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RATIONALE: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing for timely and effective intervention before cancer development. OBJECTIVES: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. METHODS: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. RESULTS: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. CONCLUSIONS: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, along with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.
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BACKGROUND: In patients with non-small cell lung cancer (NSCLC), 10%-40% will eventually develop brain metastases. We present the clinicopathologic, genomic, and biomarker landscape of a large cohort of NSCLC brain metastases (NSCLC-BM) samples. MATERIALS AND METHODS: We retrospectively analyzed 3035 NSCLC-BM tested with comprehensive genomic profiling (CGP) during routine clinical care. In addition, we compared the NSCLC-BM to a separate cohort of 7277 primary NSCLC (pNSCLC) specimens. Finally, we present data on 67 paired patients with NSCLC-BM and pNSCLC. RESULTS: Comprehensive genomic profiling analysis of the 3035 NSCLC-BMs found that the most frequent genomic alterations (GAs) were in the TP53, KRAS, CDKN2A, STK11, CDKN2B, EGFR, NKX2-1, RB1, MYC, and KEAP1 genes. In the NSCLC-BM cohort, there were significantly higher rates of several targetable GAs compared with pNSCLC, including ALK fusions, KRAS G12C mutations, and MET amplifications; and decreased frequency of MET exon14 skipping mutations (all P < .05). In the subset of NSCLC-BM (n = 1063) where concurrent PD-L1 immunohistochemistry (IHC) was performed, 54.7% of the patients with NSCLC-BM were eligible for pembrolizumab based on PD-L1 IHC (TPS ≥ 1), and 56.9% were eligible for pembrolizumab based on TMB-High status. In addition, in a series 67 paired pNSCLC and NSCLC-BM samples, 85.1% (57/67) had at least one additional GA discovered in the NSCLC-BM sample when compared with the pNSCLC sample. CONCLUSIONS: Herein, we defined the clinicopathologic, genomic, and biomarker landscape of a large cohort of patients with NSCLC-BM which can help inform study design of future clinical studies for patients with NSCLC with BM. In certain clinical situations, metastatic NSCLC brain tissue or cerebral spinal fluid specimens may be needed to fully optimize personalized treatment.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Genômica , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Fator 2 Relacionado a NF-E2/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Proteína Tirosina Quinases/genética , Estudos RetrospectivosRESUMO
High ERß/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.
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Receptor beta de Estrogênio/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética , Microambiente Tumoral/genética , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Receptor beta de Estrogênio/imunologia , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Oncogenes/genética , Oncogenes/imunologia , Receptor de Morte Celular Programada 1/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Quinazolinonas/farmacologia , Receptor ErbB-2/imunologia , Microambiente Tumoral/imunologiaRESUMO
K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. The absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-κB)-driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.
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Adenocarcinoma de Pulmão/imunologia , Transformação Celular Neoplásica/imunologia , Estrogênios/metabolismo , Imunomodulação , Neoplasias Pulmonares/imunologia , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imunidade/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Mutação , NF-kappa B/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator de Transcrição STAT3/genética , Células Tumorais CultivadasRESUMO
Tumor immune escape is now a hallmark of cancer development, and therapies targeting these pathways have emerged as standard of care. Specifically, immune checkpoint signal blockade offers durable responses and increased overall survival. However, the majority of cancer patients still do not respond to checkpoint blockade immune therapy leading to an unmet need in tumor immunology research. Sex-based differences have been noted in the use of cancer immunotherapy suggesting that sex hormones such as estrogen may play an important role in tumor immune regulation. Estrogen signaling already has a known role in autoimmunity, and the estrogen receptor can be expressed across multiple immune cell populations and effect their regulation. While it has been well established that tumor cells such as ovarian carcinoma, breast carcinoma, and even lung carcinoma can be regulated by estrogen, research into the role of estrogen in the regulation of tumor-associated immune cells is still emerging. In this chapter, we discuss the role of estrogen in the tumor immune microenvironment and the possible immunotherapeutic implications of targeting estrogen in cancer patients.
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Estrogênios/fisiologia , Imunoterapia , Neoplasias/terapia , Evasão Tumoral , Microambiente Tumoral , Humanos , Transdução de SinaisRESUMO
Oncogene-induced senescence (OIS) is considered a powerful tumor suppressor mechanism. Caveolin-1 acts as a scaffolding protein to functionally regulate signaling molecules. We demonstrate that a lack of caveolin-1 expression inhibits oncogenic K-Ras (K-RasG12V)-induced premature senescence in mouse embryonic fibroblasts and normal human bronchial epithelial cells. Oncogenic K-Ras induces senescence by limiting the detoxification function of MTH1. We found that K-RasG12V promotes the interaction of caveolin-1 with MTH1, which results in inhibition of MTH1 activity. Lung cancer cells expressing oncogenic K-Ras have bypassed the senescence barrier. Interestingly, overexpression of caveolin-1 restores cellular senescence in both A549 and H460 lung cancer cells and inhibits their transformed phenotype. In support of these findings, our in vivo data demonstrate that overexpression of oncogenic K-Ras (K-RasG12D) induces cellular senescence in the lung of wildtype but not caveolin-1-null mice. A lack of K-RasG12D-induced premature senescence in caveolin-1-null mice results in the formation of more abundant lung tumors. Consistent with these data, caveolin-1-null mice overexpressing K-RasG12D display accelerated mortality. Finally, our animal data were supported by human sample analysis in which we show that caveolin-1 expression is dramatically down-regulated in lung adenocarcinomas from lung cancer patients, both at the mRNA and protein levels, and that low caveolin-1 expression is associated with poor survival. Together, our data suggest that lung cancer cells escape oncogene-induced premature senescence through down-regulation of caveolin-1 expression to progress from premalignant lesions to cancer.
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Adenocarcinoma/metabolismo , Caveolina 1/biossíntese , Senescência Celular , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células A549 , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Substituição de Aminoácidos , Animais , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Knockout , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
RATIONALE: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. METHODS: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. MEASUREMENTS AND MAIN RESULTS: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. CONCLUSIONS: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Células Endoteliais/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Neovascularização Patológica/patologia , Animais , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Modelos Animais de Doenças , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Knockout , Neovascularização Patológica/metabolismo , Reação em Cadeia da Polimerase , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Estrogen receptors are broadly expressed in many cell types involved in the innate and adaptive immune responses, and differentially regulate the production of cytokines. While both genomic and non-genomic tumor cell promoting mechanisms of estrogen signaling are well characterized in multiple carcinomas including breast, ovarian, and lung, recent investigations have identified a potential immune regulatory role of estrogens in the tumor microenvironment. Tumor immune tolerance is a well-established mediator of oncogenesis, with increasing evidence indicating the importance of the immune response in tumor progression. Immune-based therapies such as antibodies that block checkpoint signals have emerged as exciting therapeutic approaches for cancer treatment, offering durable remissions and prolonged survival. However, only a subset of patients demonstrate clinical response to these agents, prompting efforts to elucidate additional immunosuppressive mechanisms within the tumor microenvironment. Evidence drawn from multiple cancer types, including carcinomas traditionally classified as non-immunogenic, implicate estrogen as a potential mediator of immunosuppression through modulation of protumor responses independent of direct activity on tumor cells. Herein, we review the interplay between estrogen and the tumor microenvironment and the clinical implications of endocrine therapy as a novel treatment strategy within immuno-oncology.
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Estrogênios/metabolismo , Neoplasias/imunologia , Receptores de Estrogênio/genética , Microambiente Tumoral/genética , Estrogênios/genética , Estrogênios/imunologia , Humanos , Imunoterapia , Neoplasias/terapia , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer. METHODS: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways. RESULTS: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08). CONCLUSIONS: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundário , Intervalo Livre de Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
Lung cancer has the highest incidence of brain metastases (BM) among solid organ cancers. Traditionally whole brain radiation therapy has been utilized for non-small-cell lung cancer (NSCLC) BM treatment, although stereotactic radiosurgery has emerged as the superior treatment modality for most patients. Highly penetrant central nervous system (CNS) tyrosine kinase inhibitors have also shown significant CNS activity in patients harboring select oncogenic drivers. There is emerging evidence that patients without oncogene-driven tumors derive benefit from the use of immune checkpoint inhibitors (ICIs). The CNS activity of ICIs have not been well studied given exclusion of patients with active BM from landmark trials, due to concerns of inadequate CNS penetration and activity. However, studies have challenged the idea of an immune-privileged CNS, given the presence of functional lymphatic drainage within the CNS and destruction of the blood brain barrier by BM. An emerging understanding of the interactions between tumor and CNS immune cells in the BM tumor microenvironment also support a role for immunotherapy in BM treatment. In addition, posthoc analyses of major trials have shown improved intracranial response and survival benefit of regimens with ICIs over chemotherapy (CT) alone for patients with BM. Two prospective phase 2 trials evaluating pembrolizumab monotherapy and atezolizumab plus CT in patients with untreated NSCLC BM also demonstrated significant intracranial responses. This review describes the interplay between CNS immune cells and tumor cells, discusses current evidence for ICI CNS activity from retrospective and prospective studies, and speculates on future directions of investigation.
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MET amplification/mutations are important targetable oncogenic drivers in NSCLC, however, acquired resistance is inevitable and the majority of patients with targetable MET alterations fail to respond to MET tyrosine kinase inhibitors (TKIs). Furthermore, MET amplification is among the most common mediators of TKI resistance. As such, novel therapies to target MET pathway and overcome MET TKI resistance are clearly needed. Here we show that the epithelial-mesenchymal transition (EMT) transcription factor, TWIST1 is a key downstream mediator of HGF/MET induced resistance through suppression of p27 and targeting TWIST1 can overcome resistance. We found that TWIST1 is overexpressed at the time of TKI resistance in multiple MET-dependent TKI acquired resistance PDX models. We have shown for the first time that MET directly stabilized the TWIST protein leading to TKI resistance and that TWIST1 was required for MET-driven lung tumorigenesis as well as could induce MET TKI resistance when overexpressed. TWIST1 mediated MET TKI resistance through suppression of p27 expression and genetic or pharmacologic inhibition of TWIST1 overcame TKI resistance in vitro and in vivo. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome resistance in MET-driven NSCLC as well as in other oncogene driven subtypes in which MET amplification is the resistance mechanism.
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Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento de Hepatócito , Neoplasias Pulmonares , Proteínas Nucleares , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Proteína 1 Relacionada a Twist , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Oncogenes/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The influence of sex and body mass index (BMI) on the efficacy of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a retrospective study to evaluate the relationship between sex, BMI, pretreatment weight loss (PWL), and clinical outcomes in 399 stage IV NSCLC patients treated with ICIs using data abstracted from medical records. Multivariable Cox proportional hazards models were used to assess the impact on overall survival and progression-free survival. Females were significantly more likely to experience immune-related adverse events and had a significantly lower risk of death compared to males in our patient cohort. In stratified analyses, the latter was limited to those receiving first-line monotherapy. BMI was overall not significantly associated with outcome. However, underweight patients had a significantly higher risk of both progression and death compared to normal weight patients in the first-line monotherapy group. When stratified by sex, underweight males had a significantly higher risk of progression and death compared to normal weight males. This was not observed among females. Those with PWL had overall significantly worse outcomes compared to those without. In stratified analyses, PWL was associated with significantly worse OS in both females and males. Stratified by treatment, the worse outcome was limited to those receiving ICI monotherapy. In summary, utilizing real-world data, this study suggests that male sex, being underweight, and PWL negatively impact ICI efficacy in NSCLC patients. Therapeutic approaches to improve ICI outcomes in underweight patients and those with PWL should be investigated.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Magreza , Imunoterapia , Redução de PesoRESUMO
Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression, and most human lung tumors express estrogen receptor ß (ERß) as well as aromatase. To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen, alone or in combination with the ER antagonist fulvestrant, ovariectomized female mice received treatments with the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) along with daily supplements of androstenedione, the substrate for aromatase. Placebo, anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis. The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors (mean = 0.5) compared with placebo (mean = 4.6, P < 0.001), fulvestrant alone (mean = 3.4, P < 0.001) or anastrozole alone (mean = 2.8, P = 0.002). A significantly lower Ki67 cell proliferation index was also observed compared with single agent and control treatment groups. Beginning antiestrogen treatment after NNK exposure, when preneoplastic lesions had already formed, also yielded maximum antitumor effects with the combination. Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs, whereas ERß was found in both macrophages and tumor cells. Antiestrogens, especially in combination, effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis and may have application for lung cancer prevention. An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens, beginning early in the carcinogenesis process. ERß expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production.
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Carcinógenos/toxicidade , Moduladores de Receptor Estrogênico/uso terapêutico , Neoplasias Pulmonares/prevenção & controle , Nicotiana/toxicidade , Nitrosaminas/toxicidade , Anastrozol , Animais , Inibidores da Aromatase/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Feminino , Fulvestranto , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nitrilas/uso terapêutico , Receptores de Estrogênio/metabolismo , Triazóis/uso terapêuticoRESUMO
Estrogen receptors (ERs) are known to play an important role in the proper development of estrogen-sensitive organs, as well as in the development and progression of various types of cancer. ERα, the first ER to be discovered, has been the focus of most cancer research, especially in the context of breast cancer. However, ERß expression also plays a significant role in cancer pathophysiology, notably its seemingly protective nature and loss of expression with oncogenesis and progression. Although ERß exhibits antitumor activity in breast, ovarian, and prostate cancer, its expression is associated with disease progression and worse prognosis in lung cancer. The function of ERß is complicated by the presence of multiple isoforms and single nucleotide polymorphisms, in addition to tissue-specific functions. This mini-review explores current literature on ERß and its mechanism of action and clinical implications in breast, ovarian, prostate, and lung cancer.
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Receptor beta de Estrogênio/fisiologia , Neoplasias/genética , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Receptor beta de Estrogênio/genética , Estrogênios/farmacologia , Feminino , Humanos , Masculino , Neoplasias/patologiaRESUMO
Human lung adenocarcinoma (LUAD) in current or former smokers exhibits a high tumor mutational burden (TMB) and distinct mutational signatures. Syngeneic mouse models of clinically relevant smoking-related LUAD are lacking. We established and characterized a tobacco-associated, transplantable murine LUAD cell line, designated FVBW-17, from a LUAD induced by the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in the FVB/N mouse strain. Whole-exome sequencing of FVBW-17 cells identified tobacco-associated KrasG12D and Trp53 mutations and a similar mutation profile to that of classic alkylating agents with a TMB greater than 500. FVBW-17 cells transplanted subcutaneously, via tail vein, and orthotopically generated tumors that were histologically similar to human LUAD in FVB/N mice. FVBW-17 tumors expressed programmed death ligand 1 (PD-L1), were infiltrated with CD8+ T cells, and were responsive to anti-PD-L1 therapy. FVBW-17 cells were also engineered to express green fluorescent protein and luciferase to facilitate detection and quantification of tumor growth. Distant metastases to lung, spleen, liver, and kidney were observed from subcutaneously transplanted tumors. This potentially novel cell line is a robust representation of human smoking-related LUAD biology and provides a much needed preclinical model in which to test promising new agents and combinations, including immune-based therapies.
Assuntos
Adenocarcinoma de Pulmão/induzido quimicamente , Antígeno B7-H1/metabolismo , Carcinógenos/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Nitrosaminas/toxicidade , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Camundongos , Mutação , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Fumaça/efeitos adversos , Nicotiana/toxicidade , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
PURPOSE: We determined hepatocyte growth factor (HGF) and c-Met expression and signaling in human head and neck squamous cell carcinoma (HNSCC) cells and primary tissues and tested the ability of c-Met tyrosine kinase inhibitors (TKI) to block HGF-induced biological signaling. EXPERIMENTAL DESIGN: Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs were tested for their ability to block HGF-induced signaling and biological effects in vitro and in xenografts established in nude mice. RESULTS: c-Met was expressed and functional in HNSCC cells. HGF was secreted by HNSCC tumor-derived fibroblasts, but not by HNSCC cells. Activation of c-Met promoted phosphorylation of AKT and mitogen-activated protein kinase as well as release of the inflammatory cytokine interleukin-8. Cell growth and wound healing were also stimulated by HGF. c-Met TKIs blocked HGF-induced signaling, interleukin-8 release, and wound healing. Enhanced invasion of HNSCC cells induced by the presence of tumor-derived fibroblasts was completely blocked with a HGF-neutralizing antibody. PF-2341066, a c-Met TKI, caused a 50% inhibition of HNSCC tumor growth in vivo with decreased proliferation and increased apoptosis within the tumors. In HNSCC tumor tissues, both HGF and c-Met protein were increased compared with expression in normal mucosa. CONCLUSIONS: These results show that HGF acts mainly as a paracrine factor in HNSCC cells, the HGF/c-Met pathway is frequently up-regulated and functional in HNSCC, and a clinically relevant c-Met TKI shows antitumor activity in vivo. Blocking the HGF/c-Met pathway may be clinically useful for the treatment of HNSCC.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/fisiologia , Animais , Western Blotting , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Crizotinibe , Relação Dose-Resposta a Droga , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/fisiopatologia , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Imuno-Histoquímica , Indóis/farmacologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Comunicação Parácrina/fisiologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazóis , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estresse Mecânico , Sulfonamidas/farmacologia , Transplante Heterólogo , Carga Tumoral/efeitos dos fármacosRESUMO
Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone ß-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a "hallmark" of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents.
RESUMO
Lung cancer remains the leading cause of cancer-related deaths worldwide. In order to understand lung cancer biology and evaluate novel therapeutic strategies, preclinical mouse models have been developed that mimic early and advanced-stage lung cancer. Among autochthonous models, carcinogen-induced systems are valuable preclinical tools since tobacco smoking remains the number one risk factor for lung tumor development. Among the several thousand chemicals within cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen with tumorigenic effects described in both mice and humans. Herein, we describe the methodology for inducing lung tumors in mice using the tobacco carcinogen NNK and subsequent lung fixation for quantitative assessment of tumor development and analysis of oncogenic mutations in tumors.
Assuntos
Carcinógenos/toxicidade , Modelos Animais de Doenças , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , Pulmão/cirurgia , Nitrosaminas/toxicidade , Animais , DNA/genética , DNA/isolamento & purificação , Análise Mutacional de DNA , Imuno-Histoquímica , Pulmão/citologia , Neoplasias Pulmonares/induzido quimicamente , Camundongos , Camundongos Endogâmicos , Nitrosaminas/administração & dosagem , Nicotiana/toxicidade , Fluxo de TrabalhoRESUMO
Background: Cell-membrane expressing enzymes such as ADAM (a disintegrin and metalloproteinase) superfamily members are thought to be key catalysts of vital cellular functions. To directly measure these enzymes and determine their association with particular cells and functions, individual-cell membrane-bound enzyme activity assays are required, but unavailable. Methods: We developed two such assays, using a fluorescence resonance energy transfer (FRET) peptide substrate (FPS) and flow cytometry. One assay measured live-cell natural processing of FPS and binding of its fluorescent product onto individual-cell membrane-bound enzymes. The other assay measured processing of specifically-bound and glutaraldehyde-crosslinked FPS, and consequent generation of its coupled fluorescent product onto individual-cell membrane-bound enzymes. Results: Confocal-microscopy imaging indicated that proteolytic processing of FPS selectively occurred on and labeled cell membrane of individual cells. The new assays measured specific increases of cell-associated FPS fluorescent product in substrate-concentration-, temperature- and time-dependent manners. A large proportion of processed FPS fluorescent products remained cell-associated after cell washing, indicating their binding to cell-membrane expressing enzymes. The assays measured higher levels of cell-associated FPS fluorescent product on wild-type than ADAM10-knockout mouse fibroblasts and on human monocytes than lymphocytes, which correlated with ADAM10 presence and expression levels on cell membrane, respectively. Furthermore, the enzyme activity assays could be combined with fluorescent anti-ADAM10 antibody staining to co-label and more directly associate enzyme activity and ADAM10 protein levels on cell membrane of individual cells. Conclusions: We report on two novel assays for measuring cell-membrane anchored enzyme activity on individual cells, and their potential use to directly study specific biology of cell-surface-expressing proteases.
RESUMO
Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9-11.4) and 8.9 (90% CI = 2.7-15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6-40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.