Squamous Lung Cancer Research Articles

Establishing a new human lung squamous cell carcinoma cell line, OMUL‐1, expressing insulin‐like growth factor 1 receptor and programmed cell death ligand 1

AbstractThe Main ProblemSquamous cell carcinoma is the second most prevalent type of non–small cell lung cancer. Analyzing the molecular mechanisms underlying lung carcinoma requires useful tools, such as squamous lung cancer cell lines.MethodsA novel new lung squamous cell carcinoma cell line, OMUL‐1, was developed from the primary lung cancer of a 74‐year‐old man. We assessed the characteristics and behavior of OMUL‐1 cells were examined, including their growth kinetics, tumorigenicity in mice, histological properties, gene expression profiles using reverse transcription polymerase chain reaction (RT‐PCR), and RNA sequencing and invasion assays.ResultsOMUL‐1‐an adherent cell line‐resulted in 100% tumor formation when subcutaneously injected into mice. Histological analysis of the subcutaneous tumor using hematoxylin and eosin staining revealed squamous cell carcinoma with characteristics similar to those of the primary tumor (p40 and p63 were positive, and TTF‐1 was negative). An invasion assay demonstrated that OMUL‐1 had a lower invasion ability compared to that of other developed cell lines. RT‐PCR analysis and RNA sequencing indicated that OMUL‐1 cells expressed FGFR1, FGFR2, FGFR3, FGFR4, EGFR, HER2, ErbB3, ErbB4, VEGFR3, IGF1R, c‐MET, PDGFRa, and PDGFRb. Additionally, picropodophyllin (an IGF1R inhibitor) significantly inhibited the growth of OMUL‐1 cells. Immunohistochemistry revealed that IGF1R and PD‐L1 were expressed in both the primary and subcutaneous tumors.ConclusionsWe developed a novel new squamous cell lung carcinoma cell line, OMUL‐1, that expresses IGF1R and PD‐L1.

P3.06D.01 Quantitative and Dynamic ctDNA as a Biomarker of Response and Survival in Treatment-Naive Patients with Advanced Lung Squamous Cancer

P3.06D.01 Quantitative and Dynamic ctDNA as a Biomarker of Response and Survival in Treatment-Naive Patients with Advanced Lung Squamous Cancer

Correlation of hemoglobin, albumin, lymphocyte, and platelet score with prognosis in patients with stage III squamous lung cancer.

Among cancers, lung cancer has the second highest incidence rate and the highest mortality rate in the world. Identifying suitable biomarkers to assist in the prognostic prediction of lung cancer is crucial for developing individualized treatment plans. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score has been applied to predict patient prognosis across a variety of cancers. This study aimed to investigate the predictive value of the HALP score for the prognosis of patients with stage III squamous cell lung cancer. The clinical data of patients with stage III squamous lung cancer who had undergone radical radiotherapy at the Department of Radiotherapy of The Fourth Hospital of Hebei Medical University from January 2011 to December 2020 were retrospectively analyzed. The optimal cutoff values for continuous variables were determined using X-Tile software. A Cox proportional hazards model was used for univariate and multivariate analysis, the Kaplan-Meier method was used for survival analysis, and log-rank test was used to check for differences. A total of 206 patients were included in this study, and the cutoff value for the HALP score was 24.3. There were statistically significant differences between the high- and low-HALP-score groups in terms of alcohol consumption history, tumor-node-metastasis (TNM) stage, prognostic nutritional index (PNI) score, and systemic immune-inflammation index (SII) score. The median overall survival (OS) was 11.0 and 22.0 months in the low- and high-HALP-score groups, respectively (P<0.001), and the median progression-free survival (PFS) was 8.0 and 13.0 months, respectively (P=0.002). Univariate analysis showed that a low HALP score was significantly associated with OS [hazard ratio (HR) =1.698, 95% confidence interval (CI): 1.261-2.286; P<0.001] and PFS (HR =1.584, 95% CI: 1.176-2.132; P=0.002) in patients with stage III lung squamous carcinoma, while the multivariate analysis showed that a low HALP score was the most important factor in OS (HR =1.538, 95% CI: 1.137-2.079; P=0.005) and PFS (HR =1.399, 95% CI: 1.033-1.895; P=0.03) as independent predictors of poor prognosis. In patients with stage III squamous cell lung cancer treated with radical radiotherapy, low baseline HALP score is associated with its poorer OS and PFS and may thus be valuable prognostic factor.

Therapeutic Potential and Pharmacological Activities of Moscatilin in Medicine for the Treatment of Cancers and other Human Complication: A Review of the Active Components of Dendrobium Species

Background: Plant-derived byproducts have been used to treat numerous kinds of human complications in medicine since a very early age. Moscatilin is a bibenzyl compound found to be present in Dendrobium. Moscatilin, also called 4,4′-dihydroxyl-3,3′,5-trimethoxybibenzyl has potential benefits in medicine for the treatment of ovarian, lung, breast, esophageal, hepatic, colorectal, pancreatic and neck squamous cancer. Methods: The present work summarized the health-beneficial aspects of moscatilin for its effectiveness against numerous kinds of cancerous disorders in medicine. Pharmacological activities and analytical aspects of moscatilin have been analyzed in the present work through available scientific data on Google, Scopus, Science Direct, and PubMed. Results: Scientific data analysis of moscatilin signified their therapeutic effectiveness against ovarian cancer, lung cancer, breast cancer, esophageal cancer, hepatic cancer, colorectal cancer, pancreatic cancer, neck squamous cell cancer, apoptosis, and angiogenesis. Further, moscatilin has a significant effect on inflammation, Alzheimer's disease, diabetic neuropathy, and retinal ischemia. However, analytical data on moscatilin were also discussed in the present work in order to know the effective separation, isolation and identification of moscatilin. Conclusion: Scientific information on moscatilin presented in this work will be helpful to all scientific people to understand the biological importance and therapeutic potential of moscatilin in medicine.

The association between human papillomavirus and lung cancer: A Mendelian randomization study

BackgroundTo investigate the causal relationship between human papillomavirus (HPV) and lung cancer, we conducted a study using the two-sample Mendelian randomization (TSMR). MethodData from genome-wide association studies (GWAS) were analyzed with HPV E7 Type 16 and HPV E7 Type 18 as exposure factors. The outcome variables included lung cancer, small cell lung cancer, adenocarcinoma and squamous cell lung cancer. Causality was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods. Heterogeneity testing, sensitivity analysis, and multiple validity analysis were also performed.. ResultsThe results showed that HPV E7 Type 16 infection was associated with a higher risk of squamous cell lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0149). HPV E7 Type 18 infection significantly increased the risk of lung adenocarcinoma (OR = 0.71; 95% CI: 0.38–1.31; p = 0.0079) and lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0292). No significant causal relationship was found between HPV E7 Type 16 and lung adenocarcinoma, lung cancer, or small cell lung carcinoma, and between HPV E7 Type 18 and squamous cell lung cancer or small cell lung carcinoma. ConclusionsThis study has revealed a causal relationship between HPV and lung cancers. Our findings provide valuable insights for further mechanistic and clinical studies on HPV-mediated cancer.

Exploring the causal association between uric acid and lung cancer in east Asian and European populations: a mendelian randomization study

BackgroundLung cancer still ranks first in the mortality rate of cancer. Uric acid is a product of purine metabolism in humans. Its presence in the serum is controversial; some say that its high levels have a protective effect against tumors, others say the opposite, that is, high levels increase the risk of cancer. Therefore, the aim of this study was to investigate the potential causal association between serum uric acid levels and lung cancer.MethodsMendelian randomization was used to achieve our aim. Sensitivity analyses was performed to validate the reliability of the results, followed by reverse Mendelian analyses to determine a potential reverse causal association.ResultsA significant causal association was found between serum uric acid levels and lung cancer in East Asian and European populations. Further sublayer analysis revealed a significant causal association between uric acid and small cell lung cancer, while no potential association was observed between uric acid and non-small cell lung cancer, squamous lung cancer, and lung adenocarcinoma. The sensitivity analyses confirmed the reliability of the results. Reverse Mendelian analysis showed no reverse causal association between uric acid and lung cancer.ConclusionsThe results of this study suggested that serum uric acid levels were negatively associated with lung cancer, with uric acid being a potential protective factor for lung cancer. In addition, uric acid level monitoring was simple and inexpensive. Therefore, it might be used as a biomarker for lung cancer, promoting its wide use clinical practice.

Dramatic response to crizotinib through MET phosphorylation inhibition in rare TFG-MET fusion advanced squamous cell lung cancer.

With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed in multiple cancer types. MET amplification and MET exon 14 skipping mutations induce protein autophosphorylation; however, the pathogenic mechanism and drug sensitivity of MET fusion remain unclear. The following report describes the clinical case of a patient diagnosed with squamous lung cancer bearing a TFG-MET gene fusion. In vitro assays demonstrated MET phosphorylation and oncogenic capacity due to the TFG-MET rearrangement, both of which were inhibited by crizotinib treatment. The patient was treated with crizotinib, which resulted in sustained partial remission for more than 17 months. Collectively, cellular analyses and our case report emphasize the potential of MET fusion as a predictive biomarker for personalized target therapy for solid tumors.

Efficacy and safety of PD-1 inhibitors plus chemotherapy with or without endostatin for stage IV lung squamous cancer: a retrospective study.

The study aimed to analyze the efficacy and safety of PD-1 inhibitors plus chemotherapy with or without endostatin for stage IV lung squamous cell carcinoma (LUSC). A total of 219 patients with stage IV LUSC were included. 120 received PD-1 inhibitors plus chemotherapy with or without endostatin (IC ± A), of which 39 received endostatin (IC+A) and 81 did not receive endostatin (IC-A). 99 received chemotherapy with or without endostatin (C ± A). Endpoints included overall survival (OS), progression-free survival (PFS), adverse events (AEs), and immune-related adverse events (irAEs). The median PFS in the IC ± A group versus the C ± A group was 8 and 4 months (P < 0.001), and the median OS was 17 and 9 months (P < 0.001). There was no significant difference in any grade AEs between the IC ± A and C ± A groups (P > 0.05). The median PFS in the IC+A group versus the IC-A group was 11 and 7 months (P = 0.024), and the median OS was 34 and 15 months (P = 0.01). There was no significant difference between the IC+A group and the IC-A group for all grade AEs and irAEs (P > 0.05). The subgroup analysis showed that patients with LIPI = 0 had significant OS and PFS benefits in IC+A group, while for patients with LIPI = 1-2, there was no significant difference in OS and PFS benefits between the IC+A group and IC-A group. PD-1 inhibitors plus chemotherapy with endostatin might be first-line treatment for patients with stage IV LUSC.

Inhibition of Lung Squamous Cancer Target HMGCS1 Promotes Cellular Ferroptosis

Targeted therapies are ineffective in lung squamous cancer (LUSC), and the low response rate of immunotherapy hampers its application in LUSC, so it is urgent to explore new strategies for LUSC treatment. Ferroptosis plays an important role in tumour suppression. The aim of this study was to investigate the role and mechanism of targeting 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating ferroptosis in LUSC cells, in order to provide a new research direction for LUSC therapy. The expression of HMGCS1 in LUSC was analysed by The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) online databases; the relationship between HMGCS1 and survival time of lung cancer was analysed by the Kaplan-Meier Plotter online survival database; the expression level of HMGCS1 in LUSC tissues was verified by immunohistochemistry. After interfering with HMGCS1 expression by small interfering RNA (siRNA), cell activity and cell migration ability were detected by CCK8 and Transwell assay; apoptosis was detected by flow cytometry after interfering with HMGCS1 or after treatment with the HMGCS1 inhibitor of hymeglusin; Fe2+, reactive oxygen species (ROS) and lipid peroxidation levels were detected by flow cytometry and high-content confocal fluorescence imaging systems, respectively in SKMES cells after inhibition of HMGCS1; and Western blot was performed to detect the expression of ACSL4, GPX4 and SLC7A11, which are markers of the ferroptosis pathway after inhibition of HMGCS1. HMGCS1 mRNA and protein levels were significantly high in LUSC; siRNA interference with HMGCS1 expression inhibited the proliferative activity and migration ability of LUSC cells, but had no significant effect on apoptosis. Interference with HMGCS1 or treatment with the HMGCS1 inhibitor of hymeglusin significantly promoted intracellular Fe2+, ROS and lipid peroxidation levels in SKMES cells, and induced ferroptosis in LUSC cells; Western blot assay showed that inhibition of HMGCS1 significantly promoted the expression of ACSL4. Inhibition of HMGCS1, a target of LUSC, promotes ferroptosis in lung cancer cells and provides a research basis for screening new therapeutic targets for LUSC.

Decision model for durable clinical benefit from front- or late-line immunotherapy alone or with chemotherapy in non-small cell lung cancer

Predictive biomarkers and models of immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC). However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision tree model. We consolidated data from 3,288 ICI-treated patients with NSCLC across real-world multicenter, public cohorts and the Choice-01 trial (ClinicalTrials.gov: NCT03856411). Over 50 features were examined for predicting durable clinical benefits (DCBs) from ICIs. Noteworthy biomarkers were identified to establish a decision tree model. Additionally, we explored the tumor microenvironment and peripheral CD8+ programmed death-1 (PD-1)+ Tcell receptor (TCR) profiles. Multivariate logistic regression analysis identified tumor histology, PD-ligand 1 (PD-L1) expression, tumor mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations were associated with DCB. The decision tree (DT10) model, using the ten clinicopathological and genomic markers, showed superior performance in predicting DCB in the training set (area under the curve [AUC]= 0.82) and consistently outperformed other models in test sets. DT10-predicted-DCB patients manifested longer survival, an enriched inflamed tumor immune phenotype (67%), and higher peripheral TCR diversity, whereas the DT10-predicted-NDB (non-durable benefit) group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality. The model effectively predicted DCB after front-/subsequent-line ICI treatment, with or without chemotherapy, for squamous and non-squamous lung cancer, offering clinicians valuable insights into efficacy prediction using cost-effective variables. This study was supported by the National Key R&D Program of China.

Differences in postoperative prognosis between early-stage lung adenocarcinoma and squamous cell carcinoma.

Although prognosis and treatments differ between small-cell- and nonsmall-cell carcinoma, comparisons of the histological types of NSCLC are uncommon. Thus, we investigated the oncological factors associated with the prognosis of early-stage adenocarcinoma and squamous cell carcinoma. We retrospectively compared the clinicopathological backgrounds and postoperative outcomes of patients diagnosed with pathological stage I-IIA adenocarcinoma and squamous cell carcinoma primary lung cancer completely resected at our department from January 2007 to December 2017. Multivariable Cox regression analysis for overall survival and recurrence-free survival was performed. The median follow-up duration was 55.2months. The cohort consisted of 532 adenocarcinoma and 96 squamous cell carcinoma patients. A significant difference in survival was observed between the two groups, with a 5-year overall survival rate of 90% (95% confidence interval 86-92%) for adenocarcinoma and 77% (95% CI 66-85%) for squamous cell carcinoma (P<0.01) patients. Squamous cell carcinoma patients had worse outcomes compared to adenocarcinoma patients in stage IA disease, but there were no significant differences between the two groups in stage IB or IIA disease. In multivariate analysis, invasion diameter was associated with overall survival in adenocarcinoma (hazard ratio 1.76, 95% confidence interval 1.36-2.28), but there was no such association in squamous cell carcinoma (hazard ratio 0.73, 95% confidence interval 0.45-1.14). The importance of tumor invasion diameter in postoperative outcomes was different between adenocarcinoma and squamous cell carcinoma. Thus, it is important to consider that nonsmall-cell carcinoma may have different prognoses depending on the histological type, even for the same stage.

Implications of ZNF334 gene in lymph node metastasis of lung SCC: potential bypassing of cellular senescence

BackgroundThe primary goal of this work is to identify biomarkers associated with lung squamous cell carcinoma and assess their potential for early detection of lymph node metastasis.MethodsThis study investigated gene expression in lymph node metastasis of lung squamous cell carcinoma using data from the Cancer Genome Atlas and R software. Protein-protein interaction networks, hub genes, and enriched pathways were analyzed. ZNF334 and TINAGL1, two less explored genes, were further examined through in vitro, ex vivo, and in vivo experiments to validate the findings from bioinformatics analyses. The role of ZNF334 and TINAGL1 in senescence induction was assessed after H2O2 and UV induced senescence phenotype determined using β-galactosidase activity and cell cycle status assay.ResultsWe identified a total of 611 up- and 339 down-regulated lung squamous cell carcinoma lymph node metastasis-associated genes (FDR < 0.05). Pathway enrichment analysis highlighted the central respiratory pathway within mitochondria for the subnet genes and the nuclear DNA-directed RNA polymerases for the hub genes. Significantly down regulation of ZNF334 gene was associated with malignancy lymph node progression and senescence induction has significantly altered ZNF334 expression (with consistency in bioinformatics, in vitro, ex vivo, and in vivo results). Deregulation of TINAGL1 expression with inconsistency in bioinformatics, in vitro (different types of lung squamous cancer cell lines), ex vivo, and in vivo results, was also associated with malignancy lymph node progression and altered in senescence phenotype.ConclusionsZNF334 is a highly generalizable gene to lymph node metastasis of lung squamous cell carcinoma and its expression alter certainly under senescence conditions.

Abstract 5555: Lung squamous cancer cell mTORC2 signaling suppresses antitumor immunity by up-regulation of PSGL-1, a ligand of VISTA/PD-1H checkpoint receptor

Abstract Lung squamous cell carcinoma (LUSC) represents 30% of non-small cell lung cancer (NSCLC) cases and has a high mortality rate with limited targeted therapies. Unlike lung adenocarcinoma (LUAD), which has seen advancements in targeted therapies, LUSC has not benefited from similar breakthroughs despite having similar genetic abnormalities. While immune checkpoint inhibitor therapies have shown promise in some LUSC patients, a significant portion does not respond effectively, leaving limited treatment options. In this study, we investigated vulnerabilities in NSCLC and found that a substantial number of LUSC patients have genetic alterations in the PI3K-mTORC2-AKT signaling pathway. By using CRISPR/CAS-9, we showed that disrupting mTORC2 function in LUSC cells reduced glycolysis and lactate secretion, which in turn reduced tumor growth in vivo. Remarkably, the loss of mTORC2 also enhanced the activity of CD4+ and CD8+ T cells within the tumors. To further understand the metabolic and immune changes associated with mTORC2 loss of function, we performed RNA sequencing comparing wild-type (WT) and mTORC2-deficient cells. Our results confirmed a link between mTORC2 and HIF-2α, while regulating PSGL-1, a ligand of the VISTA/PD-1H checkpoint receptor. Furthermore, introducing a stable, non-degradable form of HIF-2α in mTORC2-deficient tumor cells restored PSGL-1 expression in vitro and in vivo. These results suggest that the interaction between PSGL-1 and VISTA plays a role in suppressing the anti-tumor immune response in LUSC tumors. Indeed, anti-VISTA treatment inhibited the growth of LUSC WT tumors in vivo, suggesting that mTORC2 plays a role in regulating PSGL-1 expression in the tumor microenvironment. Together, these data demonstrate that targeting mTORC2 or inhibiting VISTA checkpoint receptor may serve as a potential therapeutic strategy for improving immunotherapy in LUSC. Citation Format: Verra M. Ngwa, Yoonha Hwang, Deanna N. Edwards, Wenqiang Song, Jin Chen. Lung squamous cancer cell mTORC2 signaling suppresses antitumor immunity by up-regulation of PSGL-1, a ligand of VISTA/PD-1H checkpoint receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5555.

Abstract 1896: Therapeutic potential of TORL-4-500, an antibody-drug conjugate directed against delta like non-canonical notch ligand 1 (DLK1)

Abstract Delta like non-canonical Notch ligand 1 (DLK1) is a transmembrane protein that belongs to the NOTCH non-canonical ligand family. It has been implicated in adipogenesis, the regulation of stem cell pools, tissue differentiation during development, cancer differentiation, and cancer stem-like cell maintenance. DLK1 is highly expressed in adrenocortical, uterine, and testicular cancers as well as in a large portion of pancreatic, sarcoma, liver and squamous lung cancer patient samples. In contrast there is limited normal tissue expression beyond the normal adrenal gland, pituitary, and ovarian tissue samples. This expression profile makes DLK1 an attractive target for development of a therapeutic antibody-drug conjugate (ADC). This study describes the generation and preclinical characterization of TORL-4-500, an ADC consisting of a humanized anti-DLK1 monoclonal antibody coupled to monomethyl auristatin E (MMAE) via a cleavable linker. TORL-4-500 showed strong binding to DLK1 by flow cytometry in DLK1 native and artificial overexpressing cell lines. In contrast no binding was observed in DLK1 non-expressing cell lines. TORL-4-500 exhibits nanomolar binding affinity for both human and cynomolgus monkey DLK1 and is rapidly internalized in DLK1 expressing cells. TORL-4-500 exhibited selective efficacy in cell line xenograft models of DLK1 positive human cancers. Treatment with TORL-4-500 induced significant regressions in four DLK1 expressing human cancer cell line xenograft studies encompassing liver, small cell lung cancer (SCLC) and sarcoma cancer. Furthermore, anti-tumor responses were sustained in each of the DLK1 expressing models for several weeks post-final dose. In the case of the two SCLC cell lines, complete regressions of xenograft tumors were measured out past 100 days in the TORL-4-500 treated animals. No significant impact on xenograft tumor growth was observed in either a DLK1 non-expressing colon cell line xenograft or in a DLK1 non-expressing melanoma xenograft study. Each of the doses tested in this study was well tolerated in mice with no dose-limiting toxicity observed. The nonclinical pharmacokinetics and toxicokinetics of TORL-4-500 were characterized in mice and monkeys and results support dosing in humans. In summary, TORL-4-500 is a novel therapeutic for DLK1 positive cancers and on the basis of these promising preclinical efficacy results, a first in human trial to evaluate safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 has been launched in patients with advanced cancer and is currently ongoing (NCT06005740). Citation Format: Martina S. McDermott, Neil A. O'Brien, Ming Lu, Jun Zhang, KeWei Gong, Benjamin Hoffstrom, Tong Luo, Min Liang, Weiping Jia, Kevin Chau, Leonard Presta, John Glaspy, Dennis J. Slamon. Therapeutic potential of TORL-4-500, an antibody-drug conjugate directed against delta like non-canonical notch ligand 1 (DLK1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1896.

Immune Gene Networks from Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

The association between immune checkpoint inhibitors (ICIs) and immune gene networks in squamous lung cancer (LUSC) and lung adenocarcinoma (LUAD) was studied. Immune gene networks were constructed using RNA-seq data from the gene expression omnibus (GEO) database. Datasets with more than 10 samples of normal control and tumor tissues were selected; of these, GSE87340, GSE120622, and GSE111907 were suitable for analysis. Gene set enrichment for pathway analysis was performed. For immune gene network construction, 998 unique immune genes were selected from 21 pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene function annotation was performed based on the KEGG, Gene Ontology, and Reactome databases. Tumor tissues showed decreased coagulation, hematopoiesis, and innate immune pathways, whereas complement- and coagulation-related genes were prominent in the tumor immune gene network. The average numbers of neighbors, clustering coefficients, network diameters, path lengths, densities, and heterogeneities were highest for normal tissue, followed by LUAD and LUSC. Decreased coagulation genes, which were prominent in tumor immune networks, imply functional attenuation. LUAD was deviated from normal tissue, based on network parameters. Tumor tissues showed decreased immune function, and the deviation of LUSC from normal tissue might explain LUSC's better therapeutic response to ICI treatment.

The causal association between serum metabolites and lung cancer based on multivariate Mendelian randomization.

This study seeks to understand the causal association between serum metabolites and different lung cancer types, an area yet to be extensively studied. We Used a two-sample Mendelian randomization (TSMR) approach, utilizing 486 blood metabolites as exposures and 3 distinct lung cancer types genome-wide association studies datasets as outcomes. We employed inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode to estimate causal effects. We performed sensitivity analyses using Cochran Q test, MR-Egger intercept test, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Linkage disequilibrium score (LDSC) analysis was conducted on the selected metabolites, and common confounding single nucleotide polymorphisms were eliminated using the human genotype-phenotype association Database. Metabolic pathway analysis was performed with MetaboAnalyst 5.0 software. Subsequently, a multivariate Mendelian randomization analysis was conducted to ascertain independent risk exposures. Our findings suggest independent risk factors for specific types of lung cancer: 7-methylxanthine and isoleucine for lung adenocarcinoma, cysteine and 1-arachidonoylglycerophosphocholine are identified as independent protective and risk factors for squamous lung cancer. Undecanoate (11:0) with Linoleate (18:2n6) showed a protective effect for small cell lung cancer. Additionally, 11 metabolic pathways were associated with lung cancer. This novel perspective offers a multidimensional understanding of lung cancer phenotypes, providing valuable guidance for identifying and screening of diverse lung cancer phenotypes.

Minimally invasive surgery role in central squamous lung cancer after neoadjuvant chemoimmunotherapy.

The present body of literature provides restricted evidence concerning the application of video-assisted thoracoscopic surgery (VATS) in individuals diagnosed with centrally located, locally advanced, and initially surgically challenging squamous cell lung carcinoma (SqCLC) following neoadjuvant chemoimmunotherapy (CIT). Further research is warranted to elucidate the role and potential benefits of VATS in this particular patient population. We performed a retrospective analysis on individuals diagnosed with centrally located and locally advanced SqCLC who received preoperative CIT at a single institution. The study evaluated the percentage of VATS performed, conversion rates, and perioperative outcomes. Furthermore, survival outcomes related to the resection extent were compared between patients who underwent standard lobectomy (SL) and extended lobectomy (EL, e.g., sleeve, bilobectomy or pneumonectomy) after neoadjuvant CIT. A total of 27 cases of centrally located SqCLC underwent neoadjuvant CIT followed by VATS, with one case requiring conversion to thoracotomy due to adhesions. Comparison of perioperative outcomes and long-term cancer-specific mortality between the VATS group (N=24) and the thoracotomy group (N=13) did not yield any statistically significant differences. However, the VATS group exhibited a significantly higher frequency of SL (66.7% vs. 30.8%, P=0.046). Notably, within the VATS group, all three patients who experienced tumor relapse or died due to tumor recurrence were from the SL subgroup. This study contributes valuable real-world evidence demonstrating the feasibility and safety of utilizing VATS in the management of patients with centrally located and locally advanced SqCLC following neoadjuvant CIT. However, careful consideration might be given to the extent of resection to optimize patient long-term outcomes.

C-Rel is a Novel Oncogene in Lung Squamous Cell Carcinoma Regulating Cell Proliferation and Migration.

Lung squamous cell carcinoma (LUSC) accounts for approximately 25% to 30% of lung cancers, but largely no targeted therapy is available against it, calling for identification of new oncogenes in LUSC growth for new therapeutic targets. In this study, REL was identified through a screening for oncogenes that are highly amplified in human LUSC. Its expression was associated with poor prognosis in LUSC patients. Furthermore, knockdown of c-Rel in LUSC cell lines lead to significant decrease in cell proliferation and migration. Mechanistically, c-Rel knockdown suppressed NFκB pathway by blocking phosphorylation of IκB. Consistently, pharmaceutic inhibition of c-Rel also. In orthotopic xenograft lung cancer mouse model, c-Rel knockdown inhibited the tumor growth. Cancer cell proliferation and epithelial-mesenchymal-transition (EMT) of the tumors were impaired by c-Rel knockdown. Finally, it's confirmed in precision-cut tumor slices of LUSC that deletion of c-Rel inhibits the NFκB pathway and cancer cell growth. Accordingly, we hypothesize that c-Rel promotes the activation of the NFκB pathway by promoting the phosphorylation of IκB in LUSC. Our study reveals REL as a novel LUSC oncogene and provides new insights into the molecular regulation of LUSC, which will provide new therapeutic targets for the treatment of squamous lung cancer.

The effect of tumor spread through air spaces on the prognosis of patients with stage Ⅰ non-small cell lung cancer: a meta-analysis

Objective: To systematically evaluate the effect of tumor spread through air spaces (STAS) on the prognosis of patients with stage Ⅰ non-small cell lung cancer (NSCLC). Methods: PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang Database and VIP were searched to collect papers related to NSCLC and STAS published from the establishment of aboves databases to November 2022. Papers were screened according to the inclusion and exclusion criteria, and data were extracted. The 5-year overall survival (OS) and relapse-free survival (RFS) of stage Ⅰ NSCLC patients with or without STAS were compared. HR(95%CI) was used as effective indicator to evaluate the impact of STAS positivity on the prognosis of NSCLC. The quality of each included study was assessed using the Newcast-Ottawa Scale (NOS). Results: A total of 24 papers concerning 29 studies were included according to the inclusion and exclusion criteria, and there was no significant heterogeneity among the included papers(all I2<50%). A total of 10 883 patients with stage Ⅰ NSCLC were included in the studies, of which 3 298 (30.3%) were STAS-positive. The 29 studies showed that STAS-positive patients had a higher risk of 5-year recurrence than STAS-negative patients with stage Ⅰ NSCLC [HR=1.94(95%CI:1.74-2.16)];and a meta-analysis of 17 of the studies showed that that STAS-positive patients had a higher risk of 5-year death [HR=2.09 (95%CI:1.80-2.43)]. Compared with stage Ⅰ NSCLC patients who underwent other surgeries, STAS-positive patients who underwent sublobar resection had a higher risk of 5-year recurrence than patients with other procedures (HR=3.44, 95%CI: 2.49-4.76) and a higher risk of 5-year death (HR=3.40, 95%CI:2.05-5.64); and patients with stage Ⅰ NSCLC who had the pathologic histologic type of squamous carcinoma had a higher risk of 5-year recurrence (HR=2.48,95%CI:1.71-3.60) and a higher risk of 5-year death (HR=3.04, 95%CI: 1.90-4.86) than other patients with the type of squamous lung cancer. Conclusion: STAS positivity is a risk factor of poor prognosis in patients with stage Ⅰ NSCLC, especially for patients underwent sublobar resection or with squamous lung cancer.

Abstract B012: Validation of the OncoSignature assay, an ACR-368-tailored response-predictive quantitative multiplexed immunofluorescent assay for prediction of sensitivity to the CHK1/2 inhibitor ACR-368 in individual patients with cancer

Abstract Background: The CHK1/2 kinase inhibitor ACR-368 (Prexasertib) demonstrated durable single-agent efficacy in a subset of patients with high grade serous ovarian, anal and head and neck cancers in past trials. Using a quantitative phospho-proteomics approach, we identified three orthogonal candidate biomarkers tailored to predict tumor response to ACR-368 treatment. The OncoSignature® assay is based on immunofluorescent staining of biomarkers in FFPE tumor sections with image acquisition, analysis, and scoring of biomarkers. The sample is OncoSignature positive if all three biomarker scores are above their thresholds. We validated the OncoSignature® assay to predict response to ACR-368 in cancer cell lines and ovarian cancer PDX models. Here, we further validated OncoSignature® assay in novel cancer indications and in patient biopsy samples from ACR-368 clinical trials. Methods: Multiple cancer types were tested with the OncoSignature® assay for prevalence of potential ACR-368 responders. For validation, endometrial cancer PDX models were tested in anACR-368 efficacy study. Blinded untreated PDX tumors were analyzed in the OncoSignature® assay and results locked prior to unblinding and statistical analysis. Adapted [CS1] Oncosignature assay was applied to frozen pretreatment ovarian cancer biopsies from a single center ACR-368 monotherapy Ph2 trial (NCT02203513). OncoSignature® assay was also applied to FFPE pretreatment ovarian cancer biopsies from a multi-center ACR-368 monotherapy Ph 2 trial (NCT03414047) and from the NCT02203513 trial. After biomarker scores were generated and locked, patient treatment outcomes were unblinded and ACR-368 response was compared with OncoSignature prediction. Results: Evaluation of multiple cancer indications revealed a concordance between OncoSignature-predicted prevalence of ACR-368 responders and results of ACR-368 treatment observed in clinical trials. Metastatic ovarian cancer had 30% of predicted responders and 30% and 14% observed RECIST responses the above-cited trials. Squamous lung cancer had no predicted responders and no RECIST responses in a clinical trial. Endometrial and bladder cancer had a high prevalence of predicted responders with 40% and 36%, respectively. The endometrial cancer PDX efficacy study had multiple complete responses predicted by OncoSignature® assay with an AUC of 0.88. For frozen and FFPE patient biopsy samples from Phase 2 ACR-368 trials, OncoSignature positive groups had highly significant response enrichment to 47% and 57%, respectively, and significant increases in progression free survival time. Conclusions: Bladder and endometrial cancers were identified as novel indications with high prevalence of predicted ACR-368 responders. The OncoSignature® assay significantly predicted response in endometrial PDX models and in samples from ovarian cancer patients treated with ACR-368. OncoSignature® assay driven clinical trial (NCT05548296) in ovarian, endometrial and bladder cancers was initiated to test benefit to patients. Citation Format: Ayesha Murshid, Christina Noe, Kailash Singh, Sibgat Choudhury, Jayakumar Nair, James Dunyak, Michail Shipitsin, Jung-Min Lee, Peter Blume-Jensen. Validation of the OncoSignature assay, an ACR-368-tailored response-predictive quantitative multiplexed immunofluorescent assay for prediction of sensitivity to the CHK1/2 inhibitor ACR-368 in individual patients with cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B012.