Nazareno González

University of Buenos Aires

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Marianela Candolfi

University of Buenos Aires

Alejandro J. Nicola Candia

University of Buenos Aires

Pablo Lorenzano Menna

National University of Quilmes

Daniel E. Gómez

National University of Quilmes

Georgina A. Cardama

National University of Quilmes

Daniel F. Alonso

Centro Científico Tecnológico - San Juan

Adriana Seilicovich

University of Buenos Aires

Jorge A. Peña Agudelo

Consejo Nacional de Investigaciones Científicas y Técnicas

Matías Garcia Fallit

University of Buenos Aires

Melanie Pérez Küper

Consejo Nacional de Investigaciones Científicas y Técnicas

Cooperative Institutions

Consejo Nacional de Investigaciones Científicas y Técnicas

National Institutes of Health

University of Buenos Aires

University of Washington

University of California, San Francisco

Johns Hopkins University

Harvard University

National Cancer Institute

Inserm

University of Michigan–Ann Arbor

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VAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma

Nature Communications (2020)

L. Francisco Lorenzo‐Martín Natalia Fernández-Parejo Mauricio Menacho-Márquez Sonia Rodríguez‐Fdez Javier Robles‐Valero

Abstract Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes.

Small GTPase

10.1038/s41467-020-18524-3

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Citations (33)

Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines

Oncotarget (2017)

Maia Cabrera Emiliana Echeverría Federico Remes Lenicov Georgina A. Cardama Nazareno González

Rac1 GTPase has long been recognized as a critical regulatory protein in different cellular and molecular processes involved in cancer progression, including acute myeloid leukemia. Here we show the antitumoral activity of ZINC69391 and 1A-116, two chemically-related Rac1 pharmacological inhibitors, on a panel of four leukemic cell lines representing different levels of maturation. Importantly, we show that the main mechanism involved in the antitumoral effect triggered by the Rac1 inhibitors comprises the induction of the mitochondrial or intrinsic apoptotic pathway. Interestingly, Rac1 inhibition selectively induced apoptosis on patient-derived leukemia cells but not on normal mononuclear cells. These results show the potential therapeutic benefits of targeting Rac1 pathway in hematopoietic malignancies.

10.18632/oncotarget.21533

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Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

Frontiers in Oncology (2021)

María Belén Garcia-Fabiani Santiago Haase Andrea Comba Stephen V. Carney Brandon L. McClellan

High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.

Bench to bedside

Brain tumor

10.3389/fonc.2021.631037

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Citations (18)

Role of RIPK1 in Diffuse Gliomas pathology

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Leslie C. Amorós Morales Santiago M. Gómez Bergna Abril Marchesini Ma. Luján Scalise Nazareno González

ABSTRACT Purpose The aim of the present work was to investigate the role of Receptor-interacting protein kinase 1 (RIPK1) both in mutated and wild type isocitrate dehydrogenase (IDH) Diffuse Gliomas (DG). Patients and Methods We analyzed RIPK1 mRNA expression in DG databases from The Cancer Genome Atlas (TCGA) containing clinical, genomic and transcriptomic information from 661 patients. Transcriptomic studies (mRNA expression levels, correlation heatmaps, survival plots and Gene Ontology and meta-analysis of immune gene signatures) were performed with USC Xena and R. Statistical significance was set at p-values less than 0.05. Results The results showed a lower survival probability in patients belonging to the high RIPK1 expression subgroup compared to those samples with low RIPK1 expression. We also observed a higher expression of RIPK1 in wtIDH samples compared to those with mIDH. In order to further characterize the role of RIPK1 in DG, we performed a Gene Ontology and Pathway Enrichment Analysis using the Xena platform’s differential expression tool. The results showed that RIPK1 is involved in inflammatory and immune responses. Hence, the expression levels of some of the genes involved in the following molecular processes crucial for cancer progression were studied: proliferation, epithelial-mesenchymal transition, immune cell infiltration and cell death pathways. Briefly, the results showed significant differences in genes related to increased cellular dedifferentiation, proinflammatory cell death pathways and tumor infiltrating immune cells gene signatures (Welch’s t-test). Conclusion RIPK1 over-expression is associated with a poor prognosis in DG. This fact, together with our results suggest that RIPK1 may play a crucial role in glioma pathogenesis highlighting the need to take into account RIPK1 expression levels for decision making when choosing or designing therapeutic alternatives. CONTEXT SUMMARY Key Objective Evaluate the role of the Receptor-interacting protein kinase 1 (RIPK1) in Diffuse Gliomas (DG) pathology through an exhaustive in silico patient database analysis. Knowledge generated We demonstrated that RIPK1 is overexpressed in more aggressive DG and correlates with clinical attributes associated with poor prognosis. In addition, our analyses showed that high RIPK1 expression correlates with key genes involved in pro inflammatory cell death pathways and an increased expression of immune gene signatures suggesting greater immunological infiltration in the tumor. Relevance Our results from patient database analyses propose RIPK1 as a new relevant molecular prognosis marker for DG. Our findings are in concordance with different preclinical studies and provide additional information that can be useful for decision making when choosing therapeutic strategies and for the development of novel therapeutic approaches such as gene or immunotherapy. This work was presented in XIII Argentine Congress of Bioinformatics and Computational Biology (XIII CAB2C), XIII International Conference of the Iberoamerican Society of Bioinformatics (XIII SoIBio) and III Annual Meeting of the Ibero-American Artificial Intelligence Network for Big BioData (III RiaBio).

RIPK1

Proinflammatory cytokine

10.1101/2023.11.11.566709

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Mitochondrial Peptide Humanin Facilitates Chemoresistance in Glioblastoma Cells

Cancers (2023)

Jorge A. Peña Agudelo Matías L. Pidre Matías Garcia Fallit Melanie Pérez Küper Camila Florencia Zuccato

Humanin (HN) is a mitochondrial-derived peptide with robust cytoprotective effects in many cell types. Although the administration of HN analogs has been proposed to treat degenerative diseases, its role in the pathogenesis of cancer is poorly understood. Here, we evaluated whether HN affects the chemosensitivity of glioblastoma (GBM) cells. We found that chemotherapy upregulated HN expression in GBM cell lines and primary cultures derived from GBM biopsies. An HN analog (HNGF6A) boosted chemoresistance, increased the migration of GBM cells and improved their capacity to induce endothelial cell migration and proliferation. Chemotherapy also upregulated FPR2 expression, an HN membrane-bound receptor, and the HNGF6A cytoprotective effects were inhibited by an FPR2 receptor antagonist (WRW4). These effects were observed in glioma cells with heterogeneous genetic backgrounds, i.e., glioma cells with wild-type (wtIDH) and mutated (mIDH) isocitrate dehydrogenase. HN silencing using a baculoviral vector that encodes for a specific shRNA for HN (BV.shHN) reduced chemoresistance, and impaired the migration and proangiogenic capacity of GBM cells. Taken together, our findings suggest that HN boosts the hallmark characteristics of GBM, i.e., chemoresistance, migration and endothelial cell proliferation. Thus, strategies that inhibit the HN/FPR2 pathway may improve the response of GBM to standard therapy.

U87

10.3390/cancers15164061

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Citations (9)

P-Rex1 expression in breast cancer patients

Annals of Oncology (2019)

A. Montero Nazareno González K. Cicinelli Gonzalo Márquez Acosta Silvia Vornetti

Triple-negative breast cancer

10.1093/annonc/mdz238.048

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Abstract LB-305: Novel Rac1-GEF inhibitors as anticancer agents for aggressive tumors.

Cancer Research (2013)

Georgina A. Cardama Nazareno González María J. Comin Adrián G. Turjanski Daniel F. Alonso

Abstract Small GTPases of the Rho family, including Rac1, regulate fundamental cellular processes like actin cytoskeleton reorganization, cell migration and cell cycle progression. Rac1 has been associated with transformation, tumor progression and tumor cell migration in different type of cancers, including aggressive breast cancer and glioma. These proteins cycle between an active, GTP-bound state and an inactive, GDP-bound state. This cycle is highly regulated by many regulatory proteins, including activators such as guanine nucleotide exchange factors (GEFs). We searched for Rac1 inhibitors able to interfere Rac1-GEF interaction using a docking-based virtual library screening approach. We selected ZINC69391 compound. This small-molecule was able to interfere Rac-Tiam1 and Rac-DOCK180 interaction in vitro and reduced Rac1-GTP intracellular levels but had no effect on the closely related Cdc42 GTPase. ZINC69391 also affected the activation of Pak1, one important Rac1 effector. This compound reduced cell migration, inhibited cell proliferation and arrested cell cycle progression in breast cancer cells and glioma cells. We also evaluated this compound in vivo and ZINC69391 was able to reduce 60% lung colonization in a breast cancer experimental metastasis model. We further evaluated novel analogs looking for more potent and specific Rac1 inhibitors. We synthesized a group of novel disubstituted guanidines and we screened these analogs in vitro. One of them, 1A-116 analog, showed to be more potent than the parental compound, reducing cancer cell proliferation and Rac1 activation at the low micromolar range. These data further confirm Rac1 GTPase as a valuable molecular target for anti-cancer therapies and drug development in breast cancer and glioma, where Rac1 presents a relevant role. Citation Format: Georgina A. Cardama, Nazareno Gonzalez, Maria Julieta Comin, Adrian G. Turjanski, Daniel Fernando Alonso, Daniel Eduardo Gomez, Pablo Lorenzano Menna. Novel Rac1-GEF inhibitors as anticancer agents for aggressive tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-305. doi:10.1158/1538-7445.AM2013-LB-305

CDC42

10.1158/1538-7445.am2013-lb-305

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Current Non-viral Gene Therapy Strategies for the Treatment of Glioblastoma

Current Medicinal Chemistry (2021)

Antonela S. Asad Alejandro J. Nicola Candia Nazareno González Camila Florencia Zuccato Adriana Seilicovich

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.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.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.

Brain tumor

Biosafety

10.2174/0929867328666210525141243

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Citations (3)

The role of the prolactin receptor pathway in the pathogenesis of glioblastoma: what do we know so far?

Expert Opinion on Therapeutic Targets (2020)

Antonela S. Asad Alejandro J. Nicola Candia Nazareno González Camila Florencia Zuccato Adriana Seilicovich

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.

Prolactin receptor

Pathogenesis

10.1080/14728222.2020.1821187

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Citations (15)

[Rho GTPases as molecular targets in cancer. Strategies and therapeutic opportunities].

PubMed (2017)

Julián Maggio Nazareno González Georgina Alexandra Cardama Daniel E. Gómez

Rho GTPases are molecular switches that control the different cellular processes. Deregulation of these proteins is associated to transformation and malignant progression in several cancer types. Given the evidence available of the role of Rho GTPases in cancer it is suggested that these proteins can serve as potential therapeutic targets. This review focuses on the strategies used to develop Rho GTPases modulators and their potential use in therapeutic settings.

CDC42

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Citations (1)