Eduardo Cararo Lopes

Pós-doutorado

Formação complementar

Áreas de atuação

Participação em eventos

Orientou

Produções bibliográficas

• CARARO LOPES, EDUARDO ; SHI, FUQIAN ; SAWANT, AKSHADA ; IBRAHIM, MARIA ; GOMEZ-JENKINS, MARIA ; HU, ZHIXIAN ; MANCHIRAJU, PRANAV ; BHATT, VRUSHANK ; WANG, WENPING ; HINRICHS, CHRISTIAN S. ; WALLACE, DOUGLAS C. ; SU, XIAOYANG ; RABINOWITZ, JOSHUA D. ; CHAN, CHANG S. ; GUO, JESSIE YANXIANG ; GANESAN, SHRIDAR ; LATTIME, EDMUND C. ; WHITE, EILEEN . Respiration defects limit serine synthesis required for lung cancer growth and survival. Nature Communications , v. 16, p. 7621, 2025.

• ZALMA, BRIAN A. ; IBRAHIM, MARIA ; RODRIGUEZ-POLANCO, FLAVIO C. ; BHAVSAR, CHINTAN T. ; RODRIGUEZ, ESTHER M. ; CARARO-LOPES, EDUARDO ; FAROOQ, SAAD A. ; LEVY, JORDAN L. ; WEK, RONALD C. ; WHITE, EILEEN ; ANTHONY, TRACY G. . Autophagy related 7 (ATG7) regulates food intake and liver health during asparaginase exposure. JOURNAL OF BIOLOGICAL CHEMISTRY , v. 301, p. 108171, 2025.

• LAN, TAIJIN ; ARASTU, SARA ; LAM, JARRICK ; KIM, HYUNGSIN ; WANG, WENPING ; WANG, SAMUEL ; BHATT, VRUSHANK ; LOPES, EDUARDO CARARO ; HU, ZHIXIAN ; SUN, MICHAEL ; LUO, XUEFEI ; GHERGUROVICH, JONATHAN M. ; SU, XIAOYANG ; RABINOWITZ, JOSHUA D. ; WHITE, EILEEN ; GUO, JESSIE YANXIANG . Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer. Nature Communications , v. 15, p. 5857, 2024.

• SAWANT, AKSHADA ; SHI, FUQIAN ; CARARO LOPES, EDUARDO ; HU, ZHIXIAN ; ABDELFATTAH, SOMER ; BAUL, JENNELE ; POWERS, JESSE R. ; HINRICHS, CHRISTIAN S. ; RABINOWITZ, JOSHUA D. ; CHAN, CHANG S. ; LATTIME, EDMUND C. ; GANESAN, SHRIDAR ; WHITE, EILEEN P. . Immune Checkpoint Blockade Delays Cancer Development and Extends Survival in DNA Polymerase Mutator Syndromes. CANCER RESEARCH , v. 1, p. 1, 2024.

• BHATT, VRUSHANK ; LAN, TAIJIN ; WANG, WENPING ; KONG, JERRY ; LOPES, EDUARDO CARARO ; WANG, JIANMING ; KHAYATI, KHOOSHEH ; RAJU, AKASH ; RANGEL, MICHAEL ; LOPEZ, ENRIQUE ; HU, ZHIXIAN SHERRIE ; LUO, XUEFEI ; SU, XIAOYANG ; MALHOTRA, JYOTI ; HU, WENWEI ; PINE, SHARON R. ; WHITE, EILEEN ; GUO, JESSIE YANXIANG . Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors. Cell Death & Disease , v. 14, p. 61, 2023.

• CARARO LOPES, EDUARDO ; SAWANT, AKSHADA ; MOORE, DIRK ; KE, HUA ; SHI, FUQIAN ; LADDHA, SAURABH ; CHEN, YING ; SHARMA, ANCHAL ; NAUMANN, JAKE ; GUO, JESSIE YANXIANG ; GOMEZ, MARIA ; IBRAHIM, MARIA ; SMITH, TRACEY L. ; RIEDLINGER, GREGORY M. ; LATTIME, EDMUND C. ; TROOSKIN, STANLEY ; GANESAN, SHRIDAR ; SU, XIAOYANG ; PASQUALINI, RENATA ; ARAP, WADIH ; et.al . Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer. CLINICAL AND TRANSLATIONAL MEDICINE , v. 13, p. e1298, 2023.

• CARARO-LOPES, EDUARDO ; DIAS, MATHEUS H. ; DA SILVA, MARCELO S. ; ZEIDLER, JULIANNA D. ; VESSONI, ALEXANDRE T. ; REIS, MARCELO S. ; BOCCARDO, ENRIQUE ; ARMELIN, HUGO A. . Autophagy buffers Ras-induced genotoxic stress enabling malignant transformation in keratinocytes primed by human papillomavirus. Cell Death & Disease , v. 12, p. 194, 2021.

• DIAS, MATHEUS H. ; FONSECA, CECÍLIA S. ; ZEIDLER, JULIANNA D. ; ALBUQUERQUE, LAYRA L. ; DA SILVA, MARCELO S. ; CARARO'LOPES, EDUARDO ; REIS, MARCELO S. ; NOËL, VINCENT ; DOS SANTOS, EDMILSON O. ; PRIOR, IAN A. ; ARMELIN, HUGO A. . Fibroblast Growth Factor 2 lethally sensitizes cancer cells to stress-targeted therapeutic inhibitors. Molecular Oncology , v. 13, p. 290-306, 2019.

• MENEZES, MILENE C. ; KITANO, EDUARDO S. ; BAUER, VERENA C. ; OLIVEIRA, ANA K. ; CARARO-LOPES, EDUARDO ; NISHIYAMA, MILTON Y. ; ZELANIS, ANDRÉ ; SERRANO, SOLANGE M.T. . Early response of C2C12 myotubes to a sub-cytotoxic dose of hemorrhagic metalloproteinase HF3 from Bothrops jararaca venom. Journal of Proteomics , v. 198, p. 163-176, 2019.

• ZEIDLER, JULIANNA D. ; FERNANDES-SIQUEIRA, LORENA O. ; CARVALHO, ANA S. ; CARARO-LOPES, EDUARDO ; DIAS, MATHEUS H. ; KETZER, LUISA A. ; GALINA, ANTONIO ; DA POIAN, ANDREA T. . Short-term starvation is a strategy to unravel the cellular capacity of oxidizing specific exogenous/endogenous substrates in mitochondria. JOURNAL OF BIOLOGICAL CHEMISTRY , v. 292, p. 14176-14187, 2017.

• IKEGAMI, AMANDA ; TEIXEIRA, LUIZ FELIPE S. ; BRAGA, MARINA S. ; DIAS, MATHEUS HENRIQUE DOS S. ; LOPES, EDUARDO C. ; BELLINI, MARIA HELENA . Knockdown of NF-κB1 by shRNA inhibits the growth of renal cell carcinoma in vitro and in vivo. ONCOLOGY RESEARCH , v. 265, p. 743-751, 2017.

• Cararo-Lopes, E. ; SAWANT, A. ; BHATT, V. ; GOMEZ, M. ; SHI, FUQIAN ; CHAN, CHANG S. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Tumor respiration defects limit the serine synthesis required to suppress oxidative stress. In: Keystone Symposium in Cancer Metabolism, 2024, Banff, Canada. Keystone Symposium in Cancer Metabolism, 2024.

• Cararo-Lopes, E. ; SAWANT, A. ; BHATT, V. ; IBRAHIM, M. ; GOMEZ, M. ; SHI, FUQIAN ; CHAN, CHANG S. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Lung tumor respiration defects limit serine synthesis required to suppress oxidative stress. In: Symposium on Cancer Metabolism and Signaling in the Tumor Microenvironment, 2024, New York, USA. Symposium on Cancer Metabolism and Signaling in the Tumor Microenvironment, New York Academy of Science. New York City: New York Academy of Sciences, 2024.

• Cararo-Lopes, E. ; SAWANT, A. ; BHATT, V. ; IBRAHIM, M. ; GOMEZ, M. ; SHI, FUQIAN ; CHAN, CHANG S. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Tumor respiration defects limit serine synthesis required to suppress oxidative stress. In: Future Leaders Conference, Cancer Grand Challenges, 2023, Lisbon, Portugal. Future Leaders Conference, Cancer Grand Challenges, 2023.

• Cararo-Lopes, E. ; SAWANT, A. ; BHATT, V. ; GOMEZ, M. ; SHI, FUQIAN ; CHAN, CHANG S. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Accumulation of mtDNA mutations limits NSCLC growth and malignancy. In: Mechanisms of Metabolic Signaling, 2023, Long Island, NY, USA. Mechanisms of Metabolic Signaling, Cold Spring Harbor, 2023.

• Cararo-Lopes, E. ; SAWANT, A. ; BHATT, V. ; IBRAHIM, M. ; GOMEZ, M. ; SHI, FUQIAN ; CHAN, CHANG S. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Tumor respiration defect limits the anabolic metabolism required to suppress oxidative stress and nucleotide synthesis. In: Annual Retreat on Cancer Research, Rutgers University, 2023, New Brunswick,USA. Annual Retreat on Cancer Research, Rutgers University, 2023.

• Cararo-Lopes, E. ; SAWANT, A. ; BHATT, V. ; GOMEZ, M. ; SHI, FUQIAN ; CHAN, CHANG S. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Accumulation of mtDNA mutations limits NSCLC growth and malignancy. In: Keystone Symposium in Cancer Metabolism, 2022, Keystone, USA. Keystone Symposium in Cancer Metabolism, 2022.

• CARARO-LOPES, E. ; SAWANT, A. ; BHATT, V. ; GOMEZ, M. ; SHI, FUQIAN ; CHAN, CHANG S. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Accumulation of mtDNA mutations limits NSCLC growth and malignancy. In: Annual Retreat on Cancer Research, 2022, New Brunswick. Annual Retreat on Cancer Research, Rutgers University, 2022.

• Cararo-Lopes, E. ; SAWANT, A. ; GUO, JESSIE YANXIANG ; SU, X. ; WHITE, E. . The lack of proofreading activity of mitochondria DNA polymerase gamma reduces NSCLC growth. In: Annual Retreat on Cancer Research, Rutgers University, 2019. Annual Retreat on Cancer Research, Rutgers University, 2019.

• Cararo-Lopes, E. ; SU, X. ; YANG, L. ; DE, SUBHAJYOTI ; GANESAN, S. ; AISNER, J. ; TROOSKIN, STANLEY ; RABINOWITZ, JOSHUA D. ; WHITE, E. . Metabolomic Profile of Papillary Thyroid Cancer. In: Annual Retreat on Cancer Research, 2018, New Brunswick, USA. Annual Retreat on Cancer Research, Rutgers University, 2018.

• Lopes, E. ; SILVA, M. S. ; FONSECA, C. S. ; REIS, M. S. ; Enrique Boccardo ; ARMELIN, H. A. . High [HRasG12V-GTP] levels lead immortalized keratinocytes to death through autophagic flux impairment.. In: 81st Symposium: Targeting Cancer, 2016, New York. 81st Symposium: Targeting Cancer. Cold Spring Harbor Laboratory, 2016.

• Lopes, E. ; SILVA, M. S. ; REIS, M. S. ; Boccardo, E. ; ARMELIN, H. A. . High levels of [HRasG12V-GTP] in E6E7-immortalized keratinocytes cause block in autophagic flux leads the cell to death.. In: 45 Annual Meeting of the Brazilian Biochemistry and Molecular Biology Society (SBBq), 2016, Natal, RN. 45 Annual Meeting of the Brazilian Biochemistry and Molecular Biology Society (SBBq), 2016.

• Lopes, E. ; Boccardo, E. ; ARMELIN, H. A. . Acute exposition and high levels of [HRasG12V-GTP] in E6E7-immortalized keratinocytes do not promote transformation.. In: Gordon Research Conference in Cell Growth and Proliferation., 2015, West Dover, VT. Gordon Research Conference in Cell Growth and Proliferation., 2015.

• Lopes, E. ; Boccardo, E. ; ARMELIN, H. A. . Acute of [HRasG12V-GTP] in E6E7-immortalized keratinocytes do not promote transformation.. In: 23rd Congress of the International Union of Biochemistry and Molecular Biology (IUBMB) and 44th Annual Meeting of Brazilian Society for Biochemistry and Molecular Biology (SBBq)., 2015, Foz do Iguaçu. 23rd Congress of the International Union of Biochemistry and Molecular Biology (IUBMB) and 44th Annual Meeting of Brazilian Society for Biochemistry and Molecular Biology (SBBq)., 2015.

• Dias, M.H.S ; Lopes, E. ; L L, A. ; ARMELIN, H. A. . Cyclin D1 Level Is A Putative Achilles Heel? Of Ras-Driven Malignant Cells.. In: Ras initiative Symposium, 2015, Frederick. Ras initiative Symposium, 2015.

• Lopes, E. ; Boccardo, E. ; ARMELIN, H. A. . High levels of [HRasG12V-GTP] in E6E7-immortalized keratinocytes do not promote transformation.. In: XVIII Reunião científica anual do Instituto Butantan., 2015, São Paulo. XVIII Reunião científica anual do Instituto Butantan., 2015.

• Lopes, E. ; Boccardo, E. ; ARMELIN, H. A. . Transformation of E6E7-immortalized keratinocytes by HRas on intracellular levels of [HrasG12V-GTP].. In: XVI Reunião científica anual do Instituto Butantan., 2013, São Paulo. XVI Reunião científica anual do Instituto Butantan., 2013.

• Lopes, E. ; ZEIDLER, J. D. ; ARMELIN, H. A. . FGFs/FGFRs in human keratinocytes.. In: 10th International congress on Cell Biology and 16th Meeting of the Brazilian Society for Cell Biology, 2012, Riode Janeiro. 10th International congress on Cell Biology and 16th Meeting of the Brazilian Society for Cell Biology., 2012.

• Lopes, E. ; ZEIDLER, J. D. ; ARMELIN, H. A. . Characterization of keratinocytes responses to FGF1, FGF2 and FGF7.. In: XL Reunião científica anual da Sociedade Brasileira de Bioquímica e Biologia Molecular, SBBQ, 2011, Foz do Iguaçu. XL Reunião científica anual da Sociedade Brasileira de Bioquímica e Biologia Molecular, SBBQ, 2011.

• Lopes, E. ; ZEIDLER, J. D. ; ARMELIN, H. A. . Characterization of keratinocytes responses to FGF1, FGF2 and FGF7.. In: XII Reunião científica anual do Instituto Butantan, 2010, São Paulo. XII Reunião científica anual do Instituto Butantan, 2010.

• Lopes, E. ; ZEIDLER, J. D. ; ARMELIN, H. A. . Caracterização do papel de FGFs e FGFRs em Queratinócitos humanos.. In: 18º SIICUSP simpósio internacional de Iniciação científica da USP, 2010, Ribeirão Preto. 18º SIICUSP simpósio internacional de Iniciação científica da USP, 2010.

• CARARO-LOPES, E. ; SAWANT, A. ; GUO, J. Y. ; SU, X. ; WHITE, E. . Tumor respiration defects limit serine synthesis required to suppress oxidative stress. 2024. (Apresentação de Trabalho/Simpósio).

• Cararo-Lopes, E. . Metformin synergizes with serine/glycine starvation to cause metabolic stress in non-small cell lung cancer. 2024. (Apresentação de Trabalho/Seminário).

• Cararo-Lopes, E. ; WHITE, E. . Mitochondrial dysfunction sensitizes non-small cell lung cancer to serine/glycine starvation. 2024. (Apresentação de Trabalho/Seminário).

• CARARO-LOPES, E. ; SAWANT, A. ; GUO, J. Y. ; SU, X. ; WHITE, E. . Tumor respiration defects limit serine synthesis required to suppress oxidative stress. 2023. (Apresentação de Trabalho/Congresso).

• CARARO-LOPES, E. ; SAWANT, A. ; BHATT, V. ; IBRAHIM, M. ; GOMEZ, M. ; SHI, F. ; CHANG, C. ; SU, X. ; GANESAN, S. ; RABINOWITZ, J. ; LATTIME, E. C. ; GUO, J. Y. ; WHITE, E. . Tumor Respiration Defects Limit the Anabolic Metabolism Required to Suppress Oxidative Stress and Nucleotide Synthesis. 2023. (Apresentação de Trabalho/Simpósio).

• Cararo-Lopes, E. ; WHITE, E. . Increased mtDNA mutation burden limits tumor growth and malignancy in non-small cell lung cancer. 2022. (Apresentação de Trabalho/Seminário).

• Cararo-Lopes, E. ; WHITE, E. . Increased mtDNA mutation burden limits tumor growth and malignancy in non-small cell lung cancer. 2022. (Apresentação de Trabalho/Seminário).

• Cararo-Lopes, E. . Autophagy and Cancer: Where do they meet?. 2021. (Apresentação de Trabalho/Seminário).

• Cararo-Lopes, E. ; WHITE, E. . Proofreading defect in polymerase gamma cause growth impairment in non-small cell lung cancer. 2019. (Apresentação de Trabalho/Seminário).

• Cararo-Lopes, E. . Metabolomic profile of human papillary thyroid cancer. 2018. (Apresentação de Trabalho/Seminário).

• Lopes, E. ; ZEIDLER, J. D. ; ARMELIN, H. A. . Characterization of keratinocytes responses to FGF1, FGF2 and FGF7.. 2010. (Apresentação de Trabalho/Seminário).

• IBRAHIM, M. ; GOMEZ-JENKINS, M. ; SCHEINFELD, A. ; ZHAO, Z. ; CARARO-LOPES, E. ; SAWANT, A. ; HU, Z. ; DHARANI, A. ; SUN, M. ; SIDDIQUI, S. ; MIREK, E. T. ; ABRAM-SALIBA, J. ; LATTIME, E. C. ; SU, X. ; JANOWITZ, T. ; GONCALVES, M. D. ; DUNN, S. M. ; PRITYKIN, Y. ; ANTHONY, T. G. ; RABINOWITZ, J. D. ; et.al . Autophagy Suppresses CCL2 to Preserve Appetite and Prevent Lethal Cachexia. Cold Spring Harbor: Cold Spring Harbor Laboratory, 2025 (Pre-print).

• Cararo-Lopes, E. ; SHI, FUQIAN ; SAWANT, A. ; IBRAHIM, M. ; GOMEZ-JENKINS, M. ; HU, Z. S. ; MANCHIRAJU, P. ; BHATT, V. ; WANG, WENPING ; HINRICHS, C. S. ; WALLACE, D. C. ; SU, X. ; RABINOWITZ, J. D. ; CHANG, C. ; GUO, J. Y. ; GANESAN, S. ; LATTIME, E. C. ; WHITE, E. . Respiration Defects Limit Serine Synthesis Required for Lung Cancer Growth and Survival. CSHL, 2024 (Pre-print).

• SAWANT, A. ; SHI, FUQIAN ; CARARO-LOPES, E. ; HU, ZHIXIAN ; ABDELFATTAH, S. ; BAUL, J. ; POWERS, J. ; HINRICHS, C. S. ; RABINOWITZ, J. D. ; CHAN, C. S. ; LATTIME, E. C. ; GANESAN, S. ; WHITE, E. . Immune Checkpoint Blockade Delays Cancer and Extends Survival in Murine DNA Polymerase Mutator Syndromes. CSHL, 2024 (Pre-print).

• CARARO-LOPES, E. ; SAWANT, A. ; MOORE, D. ; KE, H. ; SHI, F. ; LADDHA, S. ; CHEN, Y. ; SHARMA, A. ; NAUMANN, J. ; GUO, J. Y. ; GOMEZ, M. ; IBRAHIM, M. ; SMITH, T. L. ; RIEDLINGER, G. M. ; LATTIME, E. C. ; TROOSKIN, S. ; GANESAN, S. ; SU, X. ; PASQUALINI, R. ; ARAP, W. ; et.al . Integrated metabolic and genetic analysis reveals distinct features of primary differentiated thyroid cancer and its metastatic potential in humans. CSHL, 2023 (Pre-print).

• LAN, TAIJIN ; ARASTU, S. ; WANG, S. ; LAM, J. ; WANG, W. ; BHATT, V. ; CARARO-LOPES, E. ; HU, Z. ; SUN, M. ; LUO, X. ; GHERGUROVICH, J. M. ; LI, C. ; SU, X. ; RABINOWITZ, J. D. ; WHITE, E. ; GUO, J. Y. . G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer. CSH, 2023 (Pre-print).

Projetos de pesquisa

• 2025 - Atual

  Novas perspectivas terapêuticas para tumores de pulmão: foco no estresse metabólico associado à sinalização mitogênica paradoxal, Descrição: O câncer de pulmão de células não pequenas (NSCLC) é um dos tipos mais letais, tornando urgente a busca por novas alternativas terapêuticas. Uma característica fundamental do NSCLC é sua limitada flexibilidade metabólica, especialmente no eixo entre a glicólise e a via de síntese de serina (SSP), afetada pela disponibilidade de nutrientes como glicose, serina e glicina. Desequilíbrios nesse processo causam estresse metabólico, reduzindo a capacidade de sobrevivência das células de NSCLC.Embora o estresse metabólico diminua a proliferação e viabilidade celular, células resistentes podem surgir, criando desafios terapêuticos como recidivas e metástases. Por isso, é necessário um modelo terapêutico que combine o estresse metabólico, enfraquecendo as células cancerosas, com uma estratégia para eliminar as mais resistentes.Células tumorais resistentes reduzem seus impulsos mitogênicos para se adaptar ao estresse metabólico. Assim, nossa abordagem será a de induzir esses impulsos ao invés de inibi-los. Hipotetizamos que a combinação do estresse metabólico com a hiper estimulação mitogênica criará uma vulnerabilidade insuperável até mesmo para as células mais resistentes, melhorando a sobrevida dos pacientes e reduzindo riscos de metástases e recidivas.Durante a privação de serina/glicina, a glicose é desviada para a SSP, a fim de sintetizar nucleotídeos e glutationa, processo que depende da função mitocondrial, já que o ciclo dos ácidos tricarboxílicos (TCA) é acelerado para manter o equilíbrio energético. O bloqueio da função mitocondrial com Metformina sensibiliza o NSCLC à privação de serina/glicina, impedindo o desvio da glicose para SSP. Após estabelecido o estresse metabólico, a indução mitogênica pode ser realizada por meio do inibidor da proteína fosfatase 2A (PP2A), LB-100, que hiper estimula vias mitogênicas canônicas, como a ERK.Testaremos essa hipótese combinando privação de serina/glicina com Metformina e LB-100 em NSCLC. Serão utilizados modelos in vitro e in vivo, incluindo camundongos geneticamente modificados, aloenxertos, culturas 3D e análises mitocondriais, além de amostras de pacientes para validação e adaptação dos achados a modelos de xenoinjertos, demonstrando seu potencial translacional com o objetivo de melhorar a sobrevida dos pacientes com NSCLC.. , Situação: Em andamento; Natureza: Pesquisa. , Integrantes: Eduardo Cararo Lopes - Coordenador / Marcelo S. da Silva - Integrante / Jessie Yanxiang Guo - Integrante / Xiaoyang Su - Integrante / Eileen White - Integrante / Roger Chammas - Integrante / Matheus Henrique Dias - Integrante., Financiador(es): Conselho Nacional de Desenvolvimento Científico e Tecnológico - Auxílio financeiro.

• 2019 - 2025

  Impact of mutation burden on cancer growth and the immune landscape, Descrição: Immune checkpoint blockade (ICB) using antibodies that disrupt PD1 or CTLA4 signaling can lead to durable responses in a wide variety of human cancers. Unfortunately, only a minority of patients obtain clinical benefit from ICB. A high non-synonymous nuclear mutation burden has been correlated with increased likelihood of response to ICB, suggesting that mutation induced neoantigens may underlie the tumor associated activation of immune checkpoints. Although this hypothesis linking mutation burden to peptide neoantigens is compelling, it has not been completely validated. Moreover, elevated mutation burden does not always dictate response to ICB, with some low mutation tumors such as thyroid cancers showing responses. Thus, there are huge gaps in our knowledge of the underlying mechanisms dictating response to ICB. We hypothesize that a high background somatic mutation burden, through introduction of mutations in DNA polymerases, will alter the immune landscape of cancers through the presence of truncal, tumor specific neoantigens that confer response to ICB. We will test this hypothesis and decipher underlying mechanisms using novel mouse models, This will be approached through the following specific aims: Aim 1: Determine the nature of the immune response to cancers with endogenous high nuclear mutation burden arising spontaneously in mice harboring germline proofreading mutations in Pold1 and Pole and patient tumors harboring POLE and POLD1 mutations.;#894; Aim 2: Determine how a high nuclear mutation burden affects the growth of oncogene-driven autochthonous cancer models and sensitivity to immune checkpoint therapy;#894; Aim 3: Determine if proofreading mutations in Polg and elevation of mitochondrial genome mutation burden contributes to an anti-tumor immune response.. Aim 4: Determine how combining targeted therapy and immune checkpoint therapy are modulated by presence of high background mutation burden. To address these aims, we will utilize mouse models in which a high background mutation rate is induced through germline proofreading mutations in Pole and Pold1 (for nuclear mutations) and Polg (for mitochondrial mutations. We will compare how specific oncogenes (Braf in skin and lung, and Kras in lung) induce tumors in either wild type mice or in mice with germline proofreading polymerase mutations to determine how high background mutation rate alters tumor growth, local and systemic immune response, and response to targeted therapy and ICB. Our overall goal is to develop a better understanding of how mutation burden affects the immune response to solid tumors. Robust models of high mutation burden cancers can be used to guide rational development of combination treatment strategies that can be translated into the clinic.Text informed on NIH web site: https://reporter.nih.gov/project-details/10527356.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Eduardo Cararo Lopes - Integrante / Eileen White - Coordenador., Financiador(es): National Institute of Health - Bolsa., Número de produções C, T & A: 3

• 2017 - 2022

  Tumor Cell Dependence on Host Metabolism, Descrição: Rapid fermentation of glucose to lactate (the ?Warburg effect?) was the first molecular characteristic assigned to cancer. Recent years have seen an explosion of interest in the metabolic capabilities of tumor cells, including up-regulated anabolism, redox defense, and alternative routes of nutrient acquisition such as macropinocytosis and autophagy. While these cellular capabilities play a critical role, metabolically, tumors ultimately depend on circulating nutrients provided by the host. The extent to which tumors generate energy and biomass building blocks from a few preferred circulating nutrients like glucose, versus uptake diverse nutrients to minimize their own biosynthetic work, remains, however, poorly understood. For example, many tumors upregulate serine biosynthesis. At the same time, tumor growth is sensitive to dietary serine intake. Which contributes more?circulating serine from the diet or serine synthesized in the tumor? While substantial efforts have been made to understand the essential metabolic pathways within tumor cells, comparatively little effort has gone into understanding the tumor's dependency on host metabolism. We have surprisingly observed that consumption of circulating nutrients by tumors is profoundly different from that of cultured cancer cells. We have also surprisingly observed that host autophagy is important for sustaining circulating nutrients and for the growth of implanted tumors (where autophagy remains intact). These findings highlight the potential for host metabolic processes to impact tumor growth. What are the critical circulating nutrients for tumors? How is host metabolism altered by autophagy deficiency? Which are the critical changes that impair tumor growth? More broadly, how can tumor dependency on host metabolism be exploited therapeutically? To address these questions, we will employ state-of-the-art isotope tracer techniques to murine tumor models of lung cancer and melanoma. Specifically, we will address the role of host metabolism in mouse models of K-Ras lung cancer, and B-Raf lung cancer and melanoma:Aim 1 : Identify the contributions of circulating nutrients and internal tumor metabolic pathways to lung cancer and melanoma growth. We hypothesize that, rather than using glucose and glutamine as their primary substrates, tumors in vivo consume a broad diversity of circulating nutrients, including amino acids, fats, and lactate, thereby minimizing biosynthetic requirements and enhancing metabolic robustness.Aim 2 : Determine the mechanism underlying dependence of tumors on host autophagy. We hypothesize that host autophagy is required to maintain circulating nutrients to support tumor growth.Aim 3 : Assess the therapeutic potential of modulating circulating metabolites. We hypothesize that decreasing circulating levels of nutrients including arginine, methionine, and glycine will have anti-tumor activity.Public Health RelevanceTumors obtain most of their nutritional support for growth from normal tissues of the body through the circulating blood supply, yet what these nutrients are is not clear. Recent evidence suggests that nutrient scavenging pathways of normal tissues in the body contribute nutritional support for tumors, but this is also poorly understood. We propose to identify the nutrients provided by the body that are critical for the growth of lung cancers and melanomas, and to determine their role in tumor growth, as a novel approach to the eradication of these deadly cancers.Text informed on Grantome NIH web site: https://grantome.com/grant/NIH/R01-CA163591-09. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Eduardo Cararo Lopes - Integrante / Eileen White - Coordenador., Financiador(es): National Institute of Health - Cooperação.

• 2017 - 2019

  Identifying metabolic mechanisms to conquer metastatic thyroid cancer, Descrição: With 8.5 million people living in 7,500 square miles, New Jersey is the most densely populated state in the nation. Cancer incidence here is the highest in the country, and mortality is above the national average. Among these, Papillary Thyroid Cancer (PTC) is a significant health threat to those living in New Jersey. This is because our state is situated in the radon belt, and the state also has high-density population in proximity to nuclear reactors (http://www.ncbi.nlm.nih.gov/pubmed/19927407). These exposures are associated with increased risk of thyroid cancer. PTC is a deadly disease to a largely unpredictable subset of patients. Thus, distinguishing those patients with biologically aggressive disease associated with high risk of recurrence and metastatic disease from those with indolent disease with good long-term prognosis is an important unmet need. Moreover, better treatment strategies for recurrent and metastatic disease are also needed, as recurrent radioactive-iodide-refractory thyroid cancer has very poor prognosis. This problem that RCINJ needs to address to meet the needs of our patient population is to (1) identify those at risk for PTC recurrence; (2) determine the mechanisms that drive recurrent and metastatic disease, and (3) develop new treatment options based on those mechanisms. Key to addressing this problem is to identify the metabolic and genomic changes causing this progression of PTC to recurrent and metastatic disease. Metabolomics and genomics are among the marquee special scientific capabilities of RCINJ and more broadly the state of New Jersey. This proposal deploys these cutting edge technologies with their intellectual leaders in the field and brings them to bear on a significant health problem in the state, recurrent and metastatic PTC.An essential characteristic that distinguished most normal from cancer cells is altered metabolism (Vander Heiden et al., 2009; Warburg, 1956a, b; Zong et al., 2016). These metabolic changes are necessary for cancer cells to obtain the nutrients and generate the energy necessary to produce the building blocks for new cancer cells. Simply put, for one cancer cell to divide into two cancer cells, growth signals need to be turned on and all the parts of the new cell need to be synthesized. The activated growth signals in cancer cells alter their metabolism to produce the building blocks for new cancer cells. It is this continuous production of new cancer cells that is deadly. This fundamental concept of targeting cancer metabolism to block cancer growth is new and exciting (see: http://www.nytimes.com/2016/05/15/magazine/warburg-effect-an-old-idea-revived-starve-cancer-to-death.html?_r=0). Despite these revelations, the essential metabolic characteristics of most cancers, including PTC, and how they promote cancer growth, remain to be discovered and exploited for cancer therapy. Cancer is a genetic disease driven by genomic changes that promote growth and the very metabolic changes necessary for the production of new cancer cells. PTC has a low frequency of somatic mutations dominated by mutations in B-raf (60) and N-ras (13), and a favorable prognosis. For the subset of these patients that develop metastases to the lung, unfortunately the prognosis is poor and the underlying mechanisms are unknown. The genetic changes driving metastatic PTC remain to be discovered, and their underlying functions that promote growth and alter metabolism need to be identified and targeted for cancer therapy. We hypothesize that genomic alterations promote metabolic changes necessary for growth and malignancy of PTC. We propose to combine state-of-the-art metabolomic and genomic profiling of patient tumors to distinguish between metastatic and curable PTC. We further propose to discover underling metabolic and genomic mechanisms driving metastatic disease and to. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Eduardo Cararo Lopes - Integrante / Eileen White - Coordenador., Financiador(es): The Johnson & Johnson Foundation - Bolsa., Número de produções C, T & A: 1

• 2012 - 2017

  The role of autophagy in mitogenic stress promoted by HRasG12V in human keratinocytes immortalized by E6E7, Descrição: Malignant transformation involves an orchestrated rearrangement of cell cycle regulation mechanisms that must balance autonomic mitogenic impulses and deleterious oncogenic stress. Human papillomavirus (HPV) infection is highly prevalent in populations around the globe, whereas the incidence of cervical cancer is 0.15. Since HPV infection primes cervical keratinocytes to undergo malignant transformation, we can assume that the balance between transforming mitogenic signals and oncogenic stress is rarely attained. We showed that highly transforming mitogenic signals triggered by HRasG12V activity in E6E7HPVkeratinocytes generate strong replication and oxidative stresses. These stresses are counteracted by autophagy induction that buffers the rapid increase of ROS that is the main cause of genotoxic stress promoted by the oncoprotein. As a result, autophagy creates a narrow window of opportunity for malignant keratinocytes to emerge. This work shows that autophagy is crucial to allow the transition of E6E7 keratinocytes from an immortalized to a malignant state caused by HRasG12V.Text from article: https://www.nature.com/articles/s41419-021-03476-3. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Eduardo Cararo Lopes - Coordenador / Hugo Aguirre Armelin - Integrante., Financiador(es): Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Bolsa.

• 2009 - 2012

  Caracterização do papel de FGFs e FGFRs em queratinócitos humanos, Descrição: Queratinócitos humanos da linhagem HaCaT foram testados no intuito decaracterizar sua resposta a FGF1, FGF2 e KGF, bem como a expressão de FGFRs eFGFs. Por meio de PCR quantitativo identificamos a expressão de mRNA de FGFR2,FGFR3 e FGFR4, sendo que foi constatado que o receptor 3 é o mais expresso. Por PCRe seqüenciamento confirmamos a expressão de tais receptores e também de FGF1 eFGF2 por essas células. Além disso, foi observado que FGF1, FGF2 e KGF ativam a viade ERK dentro de 5 minutos em queratinócitos previamente carenciados em meio semsoro, além de induzirem proliferação e migração dessas células nas mesmas condições.KGF mostrou-se ser um estimulador muito mais potente do que FGF1 e FGF2 para estetipo celular, tanto quanto a migração quanto a proliferação. Esses resultados introduzemalgumas características do sistema FGF/FGFR em queratinócitos humanos que ajudam amelhor entender a resposta a esses fatores de crescimento, mas ainda se fazemnecessários alguns ensaios confirmatórios, como a confirmação da expressão protéica deFGFRs e FGFs, entre outros.Aqui foi confirmada a expressão protéica de FGF1, FGF2 e dos receptoresFGFR2, FGFR3 e FGFR4 em queratinócitos humanos, sendo este último a primeiradescrição nesse tipo celular. Ensaios de imunofluorecência mostram a localização deFGF1 e FGF2 em grânulos citoplamáticos. A expressão esses fatores de crescimentosugere uma ação autócrina e/ou parácrina em outras células da pele, que será avaliadaatravés de experimentos com fibroblastos, que acredita-se ser um de seus alvos. Estalinhagem celular apresentou alto basal de Akt fosforilado, sendo que esses níveis defosforilação aumentam quando a mesma é tratada com KGF, mas não com FGF1 eFGF2, o que pode indicar o motivo pelo qual KGF é o mitógeno mais potente paraqueratinócitos em relação aos outros FGFs. Os resultados mostrados aqui contribuemnão apenas para o entendimento da sinalização intracelular em queratinócitos, massugere também a participação de FGFs na comunicação intracelular na pele.. , Situação: Concluído; Natureza: Pesquisa. , Integrantes: Eduardo Cararo Lopes - Coordenador / Hugo Aguirre Armelin - Integrante., Financiador(es): Fundação de Amparo à Pesquisa do Estado de São Paulo - Bolsa.

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