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1.
JACC CardioOncol ; 6(3): 390-401, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38983382

RESUMO

Background: Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in men with prostate cancer; however, data on racial disparities in CVD outcomes are limited. Objectives: We quantified the disparities in CVD according to self-identified race and the role of the structural social determinants of health in mediating disparities in prostate cancer patients. Methods: A retrospective cohort study of 3,543 prostate cancer patients treated with systemic androgen deprivation therapy (ADT) between 2008 and 2021 at a quaternary, multisite health care system was performed. The multivariable adjusted association between self-reported race (Black vs White) and incident major adverse cardiovascular events (MACE) after ADT initiation was evaluated using cause-specific proportional hazards. Mediation analysis determined the role of theme-specific and overall social vulnerability index (SVI) in explaining the racial disparities in CVD outcomes. Results: Black race was associated with an increased hazard of MACE (HR: 1.38; 95% CI: 1.16-1.65; P < 0.001). The association with Black race was strongest for incident heart failure (HR: 1.79; 95% CI: 1.32-2.43), cerebrovascular disease (HR: 1.98; 95% CI: 1.37-2.87), and peripheral artery disease (HR: 1.76; 95% CI: 1.26-2.45) (P < 0.001). SVI, specifically the socioeconomic status theme, mediated 98% of the disparity in MACE risk between Black and White patients. Conclusions: Black patients are significantly more likely to experience adverse CVD outcomes after systemic ADT compared with their White counterparts. These disparities are mediated by socioeconomic status and other structural determinants of health as captured by census tract SVI. Our findings motivate multilevel interventions focused on addressing socioeconomic vulnerability.

2.
Nat Rev Cardiol ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600368

RESUMO

Cardiovascular disease (CVD) and cancer are among the leading causes of morbidity and mortality globally, and these conditions are increasingly recognized to be fundamentally interconnected. In this Review, we present the current epidemiological data for each of the modifiable risk factors shared by the two diseases, including hypertension, hyperlipidaemia, diabetes mellitus, obesity, smoking, diet, physical activity and the social determinants of health. We then review the epidemiological data demonstrating the increased risk of CVD in patients with cancer, as well as the increased risk of cancer in patients with CVD. We also discuss the shared mechanisms implicated in the development of these conditions, highlighting their inherent bidirectional relationship. We conclude with a perspective on future research directions for the field of cardio-oncology to advance the care of patients with CVD and cancer.

3.
Clin Lung Cancer ; 23(4): e310-e316, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35393247

RESUMO

BACKGROUND: Better therapies are needed to improve survival in metastatic non-small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non-squamous (NSQ) NSCLC. MATERIALS AND METHODS: This single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m2 and gemcitabine 1000 mg/m2 on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Thirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis. CONCLUSION: Combination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02303977 MICRO-ABSTRACT: In this phase II trial, 37 patients with metastatic non-squamous non-small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Paclitaxel , Pemetrexede/uso terapêutico , Platina/uso terapêutico , Gencitabina
4.
Cancer Discov ; 6(9): 1006-21, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27312177

RESUMO

UNLABELLED: As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways, leading to epigenetic transformation independent of canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a potent open-source EZH2 inhibitor, JQEZ5, that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer. SIGNIFICANCE: EZH2 overexpression induces murine lung cancers that are similar to human NSCLC with high EZH2 expression and low levels of phosphorylated AKT and ERK, implicating biomarkers for EZH2 inhibitor sensitivity. Our EZH2 inhibitor, JQEZ5, promotes regression of these tumors, revealing a potential role for anti-EZH2 therapy in lung cancer. Cancer Discov; 6(9); 1006-21. ©2016 AACR.See related commentary by Frankel et al., p. 949This article is highlighted in the In This Issue feature, p. 932.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Cromatina/genética , Cromatina/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Elementos Facilitadores Genéticos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Imageamento por Ressonância Magnética , Camundongos , Modelos Moleculares , Conformação Molecular , Terapia de Alvo Molecular , Regiões Promotoras Genéticas , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Immunol Res ; 4(6): 520-30, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27068336

RESUMO

Autophagy promotes tumor progression downstream of oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IκB kinase (IKK)-related kinase TBK1 in vivo, associated with increased neutrophil and T-cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFNγ signaling and involves JAK pathway activation. Treatment with the TBK1/IKKε/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting. Cancer Immunol Res; 4(6); 520-30. ©2016 AACR.


Assuntos
Autofagia/fisiologia , Pancreatite/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Doença Aguda , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Proteína 5 Relacionada à Autofagia/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/biossíntese , Benzamidas/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Ceruletídeo , Quimiocina CCL5/antagonistas & inibidores , Quimiocina CCL5/metabolismo , Citocinas/metabolismo , Ativação Enzimática/genética , Deleção de Genes , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/induzido quimicamente , Pancreatite/genética , Pancreatite/patologia , Pancreatite/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
6.
Cancer Cell ; 25(5): 590-604, 2014 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-24794706

RESUMO

Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1(+)NGFR(+) fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.


Assuntos
Antígeno B7-H1/biossíntese , Carcinoma de Células Escamosas/imunologia , Neoplasias Pulmonares/imunologia , PTEN Fosfo-Hidrolase/genética , Proteínas Serina-Treonina Quinases/genética , Evasão Tumoral/imunologia , Proteínas Quinases Ativadas por AMP , Animais , Antígenos Ly/biossíntese , Linfócitos B/imunologia , Carcinoma de Células Escamosas/genética , Modelos Animais de Doenças , Tolerância Imunológica/imunologia , Queratina-15 , Queratina-5/biossíntese , Células Matadoras Naturais/imunologia , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Proteínas de Membrana/biossíntese , Metaboloma , Camundongos , Neutrófilos/imunologia , Fosfoproteínas/biossíntese , Receptor de Fator de Crescimento Neural/biossíntese , Fatores de Transcrição SOXB1/biossíntese , Linfócitos T/imunologia , Transativadores/biossíntese , Transcrição Gênica , Células Tumorais Cultivadas
7.
Cancer Discov ; 4(4): 452-65, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24444711

RESUMO

Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKKε promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKε inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKε promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKε, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.


Assuntos
Comunicação Autócrina , Benzamidas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Quimiocina CCL5/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , Camundongos , Neoplasias Experimentais , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo
8.
Clin Cancer Res ; 20(5): 1204-1211, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24327273

RESUMO

PURPOSE: To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion. EXPERIMENTAL DESIGN: We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed. RESULTS: Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L. CONCLUSIONS: Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naïve disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Crizotinibe , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Imageamento por Ressonância Magnética , Camundongos , Proteínas de Fusão Oncogênica/genética , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Resultado do Tratamento
9.
Cancer Discov ; 3(12): 1355-63, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24078774

RESUMO

UNLABELLED: The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. SIGNIFICANCE: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Citocinas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Evasão Tumoral , Animais , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oncogenes , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Microambiente Tumoral
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