BRYAN ERIC STRAUSS
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/05 - Laboratório de Poluição Atmosférica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
11 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 11
- Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy(2017) MEDRANO, Ruan F. V.; HUNGER, Aline; MENDONCA, Samir Andrade; BARBUTO, Jose Alexandre M.; STRAUSS, Bryan E.During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-alpha and IFN-beta, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-alpha/beta share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular phenotypes. For example, type I IFNs drive not only the high maturation status of DCs, but also have a direct impact in cytotoxic T lymphocytes, NK cell activation, induction of tumor cell death and inhibition of angiogenesis. A variety of stimuli, including some standard cancer treatments, promote the expression of endogenous IFN-alpha/beta, which then participates as a fundamental component of immunogenic cell death. Systemic treatment with recombinant protein has been used for the treatment of melanoma. The induction of endogenous IFN-alpha/beta has been tested, including stimulation through pattern recognition receptors. Gene therapies involving IFN-alpha/beta have also been described. Thus, harnessing type I IFNs as an effective tool for cancer therapy continues to be studied.
- Near future of tumor immunology: Anticipating resistance mechanisms to immunotherapies, a big challenge for clinical trials(2017) CATANI, Joao Paulo Portela; RIECHELMANN, Rachel P.; ADJEMIAN, Sandy; STRAUSS, Bryan E.The success of immunotherapies brings hope for the future of cancer treatment. Even so, we are faced with a new challenge, that of understanding which patients will respond initially and, possibly, develop resistance. The examination of the immune profile, especially approaches related to the immunoscore, may foretell which tumors will have a positive initial response. Ideally, the mutation load would also be analyzed, helping to reveal tumor associated antigens that are predictive of an effective cytolytic attack. However, the response may be hindered by changes induced in the tumor and its microenvironment during treatment, perhaps stemming from the therapy itself. To monitor such alterations, we suggest that minimally invasive approaches should be explored, such as the analysis of circulating tumor DNA. When testing new drugs, the data collected from each patient would initially represent an N of 1 clinical trial that could then be deposited in large databases and mined retrospectively for trends and correlations between genetic alterations and response to therapy. We expect that the investment in personalized approaches that couple molecular analysis during clinical trials will yield critical data that, in the future, may be used to predict the outcome of novel immunotherapies.
- Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma(2017) EUGENIO, Angela Isabel Pereira; FOOK-ALVES, Veruska Lia; OLIVEIRA, Mariana Bleker de; FERNANDO, Rodrigo Carlini; ZANATTA, Daniela B.; STRAUSS, Bryan Eric; SILVA, Maria Regina Regis; PORCIONATTO, Marimelia Aparecida; COLLEONI, Gisele Wally BragaHSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed similar to 60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed similar to 60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC-PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion.
- Harnessing combined p19Arf and interferon-beta gene transfer as an inducer of immunogenic cell death and mediator of cancer immunotherapy(2017) HUNGER, Aline; MEDRANO, Ruan F. V.; STRAUSS, Bryan E.
- Induction of Oxidants Distinguishes Susceptibility of Prostate Carcinoma Cell Lines to p53 Gene Transfer Mediated by an Improved Adenoviral Vector(2017) TAMURA, Rodrigo Esaki; HUNGER, Aline; FERNANDES, Denise C.; LAURINDO, Francisco R.; COSTANZI-STRAUSS, Eugenia; STRAUSS, Bryan E.Previously, the authors developed an adenoviral vector, Ad-PG, where transgene expression is regulated by a p53-responsive promoter. When used to transfer the p53 cDNA, a positive feedback mechanism is established. In the present study, a critical comparison is performed between Ad-PGp53 and AdRGD-PGp53, where the RGD motif was incorporated in the adenoviral fiber protein. AdRGD-PGp53 provided superior transgene expression levels and resulted in the killing of prostate carcinoma cell lines DU145 and PC3. In vitro, this effect was associated with increased production of cytoplasmic and mitochondrial oxidants, DNA damage as revealed by detection of phosphorylated H2AX, as well as cell death consistent with apoptosis. Differential gene expression of key mediators of reactive oxygen species pathways was also observed. Specifically, it was noted that induction of known p53-target genes Sestrin2 and PIG3, as well as a novel target, NOX1, occurred in PC3 cells only when transduced with the improved vector, AdRGD-PGp53. The participation of NOX1 was confirmed upon its inhibition using a specific peptide, resulting in reduced cell death. In situ gene therapy also resulted in significantly improved inhibition of tumor progression consistent with oxidant-induced DNA damage only when treated with the novel AdRGD-PGp53 vector. The study shows that the improved adenovirus overcomes limitations associated with other p53-expressing vectors and induces oxidant-mediating killing, thus supporting its further development for cancer gene therapy.
conferenceObject Cancer Immunotherapy Mediated by Combined p19Arf and Interferon-Beta Gene Transfer: Evidence from Vaccine and In Situ Gene Therapy Models(2017) STRAUSS, Bryan E.; MEDRANO, Ruan F. V.; CATANI, Joao Paulo P.; HUNGER, Aline- Uncovering the immunotherapeutic cycle initiated by p19Arf and interferon-beta gene transfer to cancer cells: An inducer of immunogenic cell death(2017) MEDRANO, Ruan F. V.; HUNGER, Aline; CATANI, Joao P. P.; STRAUSS, Bryan E.Simultaneous reestablishment of p53/p19(Arf) and interferon-beta pathways in melanoma cells culminates in a cell death process that displays features of necroptosis along with the release of immunogenic cell death molecules and unleashes an antitumor immune response mediated by natural killer cells, neutrophils as well as CD4(+) and CD8(+) T lymphocytes.
- Reestablishment of p53/Arf and interferon-beta pathways mediated by a novel adenoviral vector potentiates antiviral response and immunogenic cell death(2017) HUNGER, Aline; V, Ruan F. Medrano; ZANATTA, Daniela B.; VALLE, Paulo R. Del; MERKEL, Christian A.; SALLES, Thiago de Almeida; FERRARI, Daniel G.; FURUYA, Tatiane K.; BUSTOS, Silvina O.; SAITO, Renata de Freitas; COSTANZI-STRAUSS, Eugenia; STRAUSS, Bryan E.Late stage melanoma continues to be quite difficult to treat and new therapeutic approaches are needed. Since these tumors often retain wild-type p53 and have a strong immunogenic potential, we developed a gene transfer approach which targets these characteristics. Previously, we have shown that combined gene transfer of p19Arf and interferon-beta (IFN beta) results in higher levels of cell death and superior immune-mediated antitumor protection. However, these experiments were performed using B16 cells (p53wt) with forced expression of the adenovirus receptor and also the mechanism of death was largely unexplored. Here we take advantage of a novel adenoviral vector (AdRGD-PG), presenting an RGD-modified fiber as well as a p53-responsive promoter, in order to investigate further potential benefits and cell death mechanisms involved with the combined transfer of the p19Arf and IFN beta genes to the parental B16 cell line. Simultaneous p19Arf and IFN beta gene transfer is more effective for the induction of cell death than single gene treatment and we revealed that p19Arf can sensitize cells to the bystander effect mediated by secreted IFN beta. Strikingly, the levels of cell death induced upon activating the p53/p19Arf and interferon pathways were higher in the presence of the AdRGD-PG vectors as compared to approaches using pharmacological mimetics and this was accompanied by the upregulation of antiviral response genes. Only combined gene transfer conferred immunogenic cell death revealed by the detection of key markers both in vitro and in vivo. Finally, whole-genome transcriptome analysis revealed unique expression profiles depending on gene function, including immune activation, response to virus and p53 signaling. In this way, cooperation of p19Arf and IFN beta activates the p53 pathway in the presence of an antiviral response elicited by IFN beta , culminating in immunogenic cell death.
- Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma(2017) TORICELLI, Mariana; MELO, Fabiana H. M.; HUNGER, Aline; ZANATTA, Daniela; STRAUSS, Bryan E.; JASIULIONIS, Miriam G.High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and beta 1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics. Timp1 downregulation resulted in decreased anoikis resistance, clonogenicity, dacarbazine resistance, and in vivo tumor growth and lung colonization. In metastatic cells, pAKT(Thr308) is highly expressed, contributing to anoikis resistance. We showed that PDK1(Ser241) and PKC beta IISer660 are activated by Timp1 in different stages of melanoma progression, contributing to colony formation and anoikis resistance. Moreover, simultaneous inhibition of Timp1 and AKT in metastatic cells resulted in more effective anoikis inhibition. Our findings demonstrate that Timp1 promotes cell survival with the participation of PDK1 and PKC in melanoma. In addition, Timp1 and AKT act synergistically to confer anoikis resistance in advanced tumor stages. This study brings new insights about the mechanisms by which Timp1 promotes cell survival in melanoma, and points to novel perspectives for therapeutic approaches.
conferenceObject Protein Disulfide Isomerase A1 is a Central Hub for Redox Regulation of VSMC Phenotype(2017) WOSNIAK, Joao; GONCALVES, Renata C.; TANAKA, Leonardo Y.; ZANATTA, Daniela B.; STRAUSS, Bryan E.; LAURINDO, Francisco R.; FERNANDES, Denise C.