In Silico and In Vitro Evaluation of Bevacizumab Biosimilar MB02 as an Antitumor Agent in Canine Mammary Carcinoma

Canine mammary carcinomas (CMC) are associated with major aggressive clinical behavior and high mortality. The current standard of care is based on surgical resection, without an established effective treatment scheme, highlighting the urgent need to develop novel effective therapies. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis and progression in the majority of solid cancers, including human and canine mammary carcinomas. The first therapy developed to target VEGF was bevacizumab, a recombinant humanized monoclonal antibody, which has already been approved as an anticancer agent in several human cancers. The goal of this work was to establish the therapeutic value of MB02 bevacizumab biosimilar in CMC. First, through different in silico approaches using the MUSCLE multiple-sequence alignment tool and the FoldX protein design algorithm, we were able to predict that canine VEGF is recognized by bevacizumab, after showing an extremely high sequence similarity between canine and human VEGF. Further, by using an ELISA-based in vitro binding assay, we confirmed that MB02 biosimilar was able to recognize canine VEGF. Additionally, canine VEGF-induced microvascular endothelial cell proliferation was inhibited in a concentration-dependent manner by MB02 biosimilar. These encouraging results show a high potential for MB02 as a promising therapeutic agent for the management of CMC.Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bucci, Paula Lorena. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lemos, Jesus. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Llavona, Candela. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Benavente, Micaela Andrea. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Hellmén, Eva. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Fara, María Laura. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; ArgentinaFil: Medrano, Eduardo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; ArgentinaFil: Spitzer, Eduardo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; ArgentinaFil: Demarco, Ignacio A.. No especifíca;Fil: Sabella, Patricia. No especifíca;Fil: Garona, Juan. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

A phase II dose‑escalation trial of perioperative desmopressin (1‑desamino‑8‑D‑arginine vasopressin) in breast cancer patients

Desmopressin (dDAVP) is a well-known peptide analog of the antidiuretic hormone vasopressin, used to prevent excessive bleeding during surgical procedures. dDAVP increases hemostatic mediators, such as the von Willebrand factor (vWF), recently considered a key element in resistance to metastasis. Studies in mouse models and veterinary trials in dogs with locally-advanced mammary tumors demonstrated that high doses of perioperative dDAVP inhibited lymph node and early blood-borne metastasis and significantly prolonged survival. We conducted a phase II dose-escalation trial in patients with breast cancer, administering a lyophilized formulation of dDAVP by intravenous infusion in saline, 30–60 min before and 24 h after surgical resection. Primary endpoints were safety and tolerability, as well as selection of the best dose for cancer surgery. Secondary endpoints included surgical bleeding, plasma levels of vWF, and circulating tumor cells (CTCs) as measured by quantitative PCR of cytokeratin-19 transcripts. Only 2 of a total of 20 patients experienced reversible adverse events, including hyponatremia (grade 4) and hypersensitivity reaction (grade 2). Reactions were adequately managed by slowing the infusion rate. A reduced intraoperative bleeding was noted with increasing doses of dDAVP. Treatment was associated with higher vWF plasma levels and a postoperative drop in CTC counts. At the highest dose level evaluated (2 μg/kg) dDAVP appeared safe when administered in two slow infusions of 1 μg/kg, before and after surgery. Clinical trials to establish the effectiveness of adjunctive perioperative dDAVP therapy are warranted. This trial is registered on www.clinicaltrials.gov (NCT01606072).Facultad de Ciencias Médica

A phase II dose-escalation trial of perioperative desmopressin (1-desamino-8-d-arginine vasopressin) in breast cancer patients

Desmopressin (dDAVP) is a well-known peptide analog of the antidiuretic hormone vasopressin, used to prevent excessive bleeding during surgical procedures. dDAVP increases hemostatic mediators, such as the von Willebrand factor (vWF), recently considered a key element in resistance to metastasis. Studies in mouse models and veterinary trials in dogs with locally-advanced mammary tumors demonstrated that high doses of perioperative dDAVP inhibited lymph node and early blood-borne metastasis and significantly prolonged survival. We conducted a phase II dose-escalation trial in patients with breast cancer, administering a lyophilized formulation of dDAVP by intravenous infusion in saline, 30–60 min before and 24 h after surgical resection. Primary endpoints were safety and tolerability, as well as selection of the best dose for cancer surgery. Secondary endpoints included surgical bleeding, plasma levels of vWF, and circulating tumor cells (CTCs) as measured by quantitative PCR of cytokeratin-19 transcripts. Only 2 of a total of 20 patients experienced reversible adverse events, including hyponatremia (grade 4) and hypersensitivity reaction (grade 2). Reactions were adequately managed by slowing the infusion rate. A reduced intraoperative bleeding was noted with increasing doses of dDAVP. Treatment was associated with higher vWF plasma levels and a postoperative drop in CTC counts. At the highest dose level evaluated (2 μg/kg) dDAVP appeared safe when administered in two slow infusions of 1 μg/kg, before and after surgery. Clinical trials to establish the effectiveness of adjunctive perioperative dDAVP therapy are warranted. This trial is registered on www.clinicaltrials.gov (NCT01606072).Fil: Weinberg, Ruth S.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Grecco, Marcelo O.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Ferro, Gimena S.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Seigelshifer, Debora Judith. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Perroni, Nancy V.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Terrier, Francisco J.. Instituto Universitario del Hospital Italiano de Buenos Aires; ArgentinaFil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Maronna, Esteban. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Sánchez Marull, Ricardo. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Frahm, Isabel. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; ArgentinaFil: Guthmann, Marcelo D.. Laboratorio Elea; ArgentinaFil: Di Leo, Daniela. Laboratorio Elea; ArgentinaFil: Spitzer, Eduardo. Laboratorio Elea; ArgentinaFil: Ciccia, Graciela Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Pifano, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Torbidoni, Ana Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Ripoll, Giselle Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Gomez, Roberto E.. Laboratorio Elea; ArgentinaFil: Demarco, Ignacio A.. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentin

Antibody-dependent cell-mediated cytotoxicity induced by active immunotherapy based on racotumomab in non-small cell lung cancer patients

Antitumor strategies based on positive modulation of the immune system currently represent therapeutic options with prominent acceptance for cancer patients’ treatment due to its selectivity and higher tolerance compared to chemotherapy. Racotumomab is an anti-idiotype (anti-Id) monoclonal antibody (mAb) directed to NeuGc-containing gangliosides such as NeuGcGM3, a widely reported tumor-specific neoantigen in many human cancers. Racotumomab has been approved in Latin American countries as an active immunotherapy for advanced non-small cell lung cancer (NSCLC) treatment. In this work, we evaluated the induction of Ab-dependent cell-mediated cytotoxicity (ADCC) in NSCLC patients included in a phase III clinical trial, in response to vaccination with racotumomab. The development of anti-NeuGcGM3 antibodies (Abs) in serum samples of immunized patients was first evaluated using the NeuGcGM3-expressing X63 cells, showing that racotumomab vaccination developed antigen-specific Abs that are able to recognize NeuGcGM3 expressed in tumor cell membranes. ADCC response against NeuGcGM3-expressing X63 (target) was observed in racotumomab-treated- but not in control group patients. When target cells were depleted of gangliosides by treatment with a glucosylceramide synthase inhibitor, we observed a significant reduction of the ADCC activity developed by sera from racotumomab-vaccinated patients, suggesting a target-specific response. Our data demonstrate that anti-NeuGcGM3 Abs induced by racotumomab vaccination are able to mediate an antigen-specific ADCC response against tumor cells in NSCLC patients.Fil: Segatori, Valeria Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Cuello, Héctor Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Gulino, Cynthia Antonella. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Albertó, Marina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Venier, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Guthmann, Marcelo D.. Elea Laboratories; ArgentinaFil: Demarco, Ignacio A.. Elea Laboratories; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gabri, Mariano Rolando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Preclinical Efficacy and Toxicology Evaluation of RAC1 Inhibitor 1A-116 in Human Glioblastoma Models

Malignant gliomas are the most common primary central nervous system tumor in adults. Despite current therapeutics, these tumors are associated with poor prognosis and a median survival of 16 to 19 months. This highlights the need for innovative treatments for this incurable disease. Rac1 has long been associated with tumor progression and plays a key role in glioma’s infiltrative and invasive nature. The aim of this study is to evaluate the 1A-116 molecule, a Rac1 inhibitor, as targeted therapy for this aggressive disease. We found that targeting Rac1 inhibits cell proliferation and cell cycle progression using different in vitro human glioblastoma models. Additionally, we evaluated 1A-116 in vivo, showing a favorable toxicological profile. Using in silico tools, 1A-116 is also predicted to penetrate the blood–brain barrier and present a favorable metabolic fate. In line with these results, 1A-116 i.p daily treatment resulted in a dose-dependent antitumor effect in an orthotopic IDH-wt glioma model. Altogether, our study provides a strong potential for clinical translation of 1A-116 as a signal transduction-based precision therapy for glioma and also increases the evidence of Rac1 as a key molecular target

Geophysical Methods Applied to the Study of Lakes and PaleoLakes in Tierra del Fuego

During the last years, geophysical surveys have been carried out in order to study the possible tectonic origin of Udaeta Lake and the extension and thickness of glacio-lacustrine deposits cropping out in the Río Valdez mouth. In both cases, geophysical methods proved to be a powerful tool for the investigation of Quaternary tectonic and glacial activity in a zone of Tierra del Fuego, which is covered by a very dense forest that hinders the identification of rocky outcrops and natural exposures. The geometry of Udaeta Lake, located in the central section of the Magellan-Fagnano Fault System (MFFS), previously envisaged by other authors as a possible pull-apart basin, was investigated. Magnetic, gravimetric and detailed topographic profiles and vertical electrical soundings were surveyed. Geophysical results were integrated with fieldwork data allowing the identification of a transtensional zone with two E?W main sinistral strike-slip faults with a normal component that control the North and South coasts of the Lake. The central depression occupied by the Lake was also affected by inferred NE subparallel faults. The obtained results support a genesis of Udaeta Lake consistent with a pull-apart basin model and highlight the influence of MFFS on the formation of some water bodies located along the fault zone. Moreover, the constructed models contribute to a better understanding of earthquake rupture parameters and pattern of surface and in-depth deformation, improving the knowledge of the seismological behavior of the MFFS. In the Río Valdez mouth, located in the southeastern coast of Fagnano Lake, an outcrop of 7 m thick rhythmic glacio-lacustrine sediments was identified. It was interpreted that such outcrop was formed in a frontal morainic complex during the Pleistocene. Ground magnetic and resistivity surveys were carried out, in order to determine the thickness and areal extension of these lacustrine sediments. A maximum E-W extension of ~220 m, a minimum NNW-SSE one of ~180 m, and a minimum thickness of ~20 m were estimated. Considering this thickness and an assumed average sedimentation rate, the natural dam that promoted the paleoLake and their related lacustrine deposits could have existed prior to MIS 2, when the Last Glacial Maximum took place in the region.Fil: Prezzi, Claudia Beatriz. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias Geológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Orgeira, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Coronato, Andrea Maria Josefa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Onorato, Maria Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Quiroga, Diego Rubén Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Lopez, Carlos Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Ponce, Juan Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Magneres, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Núñez Demarco, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Perucca, Laura Patricia A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Centro de Investigaciones de la Geosfera y Biosfera. Universidad Nacional de San Juan. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones de la Geosfera y Biosfera; ArgentinaFil: Palermo, Pedro. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial

Purpose: The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors,and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods: Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results: The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions: dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted.Fil: Iseas, Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: Roca, Enrique Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: O´Connor, Juan M.. Instituto Alexander Fleming; ArgentinaFil: Eleta, Martin. Imaxe Centro de Diagnóstico por Imágenes; ArgentinaFil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Di Leo, Maria Daniela. Laboratorio Elea; ArgentinaFil: Tinelli, Marcelo. Laboratorio Elea-Phoenix; ArgentinaFil: Fara, Maria L.. Laboratorio Elea-Phoenix; ArgentinaFil: Spitzer, Eduardo. Laboratorio Elea-Phoenix; ArgentinaFil: Demarco, Ignacio A.. Romikin S.A. Laboratorio de Investigación y Desarrollo; ArgentinaFil: Ripoll, Giselle Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Pifano, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentin