ROGER CHAMMAS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Radiologia, Faculdade de Medicina - Docente
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
14 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 14
- Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression-Implications for Cancer Therapy(2020) BUSTOS, Silvina Odete; ANTUNES, Fernanda; RANGEL, Maria Cristina; CHAMMAS, RogerThe tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, secreted factors, and the extracellular matrix. Additionally, TME is shaped by several processes, such as autophagy. Autophagy has emerged as a conserved intracellular degradation pathway for clearance of damaged organelles or aberrant proteins. With its central role, autophagy maintains the cellular homeostasis and orchestrates stress responses, playing opposite roles in tumorigenesis. During tumor development, autophagy also mediates autophagy-independent functions associated with several hallmarks of cancer, and therefore exerting several effects on tumor suppression and/or tumor promotion mechanisms. Beyond the concept of degradation, new different forms of autophagy have been described as modulators of cancer progression, such as secretory autophagy enabling intercellular communication in the TME by cargo release. In this context, the synthesis of senescence-associated secretory proteins by autophagy lead to a senescent phenotype. Besides disturbing tumor treatment responses, autophagy also participates in innate and adaptive immune signaling. Furthermore, recent studies have indicated intricate crosstalk between autophagy and the epithelial-mesenchymal transition (EMT), by which cancer cells obtain an invasive phenotype and metastatic potential. Thus, autophagy in the cancer context is far broader and complex than just a cell energy sensing mechanism. In this scenario, we will discuss the key roles of autophagy in the TME and surrounding cells, contributing to cancer development and progression/EMT. Finally, the potential intervention in autophagy processes as a strategy for cancer therapy will be addressed.
- Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas(2020) CAMPANELLA, Nathalia C.; SILVA, Eduardo Caetano; DIX, Gustavo; VAZQUEZ, Fabiana de Lima; PAULA, Flavia Escremim de; BERARDINELLI, Gustavo N.; BALANCIN, Marcelo; CHAMMAS, Roger; V, Rossana Mendoza Lopez; SILVEIRA, Henrique Cesar S.; CAPELOZZI, Vera Luiza; REIS, Rui ManuelBackground:Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (similar to 60% of cases) and sarcomatous (similar to 20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available.Objectives:To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients.Methods:We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and theTERTpromoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,andTP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software.Results:Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We founda TERTpromoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes wereTP53andERBB2with 7 variants each, followed byNRASBRAF,PI3KCA,EGFRandPDGFRAwith 2 variants each.KIT,AKT1, andFOXL2genes exhibited 1 variant each. Interestingly, 2 variants observed in thePDGFRAgene are classic imatinib-sensitive therapy.Conclusions:We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.
- Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress(2020) ANTUNES, Fernanda; PEREIRA, Gustavo J. S.; SAITO, Renata F.; V, Marcus Buri; GAGLIARDI, Mara; BINCOLETTO, Claudia; CHAMMAS, Roger; FIMIA, Gian Maria; PIACENTINI, Mauro; CORAZZARI, Marco; SMAILI, Soraya SoubhiSkin melanoma is one of the most aggressive and difficult-to-treat human malignancies, characterized by poor survival rates, thus requiring urgent novel therapeutic approaches. Although metabolic reprogramming has represented so far, a cancer hallmark, accumulating data indicate a high plasticity of cancer cells in modulating cellular metabolism to adapt to a heterogeneous and continuously changing microenvironment, suggesting a novel therapeutic approach for dietary manipulation in cancer therapy. To this aim, we exposed melanoma cells to combined nutrient-restriction/sorafenib. Results indicate that cell death was efficiently induced, with apoptosis representing the prominent feature. In contrast, autophagy was blocked in the final stage by this treatment, similarly to chloroquine, which also enhanced melanoma cell sensitization to combined treatment. Energy stress was evidenced by associated treatment with mitochondrial dysfunction and glycolysis impairment, suggesting metabolic stress determining melanoma cell death. A reduction of tumor growth after cycles of intermittent fasting together with sorafenib treatment was also observed in vivo, reinforcing that the nutrient shortage can potentiate anti-melanoma therapy. Our findings showed that the restriction of nutrients by intermittent fasting potentiates the effects of sorafenib due to the modulation of cellular metabolism, suggesting that it is possible to harness the energy of cancer cells for the treatment of melanoma.
- Synthesis and Evaluation of [F-18]FEtLos and [F-18]AMBF(3)Los as Novel F-18-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors(2020) PIJEIRA, Martha Sahyli Ortega; NUNES, Paulo Sergio Goncalves; SANTOS, Sofia Nascimento dos; ZHANG, Zhengxing; NARIO, Arian Perez; PERINI, Efrain Araujo; TURATO, Walter Miguel; RIERA, Zalua Rodriguez; CHAMMAS, Roger; ELSINGA, Philip H.; LIN, Kuo-Shyan; CARVALHO, Ivone; BERNARDES, Emerson SoaresLosartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT(1)Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT(1)R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [F-18]fluoroethyl-losartan ([F-18]FEtLos) and [F-18]ammoniomethyltrifluoroborate-losartan ([F-18]AMBF(3)Los). [F-18]FEtLos was radiolabeled by F-18-fluoroalkylation of losartan potassium using the prosthetic group 2-[F-18]fluoroethyl tosylate; whereas [F-18]AMBF(3)Los was prepared following an one-step F-18-F-19 isotopic exchange reaction, in an overall yield of 2.7 +/- 0.9% and 11 +/- 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT(1)R-expressing membranes showed that AMBF(3)Los presented an almost equivalent binding affinity (K-i 7.9 nM) as the cold reference Losartan (K-i 1.5 nM), unlike FEtLos (K-i 2000 nM). In vitro and in vivo assays showed that [F-18]AMBF(3)Los displayed a good binding affinity for AT(1)R-overexpressing CHO cells and was able to specifically bind to renal AT(1)R. Hence, our data demonstrate [F-18]AMBF(3)Los as a new tool for PET imaging of AT(1)R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.
- Comparative evaluation of a trastuzumab biosimilar or originator trastuzumab in association with pertuzumab: Binding and biological activities in cell culture-based assays(2020) PIMENTEL, Franklin F.; TOLEDO, Juliano S.; GONCALVES, Joao; ALVES, Leandro L.; PAULA, Mayara I. de; ANDRADE, Jurandyr M. de; TIEZZI, Daniel G.; CHAMMAS, Roger
- Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/ TRIP15/ALIEN(2020) ALVES, Christiano R. R.; NEVES, Willian das; ALMEIDA, Ney R. de; EICHELBERGER, Eric J.; JANNIG, Paulo R.; VOLTARELLI, Vanessa A.; TOBIAS, Gabriel C.; BECHARA, Luiz R. G.; FARIA, Daniele de Paula; ALVES, Maria J. N.; HAGEN, Lars; SHARMA, Animesh; SLUPPHAUG, Geir; MOREIRA, Jose B. N.; WISLOFF, Ulrik; HIRSHMAN, Michael F.; NEGRAO, Carlos E.; CASTRO JR., Gilberto de; CHAMMAS, Roger; SWOBODA, Kathryn J.; RUAS, Jorge L.; GOODYEAR, Laurie J.; BRUM, Patricia C.Objective: We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia. Methods: We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats. Results: Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to agematched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity. Conclusions: These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia. (C) 2020 The Author(s).
- Genomic Biomarkers and Underlying Mechanism of Benefit from BCG Immunotherapy in Non-Muscle Invasive Bladder Cancer(2020) BASTOS, Diogo A.; MATTEDI, Romulo L.; BARREIRO, Rodrigo; SANTOS, Filipe F. dos; BUZATTO, Vanessa; MASOTTI, Cibele; SOUZA, Jussara M.; LIMA, Mariana Z. T. de; FRIGUGLIETTI, Giulia W.; DZIK, Carlos; JARDIM, Denis L. F.; COELHO, Rafael; RIBEIRO FILHO, Leopoldo A.; CORDEIRO, Mauricio D.; NAHAS, William C.; MELLO, Evandro S. de; CHAMMAS, Roger; REIS, Luiz Fernando L.; BETTONI, Fabiana; GALANTE, Pedro A. F.; CAMARGO, Anamaria A.BACKGROUND: Optimal therapy for high-risk non-muscle invasive bladder cancer (NMIBC) includes intravesical instillation of Bacillus Calmette-Guerin (BCG). However, about 25-45% of patients do not benefit from BCG immunotherapy, and there is no biomarker to guide therapy. Also, many questions regarding BCG mechanisms of action remain unanswered. OBJECTIVE: To identify genomic biomarkers and characterize the underlying mechanism of benefit from BCG in NMIBC. PATIENTS AND METHODS: Pre-treatment archival index-tumors of 35 patients with NMIBC treated with BCG were analyzed by whole-exome sequencing (WES). Tumor mutation burden (TMB) and neoantigen load (NAL) were correlated with BCG response rate (RR) and recurrence-free survival (RFS). The presence of deleterious mutations in DNA damage response (DDR) genes was also compared between BCG-responsive (BCG-R, N= 17) and unresponsive (BCG-UR, N= 18) subgroups. RESULTS: TMB and NAL were higher in BCG-R compared to BCG-UR patients (median TMB 4.9 vs. 2.8 mutations/Mb, P = 0.017 and median NAL 100 vs. 65 neoantigens, P = 0.032). Improved RR and RFS were observed in patients with high vs. low TMB (RR 71% vs. 28%, P = 0.011 and mRFS 38.0 vs. 15.0 months, P = 0.009) and with high vs. low NAL (RR 71% vs. 28%, P = 0.011 and mRFS 36.0 vs. 18.5 months, P = 0.016). The presence of deleterious mutations in DDR genes was associated with improved RFS (mRFS 35.5 vs. 11.0 months, P = 0.017). CONCLUSIONS: In our cohort, improved outcomes after BCG immunotherapy were observed in patients with high TMB, high NAL and deleterious mutations in DDR genes. BCG may induce tumor-specific immune response by enhancing the recognition of neoantigens.
- Managing oncology clinical trials during COVID-19 pandemic(2020) ARAI, Roberto J.; V, Camila M. Moniz; CHEN, Andre T. C.; MAK, Milena P.; CHAMMAS, Roger; HOFF, Paulo M.Sao Paulo city is the epicenter of the Brazilian COVID-19 pandemic. The Instituto do Cancer do Estado de Sao Paulo is currently conducting 161 multinational sponsored trials plus 116 in house studies in the oncologic population. There are 242 currently active participants and 180 patients in follow-up. The management of the tightly controlled environment of clinical research becomes a challenge, and the Food and Drug Administration set of priority recommendations for patient safety while maintaining study integrity. Fast adaptations are necessary, and actions coalesce to participant protection from COVID-19. We pointed out critical processes for adjustments, and we believe that our experience may help other academic health centers.
- University participation in the production of molecular diagnostic tests for the novel coronavirus in Brazil: the response to health challenges(2020) SILVA, Renan Goncalves Leonel da; CHAMMAS, Roger; PLONSKI, Guilherme Ary; GOLDBAUM, Moises; FERREIRA, Luis Carlos de Souza; NOVAES, Hillegonda Maria Dutilh
- CCNA1 gene as a potential diagnostic marker in papillary thyroid cancer(2020) SILVA, Raissa Monteiro da; SANTOS, Joyce Nascimento; UNO, Miyuki; CHAMMAS, Roger; KULCSAR, Marco Aurelio Vamondes; SANT'ANNA, Luciana Barros; CANEVARI, Renata de AzevedoThe malignancy that most affects the endocrine system is thyroid neoplasm, with an increasing incidence over the years. The most prevalent histological type of the carcinomas that affect the thyroid gland is papillary carcinoma with a prevalence of 80 % worldwide. The current diagnostic methodology may present inconclusive results, emphasizing the need for new effective and sensitive techniques to aid the diagnosis. For this, it is necessary to understand molecular and protein mechanisms in the identification of diagnostic and predictive markers in the lesions. The Cyclin A1 protein, encoded by the CCNA1 gene, is an important cell cycle regulator, belonging to the MAPK/ERK signaling pathway directly involved with thyroid cancer. The aim of this study was to evaluate the CCNA1 gene and Cyclin A1 protein expression in papillary thyroid carcinoma, follicular thyroid carcinoma, and benign thyroid lesions, by real time quantitative PCR and immunohistochemistry analysis, respectively, to verify their roles as potential diagnostic and predictive markers to future applications in the clinical routine. Overexpression of CCNA1 gene was observed in the papillary carcinoma group compared to the normal group (P = 0.0023), benign lesions (P = 0.0011), colloid goiter (P = 0.0124), and follicular carcinoma (P = 0.0063). No differential expression was observed in the papillary primary tumor group from negative lymph nodes compared with the one from positive lymph nodes (P = 0.3818). Although an increased expression of Cyclin A1 was observed in the PTC group compared to the other one in the IHC analysis, no significant difference was observed (Fisher's exact Test). A Cyclin A1 overexpression was detected with weak to mid-moderate immunoreactivity in the benign group (k = 0.56), (score 1.5); mid-moderate to moderate in the goiter group (k = 0.58); weak in the FTC group (k = 0.33); and mid-moderate to moderate in the PTC group (k = 0.48). Due to the small sample size in the IHC analysis and to the fact that not all RNA is translated into protein, the diagnostic potential of Cyclin A1 could not be assessed. However, these findings highlight the potential of the CCNA1 gene as a diagnostic marker for papillary thyroid carcinoma.