Small Cell Lung Research Articles

Development of a novel cell-free DNA fragmentomics assay for monitoring disease progression in real-time for stage IV cancer patients.

e14544 Background: Advances in oncology have improved treatment response rates and overall survival. Many treatments, even targeted therapies, can fail to deliver an initial response to stage IV patients. We aimed to evaluate cfDNA as a biomarker of non-response to therapy in metastatic cancer. Methods: Blood samples were prospectively collected in Streck tubes at baseline and 12 - 21 days after initiating treatment, along with detailed clinical data, including imaging assessments captured in a cohort of metastatic non-small-cell lung (50), small-cell lung (8), breast (21), and colorectal (51) cancer study participants. To determine the fragmentation pattern of the DNA in the patient plasma, cfDNA was extracted using QIAamp Circulating Nucleic ACID Kit (Qiagen). cfDNA fragment concentrations were quantitated using two multiplexed qPCR assays on a QuantStudio 5. Primers and probes for the qPCR assay were designed using the high copy number retrotransposons Alu and SVA, represented across all 23 chromosomes. The two assays were performed on each specimen: an >80bp, >265bp and internal positive control (IPC) assay and an >105bp, >265bp with IPC assay. Following analytic validation of the assays, specimens from all participants were analyzed. The results from both assays were combined and merged with the clinical results and statistically analyzed. Results: 130 patients were included in the analysis. The qPCR assays work across all tumor and therapy types analyzed. A logit regression model was developed which calculates the likelihood that a patient’s cancer is progressing. The area under the ROC is 0.93 with a p-value of <0.001. Results clustered above the logit value of 0.65 (n=15) are all progressors by imaging (PPV=100.0%). All logit values below 0.045 (n=69) are non-progressors by imaging (NPV=0.0%). Bootstrap resampling (1,000 iterations) suggests a 99.3% PPV at the 0.9 logit cut point. Healthy subjects (9) and patients with a variety of conditions (33) known to create elevated fragmented levels of cfDNA were also analyzed to determine which patients are not appropriate patients for the assay. Results indicate patients with following conditions within 10 days of a blood draw should be excluded: stroke, myocardial infarction, severe acute autoimmune event, and severe acute COPD exacerbation; and patients treated with a chemotherapy agent (i.e., methotrexate) within 10 days of a blood draw. Conclusions: These data support the value of a blood-based biopsy test for evaluating cancer cfDNA. cfDNA fragment assay is applicable to lung, colorectal, and breast cancer, and is agnostic to any mutation status. The cfDNA fragment analysis is a promising biomarker to monitor patient treatment and save time and the expense of clinically ineffective therapies, allowing the medical oncologist to evaluate the response to therapy in real-time and provide the best care possible for the patient.

Prognostic Value of the Gustave Roussy Immune Score in Lung Cancer: A Meta-Analysis

Purpose To clarify the prognostic role of the Gustave Roussy immune (GRIm) score in lung cancer. Methods The PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases were searched up to March 30, 2024. The primary outcomes included overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the associations between the GRIm score and survival, and subgroup analyses were performed based on pathological type (non-small cell lung cancer vs. small cell lung cancer), tumor stage (advanced vs. limited stage) and treatment approach (immune checkpoint inhibitor vs. surgery vs. chemotherapy). Results Eight studies with 1,333 participants were included. The pooled results showed that a higher GRIm score predicted worse OS (HR = 1.96, 95% CI: 1.54–2.49, P < 0.001) and PFS (HR = 1.64, 95% CI: 1.22–2.21, P = 0.001). Subgroup analyses for OS and PFS showed similar results. However, subgroup analyses for PFS indicated that the association between the GRIm score and PFS was nonsignificant among patients with small cell lung cancer (P = 0.114) and among patients treated with chemotherapy (P = 0.276). Conclusion The GRIm score might serve as a novel prognostic factor for lung cancer. Additional studies are still needed to verify these findings.

A novel machine learning model for efficacy prediction of immunotherapy-chemotherapy in NSCLC based on CT radiomics

Lung cancer is categorized into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer. Of these, NSCLC accounts for approximately 85% of all cases and encompasses varieties such as squamous cell carcinoma and adenocarcinoma. For patients with advanced NSCLC that do not have oncogene addiction, the preferred treatment approach is a combination of immunotherapy and chemotherapy. However, the progression-free survival (PFS) typically ranges only from about 6 to 8 months, accompanied by certain adverse events. In order to carry out individualized treatment more effectively, it is urgent to accurately screen patients with PFS for more than 12 months under this treatment regimen. Therefore, this study undertook a retrospective collection of pulmonary CT images from 60 patients diagnosed with NSCLC treated at the First Affiliated Hospital of Wenzhou Medical University. It developed a machine learning model, designated as bSGSRIME-SVM, which integrates the rime optimization algorithm with self-adaptive Gaussian kernel probability search (SGSRIME) and support vector machine (SVM) classifier. Specifically, the model initiates its process by employing the SGSRIME algorithm to identify pivotal image features. Subsequently, it utilizes an SVM classifier to assess these features, aiming to enhance the model's predictive accuracy. Initially, the superior optimization capability and robustness of SGSRIME in IEEE CEC 2017 benchmark functions were validated. Subsequently, employing color moments and gray-level co-occurrence matrix methods, image features were extracted from images of 60 NSCLC patients undergoing immunotherapy combined with chemotherapy. The developed model was then utilized for analysis. The results indicate a significant advantage of the model in predicting the efficacy of immunotherapy combined with chemotherapy for NSCLC, with an accuracy of 92.381% and a specificity of 96.667%. This lays the foundation for more accurate PFS predictions and personalized treatment plans.

Case report on confusion: an unusual presentation of lung cancer

Introduction: Cancer of the lung can be insidious and manifest clinicallyin relatively unexpected forms. The incidence of hyponatremia in lungcancer is 18.9% [1].Case: An 87-year-old woman presented with confusion. She smoked10–15 cigarettes a day for 70 years. Blood tests done; Na: 118. I made animpression of severe symptomatic hyponatremia secondary to suspectedSiADH from possible small cell lung cancer.I requested CXR, urine Na, paired osmolality, fluid restricted and discussedwith the medical registrar who suggested a transfer to Generalhospital. CXR showed a round mass in the right upper lobe.At the GH, Na was replaced slowly and the patient was planned forCT scans. After 2 days, she developed gradual SOB (? PE). CT scans weredelayed because she could not lie flat and got SOB. ENT and anaesthesiareviewed her and suggested supported airway CT under GADay 5 – Distended neck veins? SVCO. Anaesthetists were no longercomfortable with GA. Unfortunately, steroids did not make her morecomfortable. DNAR in place, family informed of poor prognosis andrequested fast track discharge with palliative support. Died at home after18 days.Conclusion: While it is quite unusual for a respiratory condition to presentwith confusion, quick recognition, open mindedness, and inter disciplinarycooperation are essential in day-to-day practice.

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.

Impact of obstructive sleep apnea risk on prognosis and treatment responses of lung cancer

Aims: Obstructive sleep apnea (OSA) may affect oncogenic processes in a specific way for each tumor type. This study was conducted to reveal the relationship between OSA risk and prognosis and treatment responses in patients with lung cancer. Methods: This prospective study included stage III and IV lung cancer patients aged between 18 and 75 years. Patients with poor performance status, cranial metastasis, congestive heart failure, surgery history, and positive airway pressure device use were excluded. STOP-BANG questionnaire was used to assess the OSA risk. The primary end-point was the differences in the survival and treatment responses of patients at intermediate/high risk of OSA compared with those at low OSA risk. Data from the patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) were analyzed separately. Results: Ninety-eight patients (34 SCLC and 64 NSCLC), mostly male (85.7%), with a mean age of 59.3±8 were included in the analysis. Overall survival was similar in the groups. However, in the SCLC group, those at low OSA risk had a shorter progression-free survival (PFS) than those at intermediate/high risk (105±31.8 days, vs 272±16.2 days, p=0.001). Cox regression analysis showed that low OSA risk was an independent risk factor for PFS in only the SCLC group (HR:4.9 CI:1.6-14.7, p=0.005). Conclusion: IOur results showed that low OSA risk was an independent poor prognostic factor for PFS in SCLC regardless of the tumor stage.

Adherence to the low-fat diet pattern reduces the risk of lung cancer in American adults aged 55 years and above: a prospective cohort study

ObjectivesThere is little evidence on the association between low-fat dietary patterns and lung cancer risk among middle-aged and older adults. To fill this gap, we comprehensively investigated the association of adherence to a low-fat diet (LFD) and intake of different fat components including saturated, monounsaturated, and polyunsaturated fatty acids with incidence of lung cancer and its subtypes [non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)] among adults aged 55 years and older. DesignA prospective cohort study with a mean follow-up time of 8.8 years. Setting and participantsThis study used data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The study population included 98,459 PLCO participants age 55 and over at baseline who completed food frequency questionnaires providing detailed dietary information and had no history of cancer. MethodsDietary intake was assessed using a validated food frequency questionnaire at baseline. A LFD score was calculated based on fat, protein, and carbohydrate intake as a percentage of total calories. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between LFD score and intake of fat components (in quartiles) and incident lung cancer and its subtypes over follow-up. Restricted cubic spline analyses were conducted to examine possible nonlinear relationships. Subgroup analyses were performed to evaluate potential effect modifiers, and several sensitivity analyses were conducted to assess the stability of the findings. ResultsDuring a follow-up of 869,807.9 person-years, 1,642 cases of lung cancer were observed, consisting of 1,408 (85.75%) cases of NSCLC and 234 (14.25%) cases of SCLC. The highest versus the lowest quartiles of the LFD score were found to be associated with a reduced risk of lung cancer (HR, 0.76; 95% CI, 0.66−0.89), NSCLC (HR, 0.79; 95% CI, 0.67−0.93), and SCLC (HR, 0.59; 95% CI, 0.38−0.92). The restricted cubic spline plots demonstrated a linear dose-response relationship between the LFD score and the risk of lung cancer as well as its subtypes. This risk reduction association for overall lung cancer was more pronounced in smokers (HR, 0.71; 95% CI, 0.60−0.84; P for interaction = 0.003). For fat components, high consumption of saturated fatty acids was associated with an increased lung cancer risk (HR, 1.35; 95% CI, 1.10–1.66), especially for SCLC (HR, 2.05; 95% CI, 1.20–3.53). No significant association was found between consumption of monounsaturated or polyunsaturated fatty acids and incident lung cancer and its subtypes. ConclusionsOur findings suggest that adherence to LFD may reduce the lung cancer risk, particularly in smokers; while high saturated fatty acids consumption may increase lung cancer risk, especially for SCLC, among middle-aged and older adults in the US population.

MiRNA patterns in male LUSC patients - the 3-way mirror: Tissue, plasma and exosomes

Lung cancer remains one of the leading causes of cancer-related deaths worldwide. It is classified into two main histological groups: non-small cell lung cancer (NSCLC) and small cell lung cancer. Improving the outcome of cancer patients could be possible by enhancing the early diagnosis. In the current study, we evaluated the levels of three microRNAs - miR-21-5p, miR-155-5p, and miR-181a-5p in tumor (TT) vs adjacent normal tissue (NT), as well as their expression levels in plasma and extracellular vesicles (EVs) from plasma in lung squamous cell carcinoma (LUSC) male patients vs healthy individuals as means to identify a panel of miRNAs that could serve as novel biomarkers for the diagnosis of LUSC in male patients. Matched paired tissue samples from male LUSC (n=40) patients were used for miRNA expression analysis. MiR-21-5p and miR-155-5p in tumor tissue were overexpressed, while underexpression of miR-181a-5p was observed in LUSC TT vs NT. These results were further validated in the TCGA LUSC dataset, considering 279 male samples. These alterations of miR-21-5p, miR-181a-5p, and miR-155-5p in tumor tissue are also present in plasma and plasma extracellular vesicles in LUSC male patients. In addition, ROC curves were performed to assess the sensitivity and specificity of different combinations of these miRNAs, confirming a high diagnostic accuracy for LUSC of up to 88 % in male subjects. The expression levels in tissue samples and the abundance in plasma and plasma EVs of the three miRNAs combined - miR-21-5p, miR-155-5p and miR-181a-5p – could be considered for further studies on biomarkers for the early detection of LUSC in male subjects.

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.

Abstract 3294: The GSPT1 molecular glue degrader MRT-2359 is active against prostate cancer

Abstract We have previously described our GSPT1 molecular glue degrader MRT-2359, which was optimized to achieve preferential antiproliferative activity in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) expressing high N-MYC or L-MYC mRNA. A clinical trial with this new drug candidate is ongoing (NCT05546268). Here, we present pre-clinical profiling of MRT-2359 across hundreds of cancer cell lines representing multiple cancer types, aiming at identifying other cancers where preferential sensitivity is associated with high expression of a MYC family member. These studies showed that prostate cancer cell lines clearly segregate into groups that are either sensitive or insensitive. Sensitive prostate cancer cell lines could be further divided into two subgroups: (1) androgen receptor positive cell lines displaying higher c-MYC mRNA expression levels than the other prostate cancer cell lines, (2) neuroendocrine prostate cancer cell lines with or without high N-MYC. The latter is in line with our previous observation that the neuroendocrine phenotype is generally associated with heightened sensitivity to MRT-2359 independently of MYC status. The insensitive cell lines were androgen receptor and neuroendocrine negative and displayed lower c-MYC mRNA levels. GSPT1 degradation in androgen receptor-positive cell lines led to rapid and deep loss of c-MYC protein as well as reduction of androgen receptor, including the splice variant AR-V7 that is associated with resistance to agents targeting androgen signaling. In androgen receptor-negative cell lines, the levels of c-MYC protein decreased only modestly upon GSPT1 degradation. Finally, in immunocompromised mice, xenografts of the AR-V7-positive cell line 22RV1 and the neuroendocrine prostate cell line NCI-H660, both of which are sensitive to MRT-2359 in vitro, were treated with several MRT-2359 dose regimens including continuous as well as intermittent (5 days on/9 days off) dosing. Most regimens led to marked tumor regression. Tumors of both models fully regressed after a 4-week course of 10 mg/kg MRT-2359 once daily, and no tumor regrowth could be detected after cessation of treatment. No significant in vivo response was observed for xenografts of the insensitive cell line PC-3. These data support the clinical investigation of MRT-2359 in prostate cancer. Citation Format: Ralph Tiedt, Martin Schillo, Arnaud Osmont, Débora Bonenfant, Rajiv Narayan, Owen Wallace, Markus Warmuth. The GSPT1 molecular glue degrader MRT-2359 is active against prostate cancer [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 3294.

Abstract 4433: Secondary electrospray ionization mass spectrometry for volatile analysis of lung cancer

Abstract Lung cancer remains a leading cause of cancer-related mortality globally, necessitating innovative approaches for early detection and improved understanding of its metabolic landscape and consequences. Secondary Electrospray Ionization Mass Spectrometry (SESI-MS), an innovative analytical technique, has emerged as a powerful tool for the analysis of volatile organic compounds (VOCs) associated with various diseases, from metabolic disorders to bacterial infections. In this proof-of-concept study, we first utilized SESI-MS analyses of four representative lung cancer cells of both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) to demonstrate its capability to profile VOCs released by lung cancer cells. The technique allows for real-time, non-invasive analysis of the headspace above cultured cells, enabling the detection of unique VOC signatures associated with different lung cancer subtypes. Meanwhile, SESI-MS also facilitated the discrimination specific cells based on distinct VOC patterns. Furthermore, we also performed cisplatin treatment experiments and observed the metabolic signature shift post drug treatment. These results collectively offered potential applications in early diagnosis and personalized treatment strategies. Next, we continued with in vivo investigations to further extend the utility of SESI-MS in lung cancer research. Animal models, mimicking human lung cancer pathophysiology, have been subjected to SESI-MS analysis to identify volatile biomarkers indicative of tumor development and progression. Several representative cancer drug treatments were performed to the lung cancer mice model, and the drug-induced responses were also monitored via SESI-MS breath analyses. The in vivo SESI-MS approach detected many interesting breath VOC features that could provide valuable insights into the dynamic changes in VOC profiles during various stages of lung cancer, and therefore has the potential to offer a deeper understanding of the disease's metabolic alterations and potential avenues for targeted therapeutic interventions. In conclusion, SESI-MS-based volatile analysis presents a robust and versatile approach for investigating lung cancer, and our ongoing work has the potential to bridge the gap between in vitro and in vivo models for better translational research outcomes. The detection of unique VOC signatures associated with lung cancer cells and tumors holds significant promise for early detection, subtype classification, and monitoring of treatment responses. As technology continues to advance, SESI-MS stands poised to play a pivotal role in transforming the landscape of lung cancer diagnostics and research. Citation Format: Jiangjiang (Chris) Zhu, Fouad Choueiry. Secondary electrospray ionization mass spectrometry for volatile analysis of lung cancer [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 4433.

Abstract 1115: Enhancing lung cancer sensitivity to chemotherapy, radiation, and chemo-radiation through inhibition of a mitotic checkpoint kinase BUB1

Abstract Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) represent two major subtypes of lung cancer, marked by challenging treatment resistance. Our study explores the inhibition of BUB1, a critical mitotic checkpoint kinase, in conjunction with radiotherapy and chemotherapy. This approach has the potential to overcome resistance, thus enhancing the efficacy of treatment and improving treatment outcomes for lung cancer patients. We analyzed BUB1 expression in lung cancer using TCGA datasets and patient tissue microarrays (TMAs). In vitro experiments used four NSCLC and two SCLC cell lines with BUB1 inhibitor (BAY1816032), Paclitaxel, Cisplatin and Olaparib. Cells were irradiated (2, 4, or 6 Gy), and assays measured proliferation, long-term effects, DNA damage, and repair. Bioinformatic analysis in NSCLC subtype, lung adenocarcinoma (LUAD) demonstrated marked overexpression of BUB1, correlated with cancer stage, tumor grade and survival. Lung cancer TMAs revealed elevated expression of BUB1 protein in SCLC that correlated with poorer survival. BUB1 inhibition (BUB1i) induced cytotoxicity in LUAD cell lines at micromolar concentrations, while nanomolar concentrations enhanced cell death significantly when combined with radiation. Furthermore, BUB1i sensitized LUAD cells to different classes of chemotherapy (Paclitaxel, Cisplatin), and PARP inhibitor (Olaparib) alone (chemo-sensitization) or with radiation therapy (chemo-radiosensitization). H2030 and H1975 demonstrated higher chemo-radiosensitization efficacy compared to A549, likely due to genetic differences, potentially including a p53 mutation that improves sensitivity by affecting DNA repair and cell cycle regulation. Preliminary investigations revealed DNA double-strand breaks, indicated by prolonged γH2AX foci, and the inhibition of the NHEJ DNA damage repair pathway after BUB1 ablation. Among SCLC cell lines, NCI-H1876 demonstrated higher radiosensitivity upon BUB1 ablation compared to NCI-H2198, potentially due to genetic differences/mutations affecting radiation response. The study highlights the potential of BUB1i in enhancing the sensitivity of NSCLC and SCLC cells to radiotherapy and chemotherapy and provide rationale to explore BUB1i as a novel approach to enhance lung cancer therapy in clinical trials. Citation Format: Shivani Thoidingjam, Sushmitha Sriramulu, Stephen L. Brown, Farzan Siddiqui, Benjamin Movsas, Shirish Gadgeel, Shyam Nyati. Enhancing lung cancer sensitivity to chemotherapy, radiation, and chemo-radiation through inhibition of a mitotic checkpoint kinase BUB1 [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 1115.

The pancancer overexpressed NFYCAntisense 1 controls cell cycle mitotic progression through in cis and in trans modes of action

Antisense RNAs (asRNAs) represent an underappreciated yet crucial layer of gene expression regulation. Generally thought to modulate their sense genes in cis through sequence complementarity or their act of transcription, asRNAs can also regulate different molecular targets in trans, in the nucleus or in the cytoplasm. Here, we performed an in-depth molecular characterization of NFYCAntisense1 (NFYC-AS1), the asRNA transcribed head-to-head to NFYC subunit of the proliferation-associated NF-Y transcription factor. Our results show that NFYC-AS1 is a prevalently nuclear asRNA peaking early in the cell cycle. Comparative genomics suggests a narrow phylogenetic distribution, with a probable origin in the common ancestor of mammalian lineages. NFYC-AS1 is overexpressed pancancer, preferentially in association with RB1 mutations. Knockdown of NFYC-AS1 by antisense oligonucleotides impairs cell growth in lung squamous cell carcinoma and small cell lung cancer cells, a phenotype recapitulated by CRISPR/Cas9-deletion of its transcription start site. Surprisingly, expression of the sense gene is affected only when endogenous transcription of NFYC-AS1 is manipulated. This suggests that regulation of cell proliferation is at least in part independent of the in cis transcription-mediated effect on NFYC and is possibly exerted by RNA-dependent in trans effects converging on the regulation of G2/M cell cycle phase genes. Accordingly, NFYC-AS1-depleted cells are stuck in mitosis, indicating defects in mitotic progression. Overall, NFYC-AS1 emerged as a cell cycle-regulating asRNA with dual action, holding therapeutic potential in different cancer types, including the very aggressive RB1-mutated tumors.

CACA guidelines for holistic integrative management of lung cancer

Lung cancer (LC) is among the malignant tumors with the highest disease burden in the world, accounting for approximately 11.4% of all cancer cases, and LC was the 2nd most common type of malignant tumor. The editing of the CACA Guidelines for Holistic Integrative Management of Lung Cancer aimed to facilitate the enhancement of lung cancer diagnosis and comprehensive treatment in China.The CACA Guidelines for Holistic Integrative Management of Lung Cancer include the epidemiology, the early detection, the comprehensive diagnosis, the treatment (including surgical, medical and radiological treatment), rehabilitation, and some general principles for both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).The main objective of this guideline is to standardize the clinical diagnosis and treatment process of lung cancer, with a specific focus on enhancing the management of this disease in China.

Understanding veterans' experiences with lung cancer and psychological distress: A multimethod approach.

Psychological distress while coping with cancer is a highly prevalent and yet underrecognized and burdensome adverse effect of cancer diagnosis and treatment. Left unaddressed, psychological distress can further exacerbate poor mental health, negatively influence health management behaviors, and lead to a worsening quality of life. This multimethod study primarily focused on understanding veterans' psychological distress and personal experiences living with lung cancer (an underrepresented patient population). In a sample of 60 veterans diagnosed with either nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC), we found that distress is common across clinical psychology measures of depression (37% [using the Patient Health Questionnaire, PHQ-9 measure]), anxiety (35% [using the Generalized Anxiety Disorder, GAD-7 measure]), and cancer-related posttraumatic stress (13% [using the Posttraumatic Stress Symptom Checklist measure]). A total of 23% of the sample endorsed distress scores on two or more mental health screeners. Using a broader cancer-specific distress measure (National Comprehensive Cancer Network), 67% of our sample scored above the clinical cutoff (i.e., ≥ 3), and in the follow-up symptom checklist of the National Comprehensive Cancer Network measure, a majority endorsed feeling sadness (75%), worry (73%), and depression (60%). Qualitative analysis with a subset of 25 veterans highlighted that psychological distress is common, variable in nature, and quite bothersome. Future research should (a) identify veterans at risk for distress while living with lung cancer and (b) test supportive mental health interventions to target psychological distress among this vulnerable veteran population. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exploring the therapeutic potential of SGLT2 inhibitors in cancer treatment: integrating in silico and in vitro investigations.

The present study aimed to investigate the anti-cancer mechanism of canagliflozin (CANA) and dapagliflozin (DAPA), sodium-glucose co-transporter-2 (SGLT2) inhibitors, using in silico and in vitro approaches. Network pharmacology was employed to predict the targets of the inhibitors and GO gene enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation conducted to explore the interacting pathways. Molecular docking and molecular dynamic (MD) simulation studies were performed to confirm the important targets and assess conformational stability. In vitro cytotoxicity assays, MIA-PaCa-2 and DU-145 cell lines CANA and DAPA was performed. Protein-protein interaction (PPI) network analysis indicated that CANA and DAPA exert anticancer effects through MAPK, mTOR, EGFR-KRAS-BRAF, FGFR, and PI3KA pathways. KEGG analysis revealed that these inhibitors could be used in the treatment of various cancers, including breast, prostate, pancreatic, chronic myeloid leukemia, thyroid, small cell lung, gastric, and bladder cancer. Docking results showed highest affinity for MAPK1 for CANA (- 9.60kcal/mol) and DAPA (- 9.58kcal/mol). MD simulation results showed that RMSD values for the MAPK1-compound exhibit remarkable stability over a timeframe of 100ns. In cytotoxicity assays using MIA-PaCa-2 and DU-145 cell lines, CANA demonstrated a potential antiproliferative effect on the pancreatic cell line MIA-PaCa-2 after 48h of treatment at a concentration of 100µg/ml. Furthermore, CANA arrested the cell cycle in the sub-G1 phase and induced late apoptosis and necrosis in MIA-PaCa-2 cell line. Based on these findings, CANA shows promise as a potential novel treatment strategy for pancreatic cancer.

Investigating the potential causal association between consumption of green tea and risk of lung cancer: a study utilizing Mendelian randomization.

Lung cancer is the most common global cancer in terms of incidence and mortality. Its main driver is tobacco smoking. The identification of modifiable risk factors isa public health priority. Green tea consumption has been examined in epidemiological studies, with inconsistent findings. Thus, we aimed to apply Mendelian randomization to clarify any causal link between green tea consumption and the risk of lung cancer. We utilized a two-sample Mendelian randomization (MR) approach. Genetic variants served as instrumental variables. The goal was to explore a causal link between green tea consumption and different lung cancer types. Green tea consumption data was sourced from the UK Biobank dataset, and the genetic association data for various types of lung cancer were sourced from multiple databases. Our analysis included primary inverse-variance weighted (IVW) analyses and various sensitivity test. No significant associations were found between green tea intake and any lung cancer subtypes, including non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma) and small cell lung cancer. These findings were consistent when applying multiple Mendelian randomization methods. Green tea does not appear to offer protective benefits against lung cancer at a population level. However, lung cancer's complex etiology and green tea's potential health benefitssuggest more research is needed. Further studies should include diverse populations, improved exposure measurements and randomized controlled trials, are warranted.

Causality Assessment Between Idiopathic Inflammatory Myopathies and Lung Cancer: A Bidirectional 2-Sample Mendelian Randomization.

Although observational studies have revealed associations between idiopathic inflammatory myopathies (IIMs) and lung cancer (LC), they have not established a causal relationship between these 2 conditions. We used a 2-sample Mendelian randomization approach to examine the bidirectional causal associations between IIMs and LC, using single-nucleotide polymorphisms selected from high-quality genome-wide association studies in the FinnGen database. Sensitivity analyses were conducted to assess potential heterogeneity and pleiotropy impacts on the Mendelian randomization results. Our analysis demonstrated a positive causal effect of genetically increased IIM risk on LC (odds ratio, 1.114; 95% confidence interval, 1.057-1.173; p = 5.63 × 10 -5 ), particularly on the lung squamous cell carcinoma subtype (odds ratio, 1.168, 95% confidence interval, 1.049-1.300, p = 0.00451), but not on lung adenocarcinoma or small cell lung cancer. No causal effect of LC on IIMs was identified. Sensitivity analyses indicated that horizontal pleiotropy was unlikely to influence causality, and leave-one-out analysis confirmed that the observed associations were not driven by a single-nucleotide polymorphism. Our findings offer compelling evidence of a positive causal relationship between IIMs and LC, particularly with regard to lung squamous cell carcinoma, in the European population. Conversely, there is no evidence of LC causing IIMs. We recommend that LC diagnosis consider the specific characteristics of IIMs.

Lineage-specific intolerance to oncogenic drivers restricts histological transformation.

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models to follow the conversion of LUAD to SCLC and found that the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells that transcriptionally resemble the pulmonary basal lineage. These findings suggest that histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.

Abstract A010: Insights into the Impact of Fanconi Anemia Repair Genes on Immunotherapy Response in Solid Tumors

Abstract Title: Insights into the Impact of Fanconi Anemia Repair Genes on Immunotherapy Response in Solid Tumors Background: Fanconi anemia repair (FAR) genes have crucial involvement in determining immunogenicity of solid tumors due to their substantial involvement in DNA damage repair (DDR). Previous work has alluded to the significance of DDR pathways such as mismatch repair and homologous recombination genes in treatment guidance. Herein, we study the potential impact of FAR genes mutations on immunotherapy parameters in solid tumors. Methods: We used the MSK immunotherapy and Tumor Mutational Burden (TMB) dataset was used in our analysis, which includes mutational and clinical data for 1661 patients on immune checkpoint inhibitors (anti-PD-1/L1, anti-CTLA-4, or combinational therapy) from ten cancer types (bladder, breast, colorectal, esophagogastric, glioma, head and neck, melanoma, non- small cell lung, renal cell, and unknown primary cancer). All clinical ang genomic data was retrieved through the cBioPortal database. Patients were categorized into the FAR mutated group if they harbored a mutation in at least one of the FAR genes (FANCA, FANCC, BRCA2, BRIP1, PALB2, RAD51C, SLX4) included in the MSK-IMPACT targeted next-generation sequencing panel. The log rank test and the Wilcoxon test, Chi-squared test were used to compare overall survival (OS), continuous and categorical data between FAR mutated and wildtype groups. Results: The MSK TMB cohort included 220 (13%) patients with FAR mutations, of which melanoma comprised the highest percentage (26.4%) followed by non-small cell lung cancer (NSCLC; 19.6%). The most common altered FAR gene was BRCA2 (6%), followed by SLX4 (5%), while the least altered gene was RAD51C (0.7%). FAR mutated patients had significantly higher OS compared to the wildtype group (median OS (mOS): 29 vs 17 months, log rank p &amp;lt; 0.001). Among melanoma patients (n = 320), there was no significant difference in OS between the mutated and FAR groups, whereas the NSCLC (n = 350) and colorectal cancer (CRC, n = 110) subgroups had significantly higher OS in the FAR mutated groups (NSCLC - mOS: 19 vs 10 months, p = 0.0256, CRC – mOS: not reached vs 13 months, p &amp;l; 0.001). TMB was significantly higher in the FAR mutated group (median TMB: 22.3 vs 5.2, p &amp;lt; 0.001). Notably, the most frequent co-mutations in the FAR mutated group included CTLA4, STK19, E2F3, CD276, MYCL. Conclusion: Our analysis highlights the potential role of FAR genes mutations in predisposing solid tumor patients to ICI benefit, specifically in NSCLC and CRC patients. Insights into the potential interactions between FAR genes and other DDR pathways as well as their impact on tumor immune microenvironment parameters are needed in future research to understand the drivers of ICI benefit in this subset of patients. Citation Format: Ahmed M. Ashour, Amro M. Al-Omari, Mohammad S. Bani Amer, Zaid R. Kamal. Insights into the Impact of Fanconi Anemia Repair Genes on Immunotherapy Response in Solid Tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A010.