Form Of Lung Cancer Research Articles

Hybrid Approach of Multiclassification for Lung Cancer Types Identification

As a widespread health concern, lung cancer requires sophisticated detection techniques for a precise classification. This research proposes an integrated framework for improving how well lung cancer is detected by combining processing methods for images and machine learning. The dataset, which includes normal cases, large-cell carcinoma, squamous cell carcinoma, and adenocarcinoma, allows for a detailed investigation of various forms of lung cancer. K-means clustering is the initial stage of the approach of segmenting complex images. Utilizing the VGG16 model, features are extracted that are important for classification. Several classification models, such as SVM, Logistic Regression, and Feedforward Neural Network, are trained using the combined features from clustering and VGG16. This research goes beyond the dichotomy of benign and malignant cases, investigating in more detail the subtypes of large-cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Including different classes of lung cancer increases the granularity of the classification process, improving diagnostic accuracy and clinical insights. The results highlight how well the suggested strategy works, which is a major advancement in the accurate identification of distinct kinds of lung cancer.

Comparison between Carboplatin and Afatinib in the drug treatment of Non-Small Cell Lung Cancer

One of the most prevalent kinds of cancer is lung cancer, and rates have been rising since the early 1900s. Non-small cell lung cancer is the most often diagnosed of all the many forms of lung cancer. Smoking plays a large role in contributing to cancer due to tobacco that damages DNA in epithelial cells. Moreover, it is rare yet proven that lung cancer can be inherited through a mutation in the EGFR gene. While Afatinib is used especially for non-small cell lung carcinoma, including the EGFR mutation, many cancers are initially treated with Carboplatin. What makes them unique, then? In essence, through their various chemical structures, they react in the body through separate mechanisms but share the same property of halting cell proliferation. Consequently, they lead to different side effects and have unique limitations when treating certain kinds of lung cancer. This review provides information about non-small cell lung cancer along with the two categories of medications that are used to treat it.

Spatial Tumor Heterogeneity in a Young Female with Lung Adenocarcinoma and Brain Metastasis

Small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are the two different forms of lung cancer, the latter subtype accounts for approximately 85% of cases. Lung cancer is estimated to be the main cause of all cancer deaths, accounting for nearly 1,800,000 deaths globally in 2020. In this clinical case, we describe a female patient with non-specific symptoms over an approximate duration of one and a half years. Metastatic lung adenocarcinoma was diagnosed after the onset of severe neurological symptoms, brain surgery, and historical analysis of the large pathological brain mass. Following this, the tumor in the lung, which was small in size and the sole metabolically active site of the disease, was surgically removed. The recurrence in the brain and the onset of new neurological symptoms occurred rapidly—within three months, necessitating a second operation. Histological examination of the primary tumor and metastasis unveiled significant disparities–the primary tumor was moderately differentiated with PD-L1 expression (programmed death-ligand 1) within the range of 1 to 49%, while metastasis was poorly differentiated and PD-L1 negative, both absent of EGFR mutations (epidermal growth factor receptor) and ALK fusion (anaplastic lymphoma kinase). Following two brain operations, the patient underwent three-dimensional conformal radiation therapy (3DCRT). Subsequently, the initiation of systemic therapy was postponed by a two-month interval due to the activation of chronic hepatitis C virus infection. This case study contributes to the growing body of knowledge aimed at enhancing our grasp of tumor heterogeneity and dynamics of progression.

Efficacy of immunotherapy in patients with non-small cell lung cancer

Introduction. Non-small cell lung cancer (NSCLC) is a form of lung cancer with high incidence and low overall survival. Immunotherapy is a promising treatment method for which the selection of optimal treatment regimens for each individual patient is important.Aim. To evaluate the effectiveness and safety of immune checkpoint inhibitors (ICIs) in patients with advanced NSCLC.Materials and methods. The study included 247 patients (190 men and 57 women) aged 37 to 87 years who received ICIs as monotherapy with nivolumab (n = 58; 23.4%), pembrolizumab (n = 78; 31.6%) and atezolizumab (n = 13; 5.3%), and in the form of combination chemoimmune therapy (n = 98; 39.7%). The objective response of the tumor to treatment was recorded in the presence of partial or complete regression of the tumor. The tumor response to treatment was determined in accordance with the iRECIST criteria.Results. Objective response was achieved in 20.6% of patients, of which 13.7% were on the first line setting, and 7% of patients were on the 2nd or more line setting. Disease control was recorded in 83.3% of patients. Patients receiving combination chemoimmune therapy had a better response to treatment than those receiving monotherapy (χ2 = 9.309; p = 0.020). Grade 3–4 immuno-related adverse events were observed only in 5 (2.02%) patients.Conclusions. NSCLC immunotherapy allows to achieve high rates of objective response and disease control (20.6 and 83.3%, respectively), with a small number of grade 3–4 immuno-related adverse events (2.02% according to our data), which indicates an acceptable safety profile.

Entrectinib in the treatment of ROS1-positive lung cancer

The possibilities in the treatment of patients with non–small cell lung cancer are constantly expanding – thanks to high-performance genomic profiling methods, we are discovering new targets in the tumor for drug action, as a result, new targeted drugs appear, some of them have several application points. Multipurpose drugs have a number of advantages and therefore have become the main direction of drug development. Entrectinib is an oral low molecular weight multikinase inhibitor that blocks three targets at once – the receptors of tyrosine kinases ROS1, NTRK1/2/3 and ALK, in 2023 was approved by the Ministry of Health of the Russian Federation for the treatment of adult patients with ROS1-positive metastatic non-small cell lung cancer. This form of lung cancer is classified as a rare orphan disease, which usually occurs in younger people (about 50 years old), more often in women and non-smokers. Until recently , we had the only active targeted drug – crizotinib. It provided a sufficiently high immediate effect and long-term control of the disease. However, his intracranial activity was not evaluated prospectively, and a retrospective analysis showed modest results. Entrectinib is distinguished from its competitor by high intracranial activity, and, as is known, metastatic brain damage in patients with activating mutations is quite common. With comparable indicators of objective response, its duration and time to progression, entrectinib provides a high level of intracranial control and reduces the risks of progression in the central nervous system in patients who did not have brain metastases at the beginning of therapy. In addition, entrectinib demonstrates good tolerability.

Antiproliferative Activity of Gibbosic Acid H through Induction of G0/G1 Cell Cycle Arrest and Apoptosis in Human Lung Cancer Cells.

Lung cancer is one of the most common causative cancers worldwide. Particularly, non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. NSCLC is a serious form of lung cancer that requires prompt diagnosis, and the 5-year survival rate for patients with this disease is only 24%. Gibbosic acid H (GaH), a natural lanostanoid obtained from the Ganoderma species (Ganodermataceae), has antiproliferative activities against colon and lung cancer cells. The aim of the present study was to evaluate the antiproliferative activity of GaH in NSCLC cells and to elucidate the underlying molecular mechanisms. GaH was found to induce G0/G1 cell cycle arrest and autophagy by activating adenosine monophosphate-activated protein kinase in A549 and H1299 cells. The induction of this cell cycle arrest was associated with the downregulation of cyclin E1 and CDK2. Additionally, the induction of autophagy by GaH was correlated with the upregulation of LC3B, beclin-1, and p53 expression. GaH also induced apoptosis by upregulating cleaved caspase-3 and Bax in the lung cancer cells. These findings suggest that GaH has a potential in the growth inhibition of human lung cancer cells.

Brief report: High incidence of peridiagnosis thromboembolic events in patients with BRAF-mutant lung cancer

IntroductionWe aimed to determine if advanced BRAF-mutant NSCLC has a higher thromboembolic events (TEE) rate than the expected. MethodsBetween 2008 and 2021, 182 patients with BRAF-mutant advanced NSCLC (BRAF V600E, n = 70; BRAF non-V600E, n = 112) were retrospectively identified from 18 centers in Spain. Patients received chemotherapy (n = 147), immunotherapy (n = 69), targeted therapy (n = 42), and immunotherapy + chemotherapy (n = 26). ResultsIncidence rate of TEE was 26.4 % (95%CI: 19.9 %–32.9 %). A total of 72 TEE were documented among 48 patients, as 18 patients (37.5 %) developed more than one event. Median time to TEE onset was 2 months, 69 % of TEE occurred in the peridiagnostic period (+/− 90 days from cancer diagnosis), and in 16 pts. (33 %) TEE was the form of lung cancer presentation.Although most TEE were only venous (82 %; PE, n = 33; DVT, n = 16), arterial events were reported in 31 % and occurred earlier, or TEE presented in atypical locations (13.9 %).TEE were related to high hospitalization rate (59 %), recurrence (23 %), and mortality (10.4 %) despite appropriate anticoagulant/antiaggregant treatment.Median OS in patients without-TEE was 19.4 months (95%CI: 4.6–34.1), and significantly shorter in patients with arterial-TEE vs venous-TEE vs both of them: 9.9 months (95%CI: 0–23.5) vs 41.7 months (95%CI: 11.3–72.2 m) vs 2.7 months (95%CI: 2.1–3.3), p = 0.001.Neither clinical or molecular features (BRAF V600E/non-V600E), nor cancer treatment was associated to TEE occurrence. Khorana score underperformed to predict thrombosis at cancer diagnosis, as only 19.2 % of patients were classified as high-risk. ConclusionsThrombotic events represent a new clinical feature of BRAF-mutant lung cancer. Patients with almost a 30 % incidence of TEE should be offered systematic anticoagulation.

Lung cancer and COVID-19: problems and perspectives.

COVID-19 pandemic generated concerns about the healthcare of patients with cancer, not simply because of the formidable impact of COVID-19 patients in the public healthcare system, but also due to the overlapping pathognomonic signs of many forms of lung cancer with lung injuries associated with COVID-19. This report tries to shed light on the issue. We evaluated the great concern of people suffering from lung cancer and also infected with SARS-CoV-2 by discussing evidence and data from current literature. Lung cancer in Italy has represented more than 1 case/4 (27%) in the latest ten years and nevertheless, even due to the concurrence of many complex interplays between COVID-19 and cancer even at the immune level, a consensus protocol and expert guidelines to diagnose and treat lung cancer upon SARS-CoV-2 infection are yet lacking. New insights and consensus panels should be therefore proposed, even at the simplistic level about if priority must be either given to COVID-19 or to cancer therapy.

Clinicopathological Features and Status of Programmed Death Ligand-1 (PD-L1) Expression in Lung Cancer: A Single Centre Study From North India.

Introduction Programmed death ligand-1 (PD-L1) is an immunological checkpoint that supports the inhibition of the anti-tumor immune system. A higher level of PD-L1 expression was also discovered on the cell surfaces of several cancer cells, including non-small cell lung carcinoma (NSCLC). Identifying individuals who would benefit from PD-1/PD-L1 antibody immunotherapy is crucial in the era of precision medicine. The study's objective was to assess the distribution and degree of PD-L1 ligand expression in various forms of lung cancer and examine its link to clinicopathological variables. Methods This prospective, observational, cross-sectional study was done in a tertiary care hospital in North India over 2 years from 2019 to 2021. A total of 100 patients diagnosed with lung cancer through either endobronchial or image-guided biopsies were enrolled. The biopsy specimens of lung cancer patients have been subjected to immunohistochemistry (IHC) staining. PD-L1 expression was positive when at least 1% of tumor cells were stained. In our study, we used the rabbit monoclonal Anti-PD-L1 antibody (CAL10) (ab237726) (Abcam Plc, UK). Results Of the 100 patients, Squamous cell carcinoma (SQCC) was the predominant histological pattern. The mean age of the study group was 57.26 ± 10.53 years. High PDL-1 positivity (>50% ) is seen in a total of 10 patients, while low PD-L1 positivity (1-50%) is seen in 24 patients. Of all patients with high PD-L1 positivity (n=10), 80% had stage IV at the time of diagnosis. However, on similar lines, 71 % of patients with low PD-L1 positivity presented with stage IV at the time of diagnosis. (p value=0.09). Among 10 patients with epidermal growth factor receptor (EGFR) positive status, high PD-L1 positivity is seen in 20%. Among 3 patients with anaplastic lymphoma kinase (ALK) positive status, only one patient showed high PD-L1 positivity, whereas negative PDL-1 was seen in 2 patients, which was not statistically significant. Conclusion The management of lung cancer is driven by precision medicine, including PDL-1 expression, which correlates with immune checkpoint inhibitor response. In our cohort, PD-L1 expression appears to be mostly linked to the squamous cell subtype of lung cancer, with elevated tumor stage and mediastinal lymphadenopathy in Kashmiri people. Other oncogenic driver mutations are not connected to PD-L1 expression. The function of PD-L1 expression in lung tumors requires more study.

Severe hyponatremia as presenting symptom of small cell lung carcinoma

Abstract A 62-year-old female patient was admitted to ICU in our clinic with symptomatic severe hyponatremia with complaints of fatigue, vertigo, paresthesia of upper extremities and three episodes of loss of consciousness in the past month. She had been hospitalized two weeks before in neurology clinic because of the same symptoms. CT of the brain, EEG, ophthalmology examinations were negative. She did not complain of hemoptysis, cough, weight loss, fever, chest pain or dyspnea. Nephrologist was consulted and renal origin of the hyponatremia was excluded, before admission. Initial laboratory tests were glucose:5,47 umol/L,sodium:109 mEq/L,potassium;4.5 mEq/L,urea 3,9 umol/l;creatinine:52,7 mol/l,calcium:1,22umol/L,TSH 5;Cortisol 819nmol/L;ACTH:16,34 pg/ml. Her medical history included hypertension, primary hypothyroidism and history of smoking. Upon laboratory findings of low serum osmolality, high urine osmolality, high urine sodium levels and clinical euvolemia, and in the absence of renal, pituitary disfunction, adrenal insufficiency, inappropriate ADH syndrome was diagnosed and initially was treated with 3% NaCl. Since this treatment had no effect, it was started with fluid restriction, per os sodium intake was increased and therapy with loop diuretic was initiated, which resulted in correction of the hyponatremia. For the etiology consideration of inappropriate ADH syndrome CT of the thorax was performed, which revealed a neo infiltrative process with atelectasis in the poster basal segment of the left lobe. Histopathological sampling from the biopsy of the mass revealed small cell carcinoma of the lung. Metastasis were not detected. Since basal morning cortisol level was above upper range, with inappropriate measurements of ACTH constantly above 15 pg/ml, additional tests for ectopic Cushing syndrome were done. Overnight 1mg dexamethasone suppression test showed absent suppression of the morning cortisol values of 656nmol/L and ACTH of 22,14 pg/ml and absent circadian rhythm of cortisol secretion, with high measurements of midnight serum cortisol of 652 nmol/L. Diagnosis of ectopic Cushing syndrome and SIADH as part of paraneoplastic syndrome in small cell lung carcinoma was made. It is to be noted that patient had no significant symptoms or signs of hypercortisolemia. We report here a case of small cell carcinoma of the lung whose first presentation was with symptomatic hyponatremia as a result of inappropriate ADH syndrome. The most common neoplasms associated with hyponatremia are various forms of lung cancer. Because of the aggressive nature of the disease, the most common manifestation of small cell carcinoma of the lung is a metastatic one. Therefore, identifying the disease in earlier stages is very important. Unfortunately, these patients have low rates of survival and face a very poor prognosis even with treatment. The presence and early identification of paraneoplastic syndromes can be beneficial in this context.

Analysis of Circulating Tumor and Cancer Stem Cells Provides New Opportunities in Diagnosis and Treatment of Small Cell Lung Cancer.

Current methods for diagnosis and treatment of small cell lung cancer (SCLC) have only a modest efficacy. In this pilot study, we analyzed circulating tumor cells (CTCs) and cancer stem cells (CSCs) in patients with SCLC to search for new diagnostic and prognostic markers and novel approaches to improve the treatment of the disease. In other forms of lung cancer, we showed a heterogeneity of blood CTCs and CSCs populations, as well as changes in other cell populations (ALDH+, CD87+CD276+, and EGF+Axl+) in smokers. A number of CTCs and CSCs in patients with SCLC have been shown to be resistant to chemotherapy (CT). High cytotoxic activity and resistance to apoptosis of reprogrammed CD3+CD8+ T-lymphocytes (rTcells) in relation to naive CD3+CD8+ T-lymphocytes was demonstrated in a smoking patient with SCLC (Patient G) in vitro. The target for rTcells was patient G’s blood CSCs. Reprogramming of CD3+CD8+ T-lymphocytes was carried out with the MEK1/2 inhibitor and PD-1/PD-L1 pathway blocker nivolumab. The training procedure was performed with a suspension of dead CTCs and CSCs obtained from patient’s G blood. The presented data show a new avenue for personalized SCLC diagnosis and targeted improvement of chemotherapy based on the use of both CTCs and CSCs.

Gankyrin modulated non-small cell lung cancer progression via glycolysis metabolism in a YAP1-dependent manner

Non-small cell lung cancer (NSCLC) is highly malignant and heterogeneous form of lung cancer and involves various oncogene alterations. Glycolysis, an important step in tumor metabolism, is closely related to cancer progression. In this study, we investigated the biological function and mechanism of action of Gankyrin in glycolysis and its association with NSCLC. Analyzed of data from The Cancer Genome Atlas as well as NSCLC specimens and adjacent tissues demonstrated that Gankyrin expression was upregulated in NSCLC tissues compared to adjacent normal tissues. Gankyrin was found to significantly aggravate cancer-related phenotypes, including cell viability, migration, invasion, and epithelial mesenchymal transition (EMT), whereas Gankyrin silencing alleviated the malignant phenotype of NSCLC cells. Our results reveal that Gankyrin exerted its function by regulating YAP1 expression and increasing its nuclear translocation. Importantly, YAP1 actuates glycolysis, which involves glucose uptake, lactic acid production, and ATP generation and thus might contribute to the tumorigenic effect of Gankyrin. Furthermore, the Gankyrin-accelerated glycolysis in NSCLC cells was reversed by YAP1 deficiency. Gankyrin knockdown reduced A549 cell tumorigenesis and EMT and decreased YAP1 expression in a subcutaneous xenograft nude mouse model. In conclusion, both Gankyrin and YAP1 play important roles in tumor metabolism, and Gankyrin-targeted inhibition may be a potential anti-cancer therapeutic strategy for NSCLC.

Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9

Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4+ T cell-derived IL-9 promotes the expansion of both CD11c+ and CD11c− interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r−/− mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.

Abstract 109: The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation

Abstract F-box proteins are essential components of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligases in that they bind to SKP1 through the F-box motif and bring the substrate to the E3 ligase complex for ubiquitination. FBXL16 is a poorly studied F-box protein. FBXL16 doesn’t interact with Cul1 and might not form a functional SCF-E3 ligase complex. Unexpectedly, we recently found that FBXL16 upregulates several oncoproteins targeted by SCF-E3 ligases, such as SRC-3 and c-myc, by antagonizing the activity of another F-box protein, FBW7. By data mining, we found that FBXL16 is highly upregulated in many cancers, including lung adenocarcinomas (LUADs), and its upregulation is associated with poor overall survival. LUAD is the most common form of lung cancer, and about 30% of LUADs harbor constitutively active oncogenic KRAS mutants. However, currently no drug is available for effectively treating LUADs expressing KRAS mutants. Hence, there is an unmet need to identify new therapeutic targets. Here, we report that FBXL16 protein level is selectively upregulated and is strongly correlated with insulin receptor substrate-1 (IRS1) protein expression in LUAD cell lines with activating KRAS mutations. By cycloheximide treatment, we found that FBXL16 greatly increases IRS-1 protein stability and level, leading to upregulation of IGF-1 (Insulin)/IRS1/PI3K Akt signaling. Importantly, the upregulation of IRS1 protein and its signaling by FBXL16 was confirmed in mouse lungs with conditional overexpression of FBXL16 transgene. Moreover, depletion of FBXL16 by RNA interference inhibits IGF-1-induced lung cancer cell proliferation and migration. Taken together, our findings reveal FBXL16 as a potential target for treating LUADs with KRAS activating mutations. Citation Format: Marion Morel, Weiwen Long. The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 109.

Abstract 4204: CDK4/6 inhibition mitigates chemotherapy-induced immunosuppression and enhances the efficacy of chemo- immunotherapy in small cell lung cancer models

Abstract Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a notably low survival rate. Chemotherapy and more recently its combination with immunotherapy are the standard of care for extensive stage SCLC. Although this combinatorial treatment provides clinical benefit, it can be hampered by the effect of chemotherapy on inducing immunosuppression. Cyclin dependent kinases 4/6 (CDK4/6) phosphorylate retinoblastoma (Rb) protein and promote proliferation of Rb-intact hematopoietic stem progenitor cells (HSPCs) by allowing cells to progress through S phase. Rb loss is a signature mutation in SCLC tumors, making these tumor cells unresponsive to CDK4/6 inhibition. Therefore, we hypothesized that CDK4/6 inhibitors could be utilized to block the proliferation of Rb-intact HSPCs and protected them from chemotherapy without altering the effect of chemotherapy on Rb-deficient SCLC cells. We treated Rb-deficient SCLC cancer cells and Rb-intact NK and T cells with increasing concentrations of cisplatin, etoposide and topotecan with or without the CDK4/6 inhibitor G1T28. Cell proliferation, apoptosis and cell cycle were analyzed using CellTiter-Glo, Annexin V staining, and PI-based cell cycle analysis. In vitro, CDK4/6 inhibition did not alter the impact of chemotherapy on Rb-deficient SCLC cell viability, whereas with Rb-intact NK and T cells, CDK4/6 inhibitor treatment induced cell cycle arrest and prevented apoptosis induced by chemotherapeutic agents. In the TKOTmG Rb-deficient mouse model of SCLC, CDK4/6 inhibition improved the efficacy of cisplatin plus etoposide. In vivo studies using the KP-1 syngeneic mouse models showed that treatment with a CDK4/6 inhibitor improved the efficacy of chemotherapy and immunotherapy individually or chemo-immunotherapy combinations by reducing the tumor growth rate and prolonging animal survival. CDK4/6i treatment prior to chemotherapy preserved white blood cell counts in comparison to chemotherapy alone. Tissue and blood immune marker analysis showed that CDK4/6 inhibitor treatment increased both the circulating and tumor-resident NK cells. Collectively, we demonstrated that CDK4/6 inhibition does not antagonize the therapeutic impact of chemotherapy on Rb-deficient SCLC cells but enhances the efficacy of chemotherapy and immunotherapy in KP-1 syngeneic SCLC mouse model. CDK4/6i also at least partially abrogated the chemotherapy-induced reductions in subpopulatons of immune cells. CDK4/6 inhibition may be considered as a therapeutic strategy for mitigating chemotherapy-induced immunosuppression and enhance antitumor immunity in SCLC patients. Citation Format: Thiruvengadam Arumugam, Irene G. Muñoz, Alissa Poteete, Fahoa Zhang, Monique Nilsson, John S. Yi, Jessica A. Sorrentino, Andrew P. Beelen, John V. Heymach. CDK4/6 inhibition mitigates chemotherapy-induced immunosuppression and enhances the efficacy of chemo- immunotherapy in small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4204.

Coriloxin Exerts Antitumor Effects in Human Lung Adenocarcinoma Cells.

Both in Taiwan and around the world, lung cancer is a primary cause of cancer-related deaths. In Taiwan, the most prevalent form of lung cancer is lung adenocarcinoma, a type of non-small-cell lung carcinoma. Although numerous lung cancer therapies are available, their clinical outcomes are unsatisfactory. Natural products, including fungal metabolites, are excellent sources of pharmaceutical compounds used in cancer treatment. We employed in vitro cell invasion, cell proliferation, cell migration, cell viability, and colony formation assays with the aim of evaluating the effects of coriloxin, isolated from fermented broths of Nectria balsamea YMJ94052402, on human lung adenocarcinoma CL1-5 and/or A549 cells. The potential targets regulated by coriloxin were examined through Western blot analysis. The cytotoxic effect of coriloxin was more efficiently exerted on lung adenocarcinoma cells than on bronchial epithelial cells. Moreover, low-concentration coriloxin significantly suppressed adenocarcinoma cells’ proliferative, migratory, and clonogenic abilities. These inhibitory effects were achieved through ERK/AKT inactivation, epithelial–mesenchymal transition regulation, and HLJ1 expression. Our findings suggest that coriloxin can be used as a multitarget anticancer agent. Further investigations of the application of coriloxin as an adjuvant therapy in lung cancer treatment are warranted.

TCN1 is a potential prognostic biomarker and correlates with immune infiltrates in lung adenocarcinoma

BackgroundAround the world, lung cancer is the leading cause of cancer-related death. Lung adenocarcinomas are among the most common diagnosed forms of lung cancer, whose overall survival has not improved significantly, which makes finding an effective therapeutic target vital. Transcobalamin (TCN1) is a vitamin B12-binding protein which regulates cobalamin homeostasis. In tumor tissues, TCN1 is expressed highly, and its expression is correlated with cancer aggressiveness and poor prognosis according to recent studies and bioinformatic analyses. However, its effect on lung adenocarcinoma (LUAD) is unknown.MethodsWe evaluated whether TCN1 shows diagnostic and prognostic value in LUAD using bioinformatic analysis. In particular, various databases and analysis tools were used to determine TCN1’s relationship with LUAD, including TCGA, GTEx, GEO, STRING, and TISIDB.ResultsAs compared to normal lung tissue, the level of TCN1 expression in LUAD tissues was significantly higher (P < 0.001). TCN1 also had a good ability to distinguish lung adenocarcinoma from non-lung adenocarcinoma samples [area under the curve (AUC) = 0.788]. According to univariate Cox statistics, high expression levels of TCN1 correlate with poor overall survival (OS) in LUAD (P < 0.001). Moreover, based on a multivariate Cox analysis, TCN1 expression was independently correlated with OS (P = 0.011). GO/KEGG and GSEA indicated enrichment in epidermal cell differentiation (P < 0.0005), keratinocyte differentiation (P < 0.0005), neuroactive ligand–receptor interaction (P < 0.0005), epithelial–mesenchymal transition (P = 0.029, FDR = 0.023) and TNFA signaling via NFKB (P = 0.029, FDR = 0.023). Furthermore, TCN1 is associated with immune infiltration based on an analysis of immune cell infiltration.ConclusionsIn summary, TCN1 could be used as a prognostic and diagnostic biomarker and provide deeper perspectives for the development of therapies and prognostic markers in LUAD.

Vitamin D Affects the Warburg Effect and Stemness Maintenance of Non- Small-Cell Lung Cancer Cells by Regulating the PI3K/AKT/mTOR Signaling Pathway.

Non-Small-Cell Lung Cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of all lung cancer cases and resulting in high morbidity and mortality. Previous studies have demonstrated that 1,25-dihydroxy-vitamin-D3 (vitamin D) exhibited anti-cancer activity against breast and prostate cancer. The aim of the current study is to investigate the effect of vitamin D on NSCLC and its underlying mechanism. The effects of vitamin D on stemness maintenance and the Warburg effect in NSCLC cells were investigated both in vitro and in vivo. In vitro experiments revealed that vitamin D inhibited glycolysis and stemness maintenance in A549 and NCI-H1975 cells. Both in vitro and in vivo experiments indicated that vitamin D attenuated the expression of metabolism-related enzymes associated with the Warburg effect (GLUT1, LDHA, HK2, and PKM2). In addition, vitamin D down-regulated the expression of stemness-related genes (Oct-4, SOX-2, and Nanog) and the expression of PI3K, AKT, and mTOR. Overall, these findings suggest that vitamin D suppresses the Warburg effect and stemness maintenance in NSCLC cells via the inactivation of PI3K/AKT/mTOR signaling, thereby inhibiting the progression of NSCLC. The current study indicates that vitamin D is a potential candidate in therapeutic strategies against NSCLC.

Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer

Oncogenic KRAS mutations combined with the loss of the LKB1 tumor-suppressor gene (KL) are strongly associated with aggressive forms of lung cancer. N6-methyladenosine (m6A) in mRNA is a crucial epigenetic modification that controls cancer self-renewal and progression. However, the regulation and role of m6A modification in this cancer are unclear. We found that decreased m6A levels correlated with the disease progression and poor survival for KL patients. The correlation was mediated by a special increase in ALKBH5 (AlkB family member 5) levels, an m6A demethylase. ALKBH5 gain- or loss-of function could effectively reverse LKB1 regulated cell proliferation, colony formation, and migration of KRAS-mutated lung cancer cells. Mechanistically, LKB1 loss upregulated ALKBH5 expression by DNA hypermethylation of the CTCF-binding motif on the ALKBH5 promoter, which inhibited CTCF binding but enhanced histone modifications, including H3K4me3, H3K9ac, and H3K27ac. This effect could successfully be rescued by LKB1 expression. ALKBH5 demethylation of m6A stabilized oncogenic drivers, such as SOX2, SMAD7, and MYC, through a pathway dependent on YTHDF2, an m6A reader protein. The above findings were confirmed in clinical KRAS-mutated lung cancer patients. We conclude that loss of LKB1 promotes ALKBH5 transcription by a DNA methylation mechanism, reduces m6A modification, and increases the stability of m6A target oncogenes, thus contributing to aggressive phenotypes of KRAS-mutated lung cancer.

The role of social determinants on overall survival in advanced-stage non-small cell lung cancer patients.

e21117 Background: Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. Many studies have evaluated the association of social determinants with outcomes in early-stage NSCLC. These studies have shown statistically and clinically significant associations between overall survival (OS) and other social factors (e.g marital status, educational attainment). The aim of our study was to better understand the role of various social determinants of health (SDH) on OS in advanced-stage NSCLC patients in a community oncology practice in Florida. Methods: In this retrospective study, 125 patients with stage III and IV NSCLC were recruited between January 1st, 2014 until December 31st, 2018. We performed both categorical and continuous analyses (Pearson’s chi-square and Kruskal-Wallis test, respectively) to evaluate the association between median OS and several independent variables, including; gender, race, marital status, insurance status, living status, receiving financial assistance (FA), alcohol use, and smoking histories. OS is defined as the date of diagnosis up to the date of death. Other confounders that were analyzed included histology, treatment modality, comorbidities, and performance status of the patients. Results: Of the total study population (n = 125), 60% identified as male with a mean age of 73 years for the study population. The majority of patients (89%) identified as white; 56% were married, and 81% lived with someone. 66% of patients had an HMO insurance plan, and 51% of patients obtained FA to help with treatment care costs. 47% of patients identified as former smokers and 54% denied any alcohol use. The median OS for the patient population was 0.756 years. Chi-square analyses revealed that patients who received FA were more likely to live longer than median OS as opposed to patients that did not receive FA (OR = 2.41, 95% CI [1.18, 4.96], p = 0.050). Kruskal-Wallis analyses demonstrated that patients receiving FA had nearly a two-fold increase in median OS compared to patients without financial assistance (median OS = 1.01 years vs. 0.545 years, respectively; p = 0.013). However, other social determinants evaluated did not have a significant impact on relative OS in advanced-stage NSCLC. Conclusions: Ultimately, our study concludes that receiving FA has a significant association with increased OS in advanced-stage NSCLC patients. This study highlights the importance of reducing the financial burden of advanced-stage NSCLC patients and how FA impacts patient outcomes. Future prospective cohort studies with a larger sample size are warranted to identify other SDH, as well as the underlying mechanisms affecting median OS, in patients with advanced-stage NSCLC.