SCLC-J1, a novel small cell lung cancer cell line.
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ABSTRACT:
SUBMITTER: Ohara K
PROVIDER: S-EPMC8339127 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.
| S-EPMC7643325 | biostudies-literature
Project description:Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC.
| S-EPMC8024350 | biostudies-literature
Project description:Small cell lung cancer (SCLC) is an aggressive malignancy with a distinct natural history and dismal prognosis. Given its predisposition for early dissemination, patients are commonly diagnosed with metastatic disease and chemotherapy is regarded as the cornerstone of approved treatment strategies. However, over the last 30 years there has been a distinct paucity of significant breakthroughs in SCLC therapy. Thus, SCLC is characterized as a recalcitrant neoplasm with limited therapeutic options. By employing well-established research approaches, proven to be efficacious in non-small cell lung cancer (NSCLC), a growing amount of data has shed light on the molecular biology of SCLC and enhanced our knowledge of the "drivers" of tumor cell survival and proliferation. New therapeutic targets have emerged, but no significant improvement in patients' survival has been demonstrated thus far. In a sense, the more we know, the more we fail. Nowadays this is starting to change and methodical research efforts are underway. It is anticipated that the next decade will see a revolution in the treatment of SCLC patients with the application of effective precision medicine and immunotherapy strategies.
| S-EPMC4758968 | biostudies-literature
Project description:Small cell lung cancer (SCLC) remains one of the most lethal malignancies and a major health riddle. The therapeutic options are limited. The combination of etoposide or irinotecan with platinum chemotherapy is the standard of care at any stage. The last decade systemic efforts have been done to reveal specific therapeutic targets for small cell lung carcinomas. In this review, we focus on the new therapeutic strategies of SCLC, including immune-related treatment that may change the prognosis of the disease. The main genetic mutations observed in SCLC are TP53 and RB1 mutations; however, it is well known that these molecules are not yet targetable. In recent years, research has revealed other frequent genetic alterations and activated signaling pathways that might be an effective treatment target. Loss of PTEN, activating PI3K mutations, inhibition of NOTCH pathway and aurora kinase activation are among them. Moreover, FDGFR1 amplification, activation of the Hedgehog pathway and repair-protein PARP1 seem to participate in SCLC tumorigenesis. These new findings have identified some interesting targets. Moreover, immunotherapy tries to find its place in the treatment of SCLC. Immune checkpoint inhibitors are under investigation in phase I to III clinical trials. We hope that in next years the treatment of SCLC patients will be improved with the administration of targeting therapy and the introduction of immunotherapy.
| S-EPMC5952028 | biostudies-literature
Project description:There are few effective therapies for small cell lung cancer (SCLC), a highly aggressive disease representing 15% of total lung cancers. With median survival <2 years, SCLC is one of the most lethal cancers. At present, chemotherapies and radiation therapy are commonly used for SCLC management. Few protein-targeted therapies have shown efficacy in improving overall survival; immune checkpoint inhibitors (ICIs) are promising agents, but many SCLC tumors do not express ICI targets such as PD-L1. This article presents an alternative approach to the treatment of SCLC: the use of drug conjugates, where a targeting moiety concentrates otherwise toxic agents in the vicinity of tumors, maximizing the differential between tumor killing and the cytotoxicity of normal tissues. Several tumor-targeted drug conjugate delivery systems exist and are currently being actively tested in the setting of SCLC. These include antibody-drug conjugates (ADCs), radioimmunoconjugates (RICs), small molecule-drug conjugates (SMDCs), and polymer-drug conjugates (PDCs). We summarize the basis of action for these targeting compounds, discussing principles of construction and providing examples of effective versus ineffective compounds, as established by preclinical and clinical testing. Such agents may offer new therapeutic options for the clinical management of this challenging disease in the future.
| S-EPMC6769513 | biostudies-literature
Project description:IntroductionThe survival of patients with relapsed small cell lung cancer (SCLC) has achieved little progress in the last several decades. ALTER1202 confirmed the efficacy and safety of anlotinib as a third- or further-line option for relapsed SCLC. This study aimed to assess the cost-effectiveness of anlotinib compared with placebo as third- or further-line treatment for advanced SCLC in China.MethodsA Markov model was developed to simulate the process of advanced SCLC and estimate the incremental cost-effectiveness ratio (ICER) of anlotinib versus placebo. The health outcomes and utilities were derived from the ALTER1202 (NCT03059797) and published sources, respectively. Total costs were calculated from the perspective of Chinese society. One-way and probabilistic sensitivity analyses (PSA) were conducted to explore the model uncertainties.ResultsAnlotinib was estimated to result in an additional 0.12 quality-adjusted life-years (QALYs) at an incremental cost of $2131.32, resulting in an ICER of $17,741.94/QALY. The ICER did not exceed the willingness-to-pay (WTP) threshold of $30,833 per QALY, which was three times the gross domestic product (GDP) per capita of China in 2019. One-way sensitivity analysis showed that the cost of anlotinib exerted the maximum influence on the result of the model, followed by the utility of progression-free survival (PFS) state in the anlotinib group and median overall survival (mOS) in the anlotinib group. In PSA, the probability of anlotinib being cost-effective was 26.6% and 78.5% when the WTP threshold was one and three times the GDP per capita, respectively.ConclusionAnlotinib is likely to be a cost-effective option compared with placebo for patients with relapsed SCLC who experience failure of at least two lines of chemotherapy in China.
| S-EPMC8379562 | biostudies-literature
Project description:ImportanceAlthough stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited.ObjectiveTo characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT.Design, setting, and participantsFIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019.InterventionsSRS and WBRT for small cell lung cancer brain metastases.Main outcomes and measuresOverall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses.ResultsIn total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results.Conclusions and relevanceResults of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.
| S-EPMC7273318 | biostudies-literature
Project description:The American Cancer Society estimates that ~15% of all lung cancers are categorized as small cell lung cancer (SCLC) with an overall five-year survival rate of less than 7%. Due to disease aggressiveness, more other malignancies, the standard of care is based on clinical efficacy rather than helpful biomarkers. Lurbinectedin is a small molecule RNA polymerase II inhibitor that binds the minor groove of DNA to induce double-strand breaks. Lurbinectedin has efficacy towards SCLC cells at sub-nM concentration and received accelerated FDA approval in 2020 for metastatic SCLC that progressed on platinum-based therapy. ONC201/TIC10 is a TRAIL pathway-inducing compound that with demonstrated clinical efficacy in H3K27M-mutated diffuse midline glioma and neuroendocrine tumors, in early phase clinical trials. We hypothesized that combining ONC201 and lurbinectedin may yield synergistic and targeted killing of SCLC cells. SCLC cell lines H1048, H1105, H1882, and H1417 were treated with ONC201 and lurbinectedin and cell viability was determined using a CellTiter-Glo assay using varying drug concentrations. Synergistic growth inhibition of SCLC cells was noted with combination of ONC201 and lurbinectedin. Induction of the integrated stress response mediator ATF4 and CHOP was observed with ONC201 and lurbinectedin along with induction of PARP cleavage indicative of apoptosis in response to cellular stress. Additionally, SCLC lines treated with the combination therapy displayed increased DNA breakage-related proteins such as phosphorylated Chk-1, Wee1 and γ-H2AX. Combination index revealed the most potent synergy occurred at the concentrations of 0.16 μM ONC201 and 0.05 nM lurbinectedin in the H1048 cell line, demonstrating highly efficient and selective killing of these tumor cells in vitro. While these therapies showed potency against the cell lines derived from SCLC patients, it is noteworthy that the combination showed significantly less toxicity to healthy human lung epithelial cells. Future studies could explore the combination of ONC201 and lurbinectedin in SCLC cell lines, SCLC patient-derived organoids, other tumor types, including in vivo studies and clinical translation.
| S-EPMC8900004 | biostudies-literature
Project description:Differences in gene expression profiles regarding the expression of genes encoding for proteins with G protein-coupled receptor (GPCR) activity between SCLC and NSCLC and normal lung samples was successfully examined. In the present study, 8 SCLC, 16 NSCLC and 14 normal lung RNA samples (human) had been purchased from OriGene Technologies. Gene expression analysis was performed using Affymetrix microarrays (Human Exon 1.0 ST Array).
| S-ECPF-GEOD-40275 | biostudies-other
Project description:Small-cell lung cancer (SCLC) accounts for 13-15% of all new lung cancer cases in the US. The tumor has a tendency to disseminate early resulting in 80-85% of patients being diagnosed with extensive disease (ES-SCLC). Chemotherapy has provided SCLC patients considerable survival benefits over the past three decades. Nonetheless, most patients relapse and rarely survive beyond 2 years. Despite consistent overall response rates of ?50%, until recently, median survival times and 2-year survivals only ranged between 7-10 months and 10-20%, respectively. Several chemotherapy agents possess activity against SCLC, both, as single agents and in combinations but etoposide-platinum emerged as the preferred first line regimen. Upon relapse, many patients remain candidates for additional therapy. However, the sensitivity of relapsed SCLC to further therapies is markedly reduced and dependent upon the level and duration of response to the initial treatment (platinum-sensitive vs. resistant relapse). Multiple factors suggest a therapeutic role for immunotherapy in SCLC: SCLC has been associated with immune-mediated paraneoplastic processes (cerebellar degeneration, limbic encephalitis, and Lambert-Eaton syndrome) and patients presenting with these paraneoplastic syndromes have shown more favorable outcomes, suggesting an underlying immune response mechanism.Comprehensive genomic profiling of SCLC indicates that the majority lack functional p53 (90%) and Rb1 (65%). These universal genetic aberrations facilitate poor genomic stability, thus perpetuating the generation of tumor associated antigens, amenable to targeting with immunotherapy.SCLC has one of the highest mutational loads, likely a reflection of the myriad of insults inflicted by smoking-related carcinogens. The relationship between tumor mutational load and response to immune checkpoint inhibitors has been established in multiple solid tumors, including preliminary results in relapsed SCLC. In this manuscript, we review the early (some failed and discontinued, some partly successful, and still ongoing) attempts to incorporate immunotherapy (particularly vaccine based approaches) to the treatment of SCLC, and the latest attempts (mostly incorporating the use of checkpoint inhibitors), including those with favorable but preliminary results (CheckMate 032, Keynote 028 and 158), and those with more definitive positive (iMpower 133 and CASPIAN) and negative (CheckMate 331 and 451) results.
| S-EPMC7378389 | biostudies-literature