciencias Médicas ,030104 developmental biology ,Nanomedicine ,030220 oncology & carcinogenesis ,Cancer research ,GLIOMA ,business ,Glioblastoma - Abstract
Introduction: The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of this review is to describe the state of basic, translational, and clinical research as it pertains to biological and synthetic pharmacotherapy for gliomas. Areas covered: Challenges remain in designing accurate preclinical models and identifying patients that are likely to respond to a particular targeted therapy. Preclinical models for therapeutic assessment are critical to identify the most promising treatment approaches. Expert opinion: Despite promising new therapeutics, there have been no significant breakthroughs in glioma treatment and patient outcomes. Thus, there is an urgent need to better understand the mechanisms of treatment resistance and to design effective clinical trials. Fil: Altshuler, David B.. University of Michigan; Estados Unidos Fil: Kadiyala, Padma. University of Michigan; Estados Unidos Fil: Nuñez, Felipe J.. University of Michigan; Estados Unidos Fil: Nuñez, Fernando M.. University of Michigan; Estados Unidos Fil: Carney, Stephen. University of Michigan; Estados Unidos Fil: Alghamri, Mahmoud S.. University of Michigan; Estados Unidos Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos Fil: Asad, Antonela Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Lahann, Joerg. University of Michigan; Estados Unidos Fil: Moon, James J.. University of Michigan; Estados Unidos Fil: Schwendeman, Anna. University of Michigan; Estados Unidos Fil: Lowenstein, Pedro R.. University of Michigan; Estados Unidos Fil: Castro, Maria G.. University of Michigan; Estados Unidos
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- 2020
29. Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración
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Asad, Antonela Sofía, Zuccato, Camila Florencia, Nicola Candia, Alejandro Javier, Gottardo, María Florencia, Moreno Ayala, Mariela Alejandra, Theas, María Susana, Seilicovich, Adriana, and Candolfi, Marianela
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Humanina ,cáncer ,enfermedades neurodegenerativas ,cancer ,neurodegenerative diseases ,péptido mitocondrial ,mitochondrial-derived peptide ,Humanin - Abstract
Humanin is a mitochondrial-derived peptide which shows robust protective effects against large series of cytotoxic stimuli in many cell types. This makes it an interesting therapeutic target for many diseases, including cancer and neurodegenerative diseases, among others. Furthermore, this peptide could be used as a biomarker for such diseases. Over the last decade, humanin analogs and peptide mimetics have been developed, which exert highly promising results in preclinical models. Besides, the therapeutic potential of gene therapy vectors that overexpress or silence endogenous humanin is under evaluation. Nonetheless, its possible role in cancer progression and chemoresistance are critical issuesto be addressed before translating these therapeutic approaches to the clinic. All these matters will be covered in this review. La humanina es un péptido derivado de la mitocondria con efectos protectores robustos contra una gran variedad de estímulos citotóxicos en diversos tipos celulares. Esto la convierte en un blanco terapéutico interesante para muchas enfermedades, como el cáncer y enfermedades neurodegenerativas, entre otras. Además, este péptido podría utilizarse como un biomarcador en estas enfermedades. Durante la última década, han sido desarrollados análogos y péptido-miméticos de la humanina que muestran resultados prometedores en modelos preclínicos. A su vez, también se está explorando el potencial terapéutico de vectores de terapia génica que puedan sobreexpresar o silenciar la humanina endógena.Varios puntos importantes a considerar antes de trasladar estas estrategias terapéuticas a la clínica son su posible papel en la progresión del cáncer y la eventual generación de quimiorresistencia. Todos estos temas serán abordados en este artículo de revisión.
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- 2019
30. The role of the prolactin receptor pathway in the pathogenesis of glioblastoma: what do we know so far?
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Asad, Antonela S, primary, Nicola Candia, Alejandro J, additional, Gonzalez, Nazareno, additional, Zuccato, Camila F, additional, Seilicovich, Adriana, additional, and Candolfi, Marianela, additional
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- 2020
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31. Immunotherapy for gliomas: shedding light on progress in preclinical and clinical development
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Garcia-Fabiani, Maria B., primary, Ventosa, Maria, additional, Comba, Andrea, additional, Candolfi, Marianela, additional, Nicola Candia, Alejandro J., additional, Alghamri, Mahmoud S., additional, Kadiyala, Padma, additional, Carney, Stephen, additional, Faisal, Syed M., additional, Schwendeman, Anna, additional, Moon, James J., additional, Scheetz, Lindsay, additional, Lahann, Joerg, additional, Mauser, Ava, additional, Lowenstein, Pedro R., additional, and Castro, Maria G., additional
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- 2020
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32. Prospects of biological and synthetic pharmacotherapies for glioblastoma
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Altshuler, David B., primary, Kadiyala, Padma, additional, Nuñez, Felipe J., additional, Nuñez, Fernando M., additional, Carney, Stephen, additional, Alghamri, Mahmoud S., additional, Garcia-Fabiani, Maria B., additional, Asad, Antonela S., additional, Nicola Candia, Alejandro J., additional, Candolfi, Marianela, additional, Lahann, Joerg, additional, Moon, James J., additional, Schwendeman, Anna, additional, Lowenstein, Pedro R., additional, and Castro, Maria G., additional
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- 2020
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33. Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases
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María Susana Theas, Alejandro Javier Nicola Candia, Mariela Alejandra Moreno Ayala, Adriana Seilicovich, María Florencia Gottardo, Camila Florencia Zuccato, Marianela Candolfi, and Antonela Sofía Asad
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0301 basic medicine ,CIENCIAS MÉDICAS Y DE LA SALUD ,Clinical Biochemistry ,Biotecnología relacionada con la Salud ,MITOCHONDRIAL-DERIVED PEPTIDES ,THERAPEUTIC TARGETS ,Biotecnología de la Salud ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Medicine ,Molecular Targeted Therapy ,Humanin ,Pharmacology ,business.industry ,Intracellular Signaling Peptides and Proteins ,Cancer ,Neurodegenerative Diseases ,Genetic Therapy ,medicine.disease ,CANCER ,Mitochondria ,Disease Models, Animal ,030104 developmental biology ,HUMANIN ,Cardiovascular Diseases ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,business - Abstract
Introduction: Mitochondrial-derived peptides (MDPs) are encoded within the mitochondrial genome. They signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors playing a key role in the cellular stress response. The first reported and better characterized MDP is humanin (HN), which exerts robust protective effects against a myriad of cytotoxic stimuli in many cell types. These effects have led to the evaluation of HN and its analogs as therapeutic targets for several chronic diseases. Areas covered: We describe the latest findings on the mechanism of action of HN and discuss the role of HN as therapeutic target for neurodegenerative and cardiovascular diseases, diabetes, male infertility, and cancer. Since HN can be detected in circulation, we also depict its value as a biomarker for these diseases. Expert opinion: HN analogs and peptide mimetics have been developed over the last decade and show promising results in preclinical models of degenerative diseases. Local administration of gene therapy vectors that overexpress or silence endogenous HN could also hold therapeutic potential. Controversy on the role of HN in cancer progression and chemoresistance should be addressed before the translation of these therapeutic approaches. Fil: Zuccato, Camila Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Asad, Antonela Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Gottardo, María Florencia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Moreno Ayala, Mariela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of California; Estados Unidos Fil: Theas, Maria Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Seilicovich, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
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- 2019
34. Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases
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Zuccato, Camila Florencia, primary, Asad, Antonela Sofia, additional, Nicola Candia, Alejandro Javier, additional, Gottardo, María Florencia, additional, Moreno Ayala, Mariela Alejandra, additional, Theas, María Susana, additional, Seilicovich, Adriana, additional, and Candolfi, Marianela, additional
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- 2018
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35. Viral gene therapy for breast cancer: progress and challenges
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Flavia Adriana Zanetti, Marianela Candolfi, Mariela A. Moreno Ayala, Camila Florencia Zuccato, Antonela Sofía Asad, M Florencia Gottardo, Adriana Seilicovich, and Alejandro Javier Nicola Candia
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0301 basic medicine ,Clinical Biochemistry ,Genetic Vectors ,Breast Neoplasms ,Biology ,Viral gene ,Metastasis ,Adenoviridae ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Neural Stem Cells ,Drug Discovery ,medicine ,Humans ,Pharmacology ,Oncolytic Virotherapy ,Poxviridae ,Lentivirus ,Mesenchymal Stem Cells ,medicine.disease ,Virology ,Oncolytic Viruses ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female - Abstract
Breast cancer is the most common cancer in women all over the world. Furthermore, up to one third of breast tumors develop metastases that are resistant to standard therapies. Gene therapeutic strategies have been developed in order to specifically target cancer cells either directly or through the stimulation of antitumor immunity. Areas covered: This review describes the therapeutic strategies that are currently under development to treat this disease using engineered viral vectors including: adenovirus, adeno-associated virus, lentivirus, poxvirus, reovirus, baculovirus, herpesvirus and oncolytic viruses. Advantages and disadvantages of these multiple gene therapy platforms are discussed in detail. Expert opinion: Metastatic breast cancer is a perfect candidate for gene therapy approaches due to the presence of several tumor antigens and the aberrant expression of many molecular pathways. Oncolytic vectors are able to attack tumor cells while sparing normal cells and their activity is often enhanced by the administration of chemotherapy. However, more efforts are needed in order to reduce toxicity and to achieve better transduction efficiency. Improved preclinical models and a more critical patient selection for clinical trials, along with advances in gene therapy regulations, will surely facilitate the evolution of gene therapy for the treatment of metastatic breast cancer.
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- 2017
36. Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer
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Maria G. Castro, Adriana Seilicovich, Andrea De Laurentiis, Alejandro Javier Nicola Candia, Elisa Bal de Kier Joffé, Mariela A. Moreno Ayala, Gabriela Salamone, María Florencia Gottardo, Mercedes Imsen, Marianela Candolfi, Carla Mariana Caruso, María Soledad Gori, and Slobodanka Klein
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0301 basic medicine ,Agonist ,Cancer Research ,CIENCIAS MÉDICAS Y DE LA SALUD ,medicine.drug_class ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Stimulation ,Breast Neoplasms ,Adenocarcinoma ,R848 ,Cancer Vaccines ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Adjuvants, Immunologic ,Breast Cancer ,medicine ,Animals ,Humans ,Receptor ,Mice, Inbred BALB C ,Dendritic Cell Vaccines ,Toll-Like Receptors ,Otras Medicina Básica ,TLR9 ,hemic and immune systems ,General Medicine ,TLR7 ,Dendritic cell ,Dendritic Cells ,Blockade ,Mice, Inbred C57BL ,Medicina Básica ,030104 developmental biology ,Oncology ,Toll-Like Receptor 7 ,Toll-Like Receptor 9 ,Cpg ,Immunology ,Cancer research ,Female ,Adjuvant ,030215 immunology - Abstract
Purpose: Since combination of Toll-like receptor (TLR) ligands could boost antitumor immunity, we evaluated the efficacy of dendritic cell (DC) vaccines upon dual activation of TLR9 and TLR7 in breast cancer models. Methods: DCs were generated from mouse bone marrow or peripheral blood from healthy human donors and stimulated with CpG1826 (mouse TLR9 agonist), CpG2006 or IMT504 (human TLR9 agonists) and R848 (TLR7 agonist). Efficacy of antitumor vaccines was evaluated in BALB/c mice bearing metastatic mammary adenocarcinomas. Results: CpG-DCs improved the survival of tumor-bearing mice, reduced the development of lung metastases and generated immunological memory. However, dual activation of TLRs impaired the efficacy of DC vaccines. In vitro, we found that R848 inhibited CpG-mediated maturation of murine DCs. A positive feedback loop in TLR9 mRNA expression was observed upon CpG stimulation that was inhibited in the presence of R848. Impaired activation of NF-κB was detected when TLR9 and TLR7 were simultaneously activated. Blockade of nitric oxide synthase (NOS) and indoleamine-pyrrole-2,3-dioxygenase (IDO) improved the activation of CpG-DCs. When we evaluated the effect of combined activation of TLR9 and TLR7 in human DCs, we found that R848 induced robust DC activation that was inhibited by TLR9 agonists. Conclusions: These observations provide insight in the biology of TLR9 and TLR7 crosstalk and suggest caution in the selection of agonists for multiple TLR stimulation. Blockade of NOS and IDO could improve the maturation of antitumor DC vaccines. R848 could prove a useful adjuvant for DC vaccines in human patients. Fil: Moreno Ayala, Mariela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Gottardo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Biología Celular e Histología; Argentina Fil: Gori, María Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Caruso, Carla Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Biología Celular e Histología; Argentina Fil: de Laurentiis, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Fisiología; Argentina Fil: Imsen, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Klein, Slobodanka Mariana. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; Argentina Fil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Biología Celular e Histología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Salamone, Gabriela Veronica. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Castro, Maria G.. University of Michigan; Estados Unidos Fil: Seilicovich, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Biología Celular e Histología; Argentina Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
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- 2017
37. Abstract 1951: Role of mitochondrial peptide Humanin in the response of experimental breast cancer to chemotherapy
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Mariela A. Moreno Ayala, Alejandro Javier Nicola Candia, María Florencia Gottardo, Adriana Seilicovich, Marianela Candolfi, Víctor Romanowski, Matías Luis Pidre, Camila Florencia Zuccato, and Antonela Sofía Asad
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0301 basic medicine ,Cisplatin ,Cancer Research ,business.industry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Oncology ,chemistry ,Tumor progression ,Cancer research ,medicine ,Cytotoxic T cell ,Doxorubicin ,Propidium iodide ,business ,Clonogenic assay ,Triple-negative breast cancer ,Humanin ,medicine.drug - Abstract
Humanin (HN) is a mitochondrial-derived peptide with potent cytoprotective effect in many cell types. Administration of HN has been proposed as a therapeutic approach for several chronic diseases, such as diabetes, neurodegenerative conditions and cardiovascular diseases. Although HN has been shown to protect normal tissues against the toxic effects of chemotherapy, its role in tumor chemoresistance is poorly understood. Here, we aimed to elucidate the role of HN in the progression and cytotoxic response of experimental triple negative breast cancer (TNBC). We detected HN expression in murine and human TNBC cells, which was upregulated in the presence of chemotherapeutic drugs, i.e. Doxorubicin (DOXO) and Cisplatin, as assessed by flow cytometry. Addition of HN protected TNBC cells from various cytotoxic insults, such as serum deprivation, proapoptotic cytokine TNF-α or chemotherapy with DOXO. We next evaluated the role of endogenous HN in the apoptotic response of TNBC cells, using a plasmid encoding a short hairpin RNA to inhibit HN expression (pUC.shHN). To readily assess transduction efficiency, the plasmid also encodes the red fluorescent protein dTomato as a reporter gene. Transfection of TNBC 4T1 tumor cells with pUC.shHN increased the percentage of apoptotic cells when compared to cells transfected with control plasmid, as assessed by flow cytometry after staining with propidium iodide. When transfected 4T1 cells were incubated with different concentrations of DOXO, pUC.shHN reduced their clonogenic capacity. We also evaluated the effect of HN in the progression of experimental mouse 4T1 TNBC treated with DOXO. HN was readily detected in tumor samples and lung metastases. Systemic administration of HN reduced tumor apoptotic rate, accelerated tumor progression and increased the development of lung metastases. In addition, administration of HN impaired the antitumor and antimetastatic effect of chemotherapy. In summary, our findings suggest that HN inhibits the response of TNBC cells to cytotoxic stimuli, facilitating tumor progression and chemoresistance. Thus, blockade of HN could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer. Citation Format: Camila Zuccato, Mariela A. Moreno Ayala, Maria F. Gottardo, Matias Luis Pidre, Antonela S. Asad, Alejandro J. Nicola Candia, Victor Romanowski, Adriana Seilicovich, Marianela Candolfi. Role of mitochondrial peptide Humanin in the response of experimental breast cancer to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1951.
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- 2018
38. Oncolytic Adenovirus-Loaded Menstrual Blood Stem Cells Overcome the Blockade of Viral Activity Exerted by Ovarian Cancer Ascites
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Alfano, Ana Laura, primary, Nicola Candia, Alejandro, additional, Cuneo, Nicasio, additional, Guttlein, Leandro N., additional, Soderini, Alejandro, additional, Rotondaro, Cecilia, additional, Sganga, Leonardo, additional, Podhajcer, Osvaldo L., additional, and Lopez, M. Veronica, additional
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- 2017
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39. Viral gene therapy for breast cancer: progress and challenges
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Asad, Antonela S., primary, Moreno Ayala, Mariela A., additional, Gottardo, M. Florencia, additional, Zuccato, Camila, additional, Nicola Candia, Alejandro Javier, additional, Zanetti, Flavia A., additional, Seilicovich, Adriana, additional, and Candolfi, Marianela, additional
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- 2017
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40. 50. Efficacy of an Improved Cancer Stroma-Targeted Oncolytic Adenovirus on Human Derived Gynecologic Tumor Samples
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Mariela A. Gangemi, Cristian Miguel Malnero, Nicasio Cuneo, Alejandro Soderini, Ismael Rodolfo Bermúdez, Veronica M. Lopez, Alejandro Nicola Candia, Ana Laura Alfano, and Osvaldo L. Podhajcer
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Cervical cancer ,Oncolytic adenovirus ,Pharmacology ,Tumor microenvironment ,biology ,Uterus ,medicine.disease ,biology.organism_classification ,HeLa ,medicine.anatomical_structure ,Uterine cancer ,Immunology ,Drug Discovery ,Cancer research ,medicine ,Genetics ,Molecular Medicine ,Ovarian cancer ,Cervix ,Molecular Biology - Abstract
Gynecologic cancers originated in the female reproductive organs, including the cervix, ovaries, uterus, fallopian tubes, vagina and vulva. In 2013, it was estimated that 91,730 women would be diagnosed with a gynecologic cancer. Cervical cancer accounted for approximately 13%, ovarian cancer 24% and uterine cancer 54% of cases of cancer (American Cancer Society, Inc). We have recently developed a stroma-targeted CRAd also responsive to the tumor microenvironment, AdF512v4, that contain a chimeric promoter that combines a 0.5 Kb of the SPARC promoter, a Hypoxia-Response Element (HRE) and a NFkB-response element (NFkB). The chimeric promoter drives the expression of delta-RB E1A and the CRAd was pseudotyped with a chimeric fiber 5/3. We also constructed the non-replicative version of AdF512v4 (AdF512v4-luc). We have previously demonstrated the activity of the new promoter in ovarian cancer cell lines. First, we assessed the promoter activity following transduction of cervix cancer cell lines (HeLa, CaSki and SiHa) with the non-replicative adenovirus. We observed 10-35 fold induction of luciferase activity under hypoxic condition (0.1% O2) or/and TNF treatment (5 ng/ml). Next, we measured the efficacy of the CRAd in the 3 cervical cancer cell lines under normal oxygen levels (21% O2), hypoxic condition or TNF treatment. By using the MTS assay we observed that the larger lytic capacity was obtained in the presence of TNF treatment. In order to establish the potential clinical utility of AdF512v4 we assayed its replication capacity in a most rigorous preclinical setting by using slices obtained from fresh tissue explants of human tumors. AdF512v4 replicated in three out of six human cervix cancers, one tumor from uterus and three of four human ovarian carcinomas with no lytic effect on the paired normal tissues. It is of note that Ad-wt 5/3 could replicate in both malignant and normal ovarian samples. In conclusion, AdF512v4 demonstrated a strong killing effect on cervix and ovarian cancer cells in vitro, as well as a replication capacity in fresh human ovary, uterus and cervix cancer explants. AdF512v4 appears safe since no replication was observed in normal human ovary raising its potential use in the clinics.aaa
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- 2015
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41. Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases
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Zuccato, Camila Florencia, Asad, Antonela Sofia, Nicola Candia, Alejandro Javier, Gottardo, María Florencia, Moreno Ayala, Mariela Alejandra, Theas, María Susana, Seilicovich, Adriana, and Candolfi, Marianela
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ABSTRACTIntroduction: Mitochondrial-derived peptides (MDPs) are encoded within the mitochondrial genome. They signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors playing a key role in the cellular stress response. The first reported and better characterized MDP is humanin (HN), which exerts robust protective effects against a myriad of cytotoxic stimuli in many cell types. These effects have led to the evaluation of HN and its analogs as therapeutic targets for several chronic diseases.Areas covered: We describe the latest findings on the mechanism of action of HN and discuss the role of HN as therapeutic target for neurodegenerative and cardiovascular diseases, diabetes, male infertility, and cancer. Since HN can be detected in circulation, we also depict its value as a biomarker for these diseases.Expert opinion: HN analogs and peptide mimetics have been developed over the last decade and show promising results in preclinical models of degenerative diseases. Local administration of gene therapy vectors that overexpress or silence endogenous HN could also hold therapeutic potential. Controversy on the role of HN in cancer progression and chemoresistance should be addressed before the translation of these therapeutic approaches.
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- 2019
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42. 50. Efficacy of an Improved Cancer Stroma-Targeted Oncolytic Adenovirus on Human Derived Gynecologic Tumor Samples
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Nicola Candia, Alejandro, primary, Alfano, Ana L., additional, Malnero, Cristian M., additional, Bermúdez, Ismael R., additional, Cuneo, Nicasio A., additional, Gangemi, Mariela A., additional, Soderini, Alejandro, additional, Podhajcer, Osvaldo L., additional, and Lopez, Veronica M., additional
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- 2015
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43. Oncolytic Adenovirus-Loaded Menstrual Blood Stem Cells Overcome the Blockade of Viral Activity Exerted by Ovarian Cancer Ascites.
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Alfano AL, Nicola Candia A, Cuneo N, Guttlein LN, Soderini A, Rotondaro C, Sganga L, Podhajcer OL, and Lopez MV
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Patients with ovarian cancer present peritoneal ascites at recurrence as a marker of disseminated disease and dismal prognosis. Oncolytic immunotherapy is an emerging approach for the treatment of disseminated cancer. In the present work, we constructed a novel oncolytic adenovirus, AR2011, to target malignant ovarian tumors. AR2011 exhibited a clear lytic effect in vitro in human ovarian cancer cell lines and malignant cells obtained from ascitic fluids (AFs) of patients with ovarian cancer. AR2011 activity was neutralized by antibodies present in 31 samples of patient-derived AFs. However, this blockade was overridden by preloading menstrual blood stem cells (MenSCs) with AR2011 (MenSC-AR), since AFs exerted no in vitro inhibitory effect on viral lytic activity under these conditions. Moreover, soluble factors present in AFs act as MenSC chemoattractants. MenSC-AR treatment of nude mice carrying established peritoneal carcinomatosis following administration of human ovarian cancer cells was able to inhibit tumor growth at levels similar to those observed with AR2011 alone. This study demonstrates that MenSCs can be used to override the blockade that AFs exert on viral oncolytic effects.
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- 2017
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