GSE137749 scRNA-seq of two triple knockout SCLC mouse models for subtyping

Contributors : Vito Quaranta ; Julien SageSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusAdopting a systems approach, we devise a general workflow to define actionable subtypes in human cancers. Applied to small cell lung cancer (SCLC), the workflow identifies four subtypes based on global gene expression patterns and ontologies. Three correspond to known subtypes, while the fourth is a previously undescribed neuroendocrine variant (NEv2). Tumor deconvolution with subtype gene signatures shows that all of the subtypes are detectable in varying proportions in human and mouse tumors. To understand how multiple stable subtypes can arise within a tumor, we infer a network of transcription factors and develop BooleaBayes, a minimally-constrained Boolean rule-fitting approach. In  silico perturbations of the network identify master regulators and destabilizers of its attractors. Specific to NEv2, BooleaBayes predicts ELF3 and NR0B1 as master regulators of the subtype, and TCF3 as a master destabilizer. Since the four subtypes exhibit differential drug sensitivity, with NEv 2 consistently least sensitive, these findings may lead to actionable therapeutic strategies that consider SCLC intratumoral heterogeneity. Our systems-level approach should generalize to other cancer types.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research

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Authors: Simeone E, Grimaldi AM, Festino L, Trojaniello C, Vitale MG, Vanella V, Curvietto M, Ascierto PA Abstract Introduction: Treatment of extensive-stage SCLC is still a challenge but immunotherapy with checkpoint inhibitors is showing promising results. Nivolumab alone or in combination with ipilimumab has demonstrated a benefit in terms of response and survival in patients with pre-treated extensive stage disease and has been approved as third-line therapy after failure of chemotherapy. However, data from two phase III trials with nivolumab are negative. In the first trial, nivolumab was administered as singl...
Source: Expert Review of Respiratory Medicine - Category: Respiratory Medicine Tags: Expert Rev Respir Med Source Type: research
geer Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancers. The prognosis is poor with median survival in the advanced stage remaining at around 12 months. Despite applying every known therapeutic approach, no major breakthrough has improved the overall survival in the last 30 years. Historically, experiments performed on conventional cell lines may have limitations of not accurately reflecting the complex biological and genomic heterogeneity of this disease. However, additional knowledge gained from recently developed genetically engineered mouse models (GEMMs) and patient deriv...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) are aggressive neuroendocrine tumors with poor survival rates [1 –3]. For stage IV SCLC, treatment has not advanced significantly over the last decades and consists of palliative chemotherapy. The same applies to stage IV LCNEC, were no standard treatment exists and palliative chemotherapy with SCLC and non-small cell lung cancer (NSCLC) regimens are both deeme d appropriate [4]. Recently, targeted therapy focusing on delta like protein 3 (DLL3) has received attention to improve outcomes for SCLC and LCNEC [5].
Source: Lung Cancer - Category: Cancer & Oncology Authors: Source Type: research
Purpose of review The current article reviews the state of art of prevention strategies for brain metastases from solid tumors and touches both old pivotal studies and new directions of personalized molecular approaches. Recent findings Prophylactic cranial irradiation (PCI) has a definite role in the prevention of relapse into the brain for patients with small cell lung cancer (SCLC) responding to chemotherapy and radiotherapy as it prolongs overall survival (OS). However, the risk of late cognitive deficit following whole brain radiotherapy (WBRT) in this patient population is still not well known. Conversely, PCI s...
Source: Current Opinion in Oncology - Category: Cancer & Oncology Tags: BRAIN AND NERVOUS SYSTEM: Edited by Marc Sanson Source Type: research
Conclusions: Total FAK and activated FAK expressions are significantly higher in lung cancer than in normal lung, and significantly higher in SCLC compared to NSCLC, but are not prognostic biomarkers in this study.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing.FindingsPatients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum–etoposide group and 269 to the platinum–etoposide group. Durvalumab plus platinum–etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumab plus platinum–etoposide group versus 10&m...
Source: The Lancet - Category: General Medicine Source Type: research
Publication date: 3 October 2019Source: Cell, Volume 179, Issue 2Author(s): Youcef Ouadah, Enrique R. Rojas, Daniel P. Riordan, Sarah Capostagno, Christin S. Kuo, Mark A. KrasnowSummaryPulmonary neuroendocrine (NE) cells are neurosensory cells sparsely distributed throughout the bronchial epithelium, many in innervated clusters of 20–30 cells. Following lung injury, NE cells proliferate and generate other cell types to promote epithelial repair. Here, we show that only rare NE cells, typically 2–4 per cluster, function as stem cells. These fully differentiated cells display features of classical stem cells. Mos...
Source: Cell - Category: Cytology Source Type: research
This study explored whether surgery offered a survival benefits for patients with SCLC. Patients diagnosed with SCLC between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The tumor, node, and metastasis (TNM) stage of SCLC in these patients was reclassified according to the 8th edition of the TNM classification for lung cancer. Overall survival (OS) was separately compared according to TNM stage between patients who underwent surgery and those who did not using Kaplan–Meier method. A Cox regression model was used to identify relevant variables affecting survival. A...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
AbstractBackgroundIn the phase III CASPIAN trial, durvalumab (D) in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved the primary endpoint of OS vs EP alone in pts with extensive-stage small-cell lung cancer (ES-SCLC). Here we describe clinically relevant analyses for D + EP vs EP based on PD-L1 expression, progression patterns and PROs.MethodsTx-naive ES-SCLC (WHO PS 0/1) pts received 4 cycles of EP plus D q3w followed by maintenance D q4w or up to 6 cycles of EP q3w + prophylactic cranial irradiation (PCI; investigator ’s discretion). PD-L1 expression in optional archival t...
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
ConclusionsQuantifying CT density change within irradiated lung parenchyma may offer a novel approach to predict radiation associated pulmonary toxicities. Measuring density changes across patient cohorts receiving TRT with novel systemic therapies may help to identify combined treatment strategies likely to be associated with diminished risk of toxicity.Legal entity responsible for the studyThe authors.FundingBristol-Myers Squibb.DisclosureS. Kim: Research grant / Funding (institution): Bristol-Myers Squibb. S.A. Rosenberg: Advisory / Consultancy: Novocure. J.E. Gray: Honoraria (self), Advisory / Consultancy, Research gra...
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
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