Small Cell Lung Carcinoma Research Articles

Unlikely Cohabitants: A Collision Tumor of Metastatic Small Cell Lung Carcinoma and Adrenal Adenoma

Unlikely Cohabitants: A Collision Tumor of Metastatic Small Cell Lung Carcinoma and Adrenal Adenoma

The predictive value of delta-like3 and serum NSE in evaluating chemotherapy response and prognosis in patients with advanced small cell lung carcinoma: An observational study.

Lung cancer is one of the most malignant tumors with fastest morbidity and mortality. Small cell lung cancer (SCLC) is the most malignant pathological type of lung cancer with early metastasis and poor prognosis. At present, there is a lack of effective indicators to predict prognosis of SCLC patients. Delta-like 3 protein (DLL3) is selectively expressed on the surface of SCLC and is involved in proliferation and invasion. Neuron-specific enolase (NSE) is an enolase isoenzyme that is generally regarded as a biomarker for SCLC and may correlate with stage of SCLC, prognosis and chemotherapy response. NSE can be influenced by different types of factors. To explore the associations between expression levels of DLL3 in tumor tissues with platinum/etoposide chemotherapy response, and assess the prognostic values of DLL3, NSE and other potential prognostic factors in advanced SCLC patients were herein studied. Ninety-seven patients diagnosed with SCLC in Zhongda Hospital from 2014 to 2020 were enrolled in the study. Serum NSE levels were tested using ELISA methods before any treatment. The expression of DLL3 in tumor tissue was detected by Immunohistochemistry (IHC). We investigated the relationship of DLL3 expression with chemotherapy and survival. Progression free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Multivariate Cox-proportional hazard regression was used to identify predictors of PFS and OS. DLL3 was detected in 84.5% (82/97) of all patients' tumor samples by IHC, mainly located on the surface of SCLC cells. Lower DLL3 expression was associated with longer PFS and better chemotherapy response. OS had no significant differences. Multivariate analysis by Cox Hazard model showed that, high DLL3 expression and maximum tumor size >5 cm were independent risk factors for PFS, where NSE < 35 ng/mL and age < 70 were independent prognostic factors for OS. Early stage was independent prognostic factors for PFS and OS (P < .05 log-rank). DLL3 was expressed in the most of SCLCs. DLL3 expression level in the tumor and NSE level in the serum may be useful biomarkers to predict the prognosis of SCLC. DLL3 may be a potential therapeutic target for SCLC in the future.

Differentially expressed microRNAs in prediagnostic serum linked to lung cancer up to eight years before diagnosis in prospective, population-based cohorts: A HUNT study.

8041 Background: With lung cancer incidence and mortality on the rise, blood biomarkers are increasingly in demand for early detection. The aim of this study is to discover and validate novel biomarkers based on next-generation sequencing performed on blood samples from non-cancer, ever-smokers up to eight years prior to diagnosis. Methods: Initial consideration was given to serum samples from the population-based prospective HUNT2 and HUNT3 cohorts, age &gt; 18 (n = 98,737). Inclusion criteria for cases were ever-smokers, no prior cancer at study entry, and 0–8 years between blood sampling and lung cancer diagnosis in the discovery and 0-4 years in the validation cohort. Among future cases, equal numbers of adenocarcinoma, squamous cell carcinoma and small-cell lung carcinoma were included. Every subsequent case of lung cancer had a matched control, ratio 1:1. The controls were matched for sex, age at study entry, pack-years, smoking cessation duration, comparable HUNT Lung Cancer Model risk score and no cancer diagnosis until the end of the study. The total number of serum samples included in the discovery and validation dataset were 240 (from HUNT2) and 72 (from HUNT3), respectively. The samples were analyzed by genome-wide small RNA seq (Illumina). Results: When we contrasted all cases against all controls, nine differentially expressed microRNAs with AUC &gt; 0.60 (FDR &lt; 0.25) and total raw count of &gt; 0.5 appeared in common in the discovery and validation datasets. Among these, three microRNAs were associated with non-small cell metastatic with mean AUC of 0.65 and 0.76 in the discovery and validation datasets, respectively. Furthermore, the signature of these three microRNAs in combination reached an AUC of 0.75 (discovery) and 0.90 (validation). Conclusions: Up to eight years before diagnosis, a small number of substantially differentially expressed microRNAs were found in serum. These intriguing microRNAs can potentially function as early diagnostic indicators for lung cancer, either alone or in combination. Further investigation and validation of these results in a larger prospective serum dataset are required.

Surgery and Stereotactic Radiotherapy for Stage I Small-Cell Lung Carcinoma: A 25-Year Experience

ObjectivesSmall-cell lung carcinoma (SCLC) is usually a wide-spread, highly-lethal malignancy but occasionally presents as localized, limited stage cancer amenable to local treatment. We reviewed our experience using surgery or stereotactic body radiotherapy (SBRT) to assess safety, survival rates and treatment toxicity in clinical stage I SCLC patients. Materials and MethodsElectronic medical records of patients with clinical stage I lymph node-negative SCLC who underwent surgical resection or SBRT between 1996 and 2021 were retrospectively reviewed. A multivariable Cox Proportional Hazards model was constructed. ResultsOf 96 patients meeting inclusion criteria, 77 underwent resection and 19 underwent SBRT. Surgical patients were younger (mean 68.4 ± 9.2 years surgery versus 74.3 ± 6.6 years SBRT, P = .005) and had better pulmonary function (81.5 ± 19.6 FEV1% of predicted surgery versus 44.0 ± 20.9% SBRT, P < .001). SBRT patients had significantly more comorbidities. For both cohorts, 59 tumors were pure SCLC and 37 were mixed SCLC/NSCLC histology. Median survivals were 21 months versus 31 months for SBRT and surgery patients respectively (P = .07). There were no treatment-related mortalities. Mean length of hospital stay for surgical patients was 5.4 ± 5.7 days. Survival was longer in lymph node-negative surgery patients (median 48 months node-negative versus 19 months node-positive, P = .04). For node-negative-surgery patients, the estimated 2- and 5-year survival rates are 60% and 48%. ConclusionsOur single-institutional experience over 25 years demonstrates that local treatment with surgery or SBRT for clinical stage I SCLC is safe and effective, with survivals lower than similar stage non–small-cell carcinoma patients. However, our results compare favorably with prior small-cell surgical series and far better than reported results of chemoradiotherapy for similar stage patients, thereby validating current recommendations for employing surgery or SBRT for stage I SCLC.

DAREON-8: A phase I, open-label, dose escalation/expansion trial of the DLL3-targeting T-cell engager, BI 764532, combined with first-line (1L) standard of care (platinum, etoposide, and anti-PD-L1 antibody) in patients (pts) with extensive-stage small cell lung carcinoma (ES-SCLC).

TPS8127 Background: Platinum/etoposide chemotherapy in combination with anti-PD-L1 antibodies is the 1L standard of care (SoC) for pts with ES-SCLC. However, most pts relapse and subsequent treatment (Tx) options are limited. Hence, outcomes are poor with a 5-year survival rate of &lt; 7%. Delta-like ligand 3 (DLL3) is a Notch receptor ligand expressed on tumor cells but not on normal cells. BI 764532 is an IgG-like T-cell engager (TcE) that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in selective, T-cell mediated tumor cell lysis. An ongoing Phase I trial of BI 764532 (NCT04429087) in pts with pretreated DLL3-positive tumors demonstrated an overall response rate of 28%, a disease control rate of 54%, and a manageable safety profile. Here, we describe DAREON-8 (NCT06077500), a Phase I open-label dose escalation/expansion trial of BI 764532 plus SoC as a 1L Tx for pts with ES-SCLC. Methods: Pts will be recruited from ~20 sites into this two-part trial. In Part A (dose escalation), ~30 pts will receive escalating doses of intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide + atezolizumab. Dose escalation will be guided by a Bayesian logistic regression model with overdose control. Tx with BI 764532 will continue for 36 months, withdrawal or progressive disease (PD). The primary objective is to determine the maximum tolerated dose (MTD) of BI 764532 and/or the recommended dose for expansion (RDE)/recommended Phase II dose (RP2D) for BI 764532 plus SoC. Safety, efficacy and/or PK assessments will guide the RDE/RP2D. The primary endpoint focuses on the occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation period. In Part B (dose expansion), ~30 pts will receive BI 764532 at the RDE/RP2D determined in Part A for 36 months, withdrawal or PD and platinum/etoposide + either atezolizumab or durvalumab. The primary objective of Part B is to confirm the safety and tolerability of BI 764532 at the RDE/RP2D plus SoC Tx as measured by the occurrence of DLTs during the on-Tx period. Key inclusion criteria include confirmed ES-SCLC; no prior systemic treatment for ES-SCLC; and eligibility to receive platinum/etoposide chemotherapy + anti-PD-L1 antibodies. Key exclusion criteria include previous Tx with DLL3-targeting TcEs; persistent, unresolved toxicity from previous Txs; immunodeficiency, or systemic steroid or other immunosuppressive therapy ≤7 days prior to first dose of BI 764532; and significant cardio/cerebrovascular disease. Clinical trial information: NCT06077500 .

Head-to-head: Should Ki67 proliferation index be included in the formal classification of pulmonary neuroendocrine neoplasms?

The reporting of lung neuroendocrine neoplasms (NENs) according to the 2021 World Health Organisation (WHO) is based on mitotic count per 2 mm2, necrosis assessment and a constellation of cytological and immunohistochemical details. Accordingly, typical carcinoid and atypical carcinoid are low- to intermediate-grade neuroendocrine tumours (NETs), while large-cell neuroendocrine carcinoma (NEC) and small-cell lung carcinoma are high-grade NECs. In small-sized diagnostic material (cytology and biopsy), the noncommittal term of carcinoid tumour/NET not otherwise specified (NOS) and metastatic carcinoid NOS have been introduced with regard to primary and metastatic diagnostic settings, respectively. Ki-67 antigen, a well-known marker of cell proliferation, has been included in the WHO classification as a non-essential but desirable criterion, especially to distinguish NETs from high-grade NECs and to delineate the provisional category of carcinoid tumours/NETs with elevated mitotic counts (> 10 mitoses per mm2) and/or Ki-67 proliferation index (≥ 30%). However, a wider use of this marker in the spectrum of lung NENs continues to be highly reported and debated, thus witnessing a never-subsided attention. Therefore, the arguments for and against incorporating Ki-67 in the classification and clinical practice of these neoplasms are discussed herein in detail.

Paraneoplastic opsoclonus-myoclonus syndrome as a rare presentation of parotid adenocarcinoma

Paraneoplastic Opsoclonus-Myoclonus Ataxia Syndrome (POMA) is a rare neurological condition that affects approximately 1 in 10,000,000 people annually. This syndrome is poorly understood and can lead to long-term cognitive, behavioral, and motor complications. Opsoclonus is characterized by involuntary, rapid, repetitive, multi-vectorial oscillations of the eyes occurring in all directions of gaze. It is accompanied by diffuse or focal body myoclonus and may or may not include ataxia and other cerebellar signs. POMA is typically a paraneoplastic syndrome associated with neuroblastoma in childhood and breast carcinoma or small-cell lung carcinoma in adults. Additionally, viral or toxic agents are known to play a role in its etiology, and the immune system is involved in the pathogenesis. We report a case of a 41-year-old man with anti-Ri antibody opsoclonus-myoclonus syndrome and parotid adenocarcinoma involvement. After diagnosing opsoclonus-myoclonus syndrome, the patient underwent multimodal immunotherapy treatment, resulting in partial remission of the neurological symptoms.

Precise and automated lung cancer cell classification using deep neural network with multiscale features and model distillation

Lung diseases globally impose a significant pathological burden and mortality rate, particularly the differential diagnosis between adenocarcinoma, squamous cell carcinoma, and small cell lung carcinoma, which is paramount in determining optimal treatment strategies and improving clinical prognoses. Faced with the challenge of improving diagnostic precision and stability, this study has developed an innovative deep learning-based model. This model employs a Feature Pyramid Network (FPN) and Squeeze-and-Excitation (SE) modules combined with a Residual Network (ResNet18), to enhance the processing capabilities for complex images and conduct multi-scale analysis of each channel's importance in classifying lung cancer. Moreover, the performance of the model is further enhanced by employing knowledge distillation from larger teacher models to more compact student models. Subjected to rigorous five-fold cross-validation, our model outperforms existing models on all performance metrics, exhibiting exceptional diagnostic accuracy. Ablation studies on various model components have verified that each addition effectively improves model performance, achieving an average accuracy of 98.84% and a Matthews Correlation Coefficient (MCC) of 98.83%. Collectively, the results indicate that our model significantly improves the accuracy of disease diagnosis, providing physicians with more precise clinical decision-making support.

Metastasis of small cell lung cancer to bilateral extraocular muscles: a case report

BackgroundOrbital metastasis is a possible complication of small cell lung cancer and a pattern of bilateral invasion of the extraocular muscles has rarely been reported in literature.Case presentationA 46-year-old white male with a past medical history of smoking and stage IV small cell lung carcinoma presented with loss of vision and pain in the left eye. Examination revealed bilateral proptosis and left afferent pupillary defect, and visual acuity was hand motion on the left eye and 4/10 on the right eye. An orbital computed tomography scan showed a compression of the left optic nerve between the extraocular muscles at the apex, and a lateral canthotomy was performed for a new-onset compressive optic neuropathy, with residual visual improvement. There was also significant enlargement of the extraocular muscles in the right orbit. The patient was maintained in palliative treatment with both chemotherapy and local medical and surgical (amniotic membrane cover for exposure keratopathy) ophthalmological treatments until he eventually died 5 months after.ConclusionBilateral metastasis to the extraocular muscles is a very rare manifestation of small cell lung cancer and the palliative treatment in these cases is challenging.

Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder that affects the neuromuscular junction, is characterized by proximal muscle weakness, reduction of tendon reflexes, and autonomic dysfunction. LEMS shows a prevalence of approximately 0.25-0.27 per 100,000 population. The characteristic muscle weakness observed in patients with LEMS is attributed to the role of pathogenic autoantibodies directed against voltage-gated calcium channels (VGCC) present on the presynaptic nerve terminal. Notably, 50-60% of patients with LEMS have an associated tumor, small-cell lung carcinoma (SCLC), which also expresses functional voltage-gated calcium channels (VGCC). The Japanese LEMS diagnostic criteria 2022 recommend documentation of typical electrophysiological abnormalities combined with myasthenic symptoms for accurate diagnosis. P/Q-type VGCC antibody positivity strongly supports the diagnosis. Treatment options are categorized as oncological treatment, immunotherapy, and symptomatic treatments. Effective treatment of the tumor can improve LEMS in patients with SCLC. Most patients benefit from 3,4-diaminopyridine administration for symptomatic treatment. A treatment algorithm is established by the clinical practice guidelines 2022.

Genetic diversity in small cell lung carcinoma

Genetic diversity in small cell lung carcinoma

S100A6 could not promote the differentiation of Calu-6 lung cancer cell line.

Our previous study demonstrated that S100 calcium binding protein A6 (S100A6) impairs tumorigenesis by Calu-6 lung cancer cells, as well as inhibit their growth. However, the role that S100A6 plays in tumor cell differentiation has not been previously explored. This study aimed to confirm the effect of S100A6 on the direction of differentiation in the human lung cancer cell linem Calu-6m based on our previous published research. A S100A6-overexpressing lentiviral vector was successfully constructed in our previous study. Nude mouse tumorigenicity was then applied successfully, and 15 mice were divided into three groups (Calu-6, Calu-6/neo, Calu-6/S100A6). After 5 weeks, we detected lung cancer markers with immunohistochemistry in mice tumor tissues, including the adenocarcinoma markers, TTF-1 and NapsinA, the squamous cell carcinoma markers, P40, CK5/6 and P63, and the small cell lung cancer markers CD56, Syn, CgA, TTF-1, CK, and Ki-67. Differences among the three groups were statistically compared. All the above-mentioned markers were positive in the tumor tissues of all three groups, and there were no significant differences. S100A6 cannot promote differentiation of the undifferentiated human lung cancer cell line, Calu-6, into adenocarcinoma, squamous, or small cell carcinoma cell lines.

Complex Presentation of Lung Cancer with Obstructive Jaundice

Background: Lung cancer, particularly small-cell lung carcinoma (SCLC), often presents with respiratory symptoms. However, atypical manifestations including jaundice and abdominal pain can obscure the diagnosis, leading to challenges in early detection and treatment. Case Presentation: A 49-year-old male, with a history of smoking and diagnosed with Chronic Obstructive Pulmonary Disease (COPD), presented to the emergency department with a 3-day history of jaundice and a 3-week duration of mild abdominal pain. Initial investigations, including blood tests, showed hyperbilirubinemia and elevated lipase and amylase levels. An abdominal ultrasound was performed and revealed a hypoechoic, inhomogeneous mass in the head of the pancreas and multiple liver masses, suggesting a cephalo-pancreatic formation with liver metastasis. Further diagnostic procedures, including upper endoscopy and ERCP, followed by a TAP CT scan, identified a large mediastinal-pulmonary mass with invasion into major vessels and extensive metastasis. The immunohistochemical analysis of a duodenal ulcer biopsy confirmed a diagnosis of duodenal metastasis from a small-cell neuroendocrine lung carcinoma. Conclusion: Our case highlights that while rare, the possibility of metastatic spread should be included in the differential diagnosis when obstructive jaundice occurs in the context of high-risk factors for lung cancer.

A Novel Cause of Sudden Onset Right Gaze Paresis: Acute Onset Limbic Encephalitis Secondary to ANNA-1 Antibodies and Biopsy-proven Small Cell Lung Carcinoma (SCLC) (P1-14.016)

A Novel Cause of Sudden Onset Right Gaze Paresis: Acute Onset Limbic Encephalitis Secondary to ANNA-1 Antibodies and Biopsy-proven Small Cell Lung Carcinoma (SCLC) (P1-14.016)

A Deep Learning–Based Assay for Programmed Death Ligand 1 Immunohistochemistry Scoring in Non–Small Cell Lung Carcinoma: Does it Help Pathologists Score?

Several studies have developed various artificial intelligence (AI) models for immunohistochemical analysis of programmed death ligand 1 (PD-L1) in patients with non–small cell lung carcinoma; however, none have focused on specific ways by which AI-assisted systems could help pathologists determine the tumor proportion score (TPS). In this study, we developed an AI model to calculate the TPS of the PD-L1 22C3 assay and evaluated whether and how this AI-assisted system could help pathologists determine the TPS and analyze how AI-assisted systems could affect pathologists’ assessment accuracy. We assessed the 4 methods of the AI-assisted system: (1 and 2) pathologists first assessed and then referred to automated AI scoring results (1, positive tumor cell percentage; 2, positive tumor cell percentage and visualized overlay image) for final confirmation, and (3 and 4) pathologists referred to the automated AI scoring results (3, positive tumor cell percentage; 4, positive tumor cell percentage and visualized overlay image) while determining TPS. Mixed-model analysis was used to calculate the odds ratios (ORs) with 95% CI for AI-assisted TPS methods 1 to 4 compared with pathologists’ scoring. For all 584 samples of the tissue microarray, the OR for AI-assisted TPS methods 1 to 4 was 0.94 to 1.07 and not statistically significant. Of them, we found 332 discordant cases, on which the pathologists’ judgments were inconsistent; the ORs for AI-assisted TPS methods 1, 2, 3, and 4 were 1.28 (1.06-1.54; P = .012), 1.29 (1.06-1.55; P = .010), 1.28 (1.06-1.54; P = .012), and 1.29 (1.06-1.55; P = .010), respectively, which were statistically significant. For discordant cases, the OR for each AI-assisted TPS method compared with the others was 0.99 to 1.01 and not statistically significant. This study emphasized the usefulness of the AI-assisted system for cases in which pathologists had difficulty determining the PD-L1 TPS.

Non-Hodgkin’s Lymphoma of the Central Nervous System with N-Methyl-D-Aspartate Receptor Antibody Positivity - A Case Report

Purpose: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, among the paraneoplastic syndromes, is a recently characterized autoimmune encephalitis most commonly associated with antibodies against subunits of the NMDAR in the central nervous system. As a paraneoplastic syndrome, anti-NMDAR encephalitis is commonly associated with ovarian teratomas, small cell lung carcinomas and testicular germ cell tumors. To our knowledge, there have been no cases with primary central nervous system lymphoma (PCNSL), a rare type of extranodal non-Hodgkin’s lymphoma, without lymph node involvement associated with anti-NMDAR encephalitis. Case Report: A 58-year-old right-handed male patient with complaints of instability in walking for two months, progressively smaller handwriting, hallucinations when falling asleep or waking up, decreased memory, inability to maintain attention was admitted to our hospital for further diagnosis and treatment. Lumbar puncture was performed with the diagnosis of possible encephalitis after many further examinations and CSF studies revealed NMDAR antibody positivity, leading to the initial diagnosis of anti - NMDAR encephalitis. He was treated with high dose methylprednisolone and intravenous immunoglobulin. Due to the continuation of the patient’s presenting symptoms and cranial magnetic resonance imaging findings, a stereotactic brain biopsy was performed from the area with contrast enhancement and the diagnosis was revised as PCNSL associated with NMDAR antibody positivity. Conclusion: This report emphasizes the importance of anti-NMDAR encephalitis as a paraneoplastic syndrome in previously undiagnosed PCNSL. Therefore, it is crucial to be aware of anti-NMDAR encephalitis as a paraneoplastic neurological syndrome that can present with non-Hodgkin’s lymphoma. It is necessary to continually observe the evolution of the disease and perform further diagnostic tests for early identification.

Efectos del Mebendazol Sobre el Mecanismo de Apoptosis Mediado por Caspasa en Cultivos de Células Cancerosas

This study was conducted to compare Mebendazole in terms of its apoptosis–inducing and tubulin–inhibitory effects when combined with vincristine and paclitaxel, both of which are used in cancer treatment. Lung fibroblast cells (MRC–5) and small cell lung carcinoma (NCI–H209) cell lines were used in the study. Concentrations of Mebendazole, vincristine, and paclitaxel at 0.5 µM, 1 µM, 1.5 µM, and 2 µM were separately applied to these cell lines, as well as in combinations. After the cells were kept in the culture medium for 24 hours following drug administration, cell proliferation, apoptotic DNA levels, caspase 3, 8, and 9 levels, and in vitro wound healing experiments were performed. It was determined that Mebendazole suppressed cell proliferation and cell healing, increased caspase–3, caspase–8, caspase–9 levels and apoptotic DNA formation in NCI–H209 cancer lung cells. Compared to the groups given Mebendazole and vincristine alone, it was observed that cell proliferation was more suppressed and, the level of apoptosis increased in cancerous cells in the groups given the combination of the two drugs. According to the findings obtained from the present study, it was believe that Mebendazole may possess therapeutic activity against cancerous lung cells (NCI–H209) due to its apoptosis–inducing and cell proliferation–suppressive effects.

Causal relationships between mitochondrial proteins and different pathological types of lung cancer: a bidirectional mendelian randomization study.

An increasing number of studies point to an association between mitochondrial proteins (MPs) and lung cancer (LC). However, the causal relationship between MPs and LC remains unclear. Consequently, our study employed a bidirectional Mendelian randomization (MR) analysis to explore the causal association between MPs and different pathological types of LC. A two-sample MR study was performed using the genome-wide association study (GWAS) data publicly available. We applied the primary inverse variance weighted (IVW) method along with additional MR methods to validate the causality between MPs and different pathological types of LC. To ensure the robustness of our findings, sensitivity analyses were employed. Moreover, we performed a bi-directional MR analysis to determine the direction of the causal association. We identified a total of seven MPs had significant causal relationships on overall LC, lung squamous cell carcinoma (LUSC), and small cell lung carcinoma (SCLC). We found two MPs had significant associations with overall LC, four MPs had significant associations with LUSC, and four MPs had significant associations with SCLC. Additionally, an MP was found to have a nominal relationship with LUSC. Moreover, no causality was found between MPs and lung adenocarcinoma (LUAD). Bidirectional MR showed no reverse effect between identified MPs and different pathological types of LC. In general, our findings of this MR study suggest causal associations of specific MPs with overall LC, LUSC, and SCLC. However, no such causality was found in LUAD.

NDRG2 acts as a negative regulator of the progression of small-cell lung cancer through the modulation of the PTEN-AKT-mTOR signalling cascade

N-myc downstream-regulated gene 2 (NDRG2) has been recognised as a negative regulator of the progression of numerous tumours, yet its specific role in small-cell lung carcinoma (SCLC) is not fully understood. The purpose of the current study was to investigate the biological role and mechanism of NDRG2 in SCLC. Initial investigation using the Gene Expression Omnibus (GEO) dataset revealed marked downregulation of NDRG2 transcripts in SCLC. The decreased abundance of NDRG2 in SCLC was verified by examining clinical specimens. Increasing NDRG2 expression in SCLC cell lines caused significant changes in cell proliferation, cell cycle progression, colony formation, and chemosensitivity. NDRG2 overexpression decreased the levels of phosphorylated PTEN, AKT and mTOR. In PTEN-depleted SCLC cells, the upregulation of NDRG2 did not result in any noticeable impact on AKT or mTOR activation. Additionally, the reactivation of AKT reversed the antitumour effects of NDRG2 in SCLC cells. Notably, increasing NDRG2 expression retarded the growth of SCLC cell-derived xenografts in vivo. In conclusion, NDRG2 serves as an inhibitor of SCLC, and its cancer-inhibiting effects are achieved through the suppression of AKT/mTOR via the activation of PTEN. This work suggests that NDRG2 is a potential druggable target for SCLC treatment.

Abstract 7558: Novel liquid biopsy based determination of lung cancer histology using a comprehensive epigenomic platform reveals enhancer activity as a key determinant for accurate classification

Abstract BACKGROUND: Accurate molecular characterization of lung cancer including histology classification and therapeutic target profiling is critical for treatment planning and resistance monitoring. For example, detecting lineage transformation from lung adenocarcinoma (LUAD) to small cell lung carcinoma (SCLC) following treatment, an established resistance mechanism, is challenging due to deteriorating patient health and complicated invasive procedures. Here, we describe an accurate lung cancer histological classification using an innovative, multimodal epigenomic liquid biopsy method that comprehensively profiles tumor-specific transcription activation from 1 mL of patient plasma. METHODS: 37 LUAD, 34 SCLC patient plasma samples collected from commercial biobanks, and reference cell lines were profiled for enhancer, promoter and DNA methylation activity to identify epigenomic loci characteristic of LUAD and SCLC. The resulting map of select quantified loci was used as input to a machine learning algorithm that distinguishes SCLC from LUAD, in a cross validated training and testing approach. RESULTS: The epigenomic maps derived from lung cancer patient plasma were highly informative of the regulatory programming of the tumor cells. The enhancers and promoters most strongly linked to lung cancer profiles across the patient population include key, histology-specific driver genes such as NKX2-1, FOXA1, FOXA2, ONECUT2, DLL3, and ASCL1. The resulting classifier was able to accurately predict histology with a cross validated AUC greater than 0.94. In silico simulation results suggest that accurate classification can be achieved with ctDNA content below 1%. Further correlative examination of the SCLC enhancer landscape revealed a partitioning of SCLC patients into molecular subtypes characterized by active enhancer marks at subtype-specific transcripts, including ASCL1, POU2F3, NEUROD1, and YAP1. The transcriptional regulation of ADC targets is apparent through comprehensive epigenomic profiling of plasma in both SCLC and LUAD, with the expression of Claudin 18.2, SEZ6, and others showing a strong dynamic range independent of ctDNA levels. This represents a novel liquid biopsy approach to distinguish LUAD from SCLC and provide simultaneous insight into expression of key targets at clinically relevant ctDNA levels. CONCLUSION: These data demonstrate the feasibility of epigenomic mapping from 1mL of plasma in lung cancer patients to distinguish lung cancer histology. The resulting data is biologically interpretable through the lens of transcriptional activation of key histology specific genes. This liquid-biopsy based approach may provide a non-invasive alternative to invasive and challenging tissue biopsies for biomarker investigation and therapeutic decision making. Citation Format: Jamey Guess, Aparna Gorthi, Anthony D'ippolity, Jonathan Beagan, Travis Clark, Michael Coyne, Tyrone Tamakloe, Baovy Tran, Hyun-Hwan Jeong, Kristian Cibulskis, Hathairat Sawaengsri, Juliann Chmielecki, Corrie A. Painter, J Carl Barrett, Matthew Eaton. Novel liquid biopsy based determination of lung cancer histology using a comprehensive epigenomic platform reveals enhancer activity as a key determinant for accurate classification [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 7558.