Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers.
TL;DR: In this paper, the potential clinical utility of SLFN11 in the treatment of gastric cancer was investigated and the correlation between SLFN 11 expression and overall survival in 169 GC patients by an established immunohistochemical approach.
Abstract: Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression
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TL;DR: Schlafen 11 (SLFN11) is a putative DNA/RNA helicase that induces irreversible replication block, which is emerging as an important regulator of cellular response to DNA damage as mentioned in this paper.
Abstract: DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors respond well to these treatments, suggesting additional determinants of response are required. Schlafen 11 (SLFN11), a putative DNA/RNA helicase that induces irreversible replication block, is emerging as an important regulator of cellular response to DNA damage. Preclinical and emerging clinical trial data suggest that SLFN11 is a predictive biomarker of response to a wide range of therapeutics that cause DNA damage including platinum salts and topoisomerase I/II inhibitors, as well as PARP inhibitors, which has raised exciting possibilities for its clinical application. In this article, we review the function, prevalence, and clinical testing of SLFN11 in tumor biopsy samples and circulating tumor cells. We discuss mounting evidence of SLFN11 as a key predictive biomarker for a wide range of cancer therapeutics and as a prognostic marker across several cancer types. Furthermore, we discuss emerging areas of investigation such as epigenetic reactivation of SLFN11 and its role in activating immune response. We then provide perspectives on open questions and future directions in studying this important biomarker.
16 citations
12 Aug 2021
TL;DR: In this paper, a case of neuroendocrine prostate cancer (NEPC) with significant intra-patient heterogeneity observed across metastases was highlighted. And the authors further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.
Abstract: Neuroendocrine prostate cancer is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. The combined loss of tumor suppressors RB1, TP53, and PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.
14 citations
TL;DR: The cryo-EM structure of full-length human Schlafen 5 and the high-resolution crystal structure of the highly conserved N-terminal core domain show that the core domain does not resemble an ATPase-like fold and neither binds nor hydrolyzes ATP.
Abstract: Abstract The Schlafen family belongs to the interferon-stimulated genes and its members are involved in cell cycle regulation, T cell quiescence, inhibition of viral replication, DNA-repair and tRNA processing. Here, we present the cryo-EM structure of full-length human Schlafen 5 (SLFN5) and the high-resolution crystal structure of the highly conserved N-terminal core domain. We show that the core domain does not resemble an ATPase-like fold and neither binds nor hydrolyzes ATP. SLFN5 binds tRNA as well as single- and double-stranded DNA, suggesting a potential role in transcriptional regulation. Unlike rat Slfn13 or human SLFN11, human SLFN5 did not cleave tRNA. Based on the structure, we identified two residues in proximity to the zinc finger motif that decreased DNA binding when mutated. These results indicate that Schlafen proteins have divergent enzymatic functions and provide a structural platform for future biochemical and genetic studies.
13 citations
TL;DR: In this article, the authors provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.
Abstract: Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.
12 citations
TL;DR: Schlafens (SLFN) as mentioned in this paper are a family of genes widely expressed in mammals, including humans and rodents, which play different roles in regulating cell proliferation, cell differentiation, immune cell growth and maturation, and inhibiting viral replication.
Abstract: Schlafens (SLFN) are a family of genes widely expressed in mammals, including humans and rodents. These intriguing proteins play different roles in regulating cell proliferation, cell differentiation, immune cell growth and maturation, and inhibiting viral replication. The emerging evidence is implicating Schlafens in cancer biology and chemosensitivity. Although Schlafens share common domains and a high degree of homology, different Schlafens act differently. In particular, they show specific and occasionally opposing effects in some cancer types. This review will briefly summarize the history, structure, and non-malignant biological functions of Schlafens. The roles of human and mouse Schlafens in different cancer types will then be outlined. Finally, we will discuss the implication of Schlafens in the anti-tumor effect of interferons and the use of Schlafens as predictors of chemosensitivity.
8 citations
References
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TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
Abstract: Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).
24,414 citations
TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Abstract: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
6,417 citations
TL;DR: A comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project is described and a molecular classification dividing gastric cancer into four subtypes is proposed.
Abstract: Gastric cancer was the world’s third leading cause of cancer mortality in 2012, responsible for 723,000 deaths1. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification2. An alternative system, proposed by the World Health Organization, divides gastric cancer into papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas3. These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority.
The majority of gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori4 and Epstein–Barr virus (EBV). The distribution of histological subtypes of gastric cancer and the frequencies of H. pylori and EBV associated gastric cancer vary across the globe5. A small minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1)6 or mismatch repair genes7 (Lynch syndrome), whereas sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP)8. Molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing9–12, but has not led to a clear biologic classification scheme. The goals of this study by The Cancer Genome Atlas (TCGA) were to develop a robust molecular classification of gastric cancer and to identify dysregulated pathways and candidate drivers of distinct classes of gastric cancer.
4,583 citations
TL;DR: Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
Abstract: Summary Background Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. Methods In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m 2 per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French–American–British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Findings Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21·1 months (IQR 15·1–26·9), median overall survival was 24·5 months (9·9–not reached) for the azacitidine group versus 15·0 months (5·6–24·1) for the conventional care group (hazard ratio 0·58; 95% CI 0·43–0·77; stratified log-rank p=0·0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50·8% (95% CI 42·1–58·8) of patients in the azacitidine group were alive compared with 26·2% (18·7–34·3) in the conventional care group (p Interpretation Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care. Funding Celgene Corporation.
2,282 citations
Paris Diderot University1, Peter MacCallum Cancer Centre2, Wrocław Medical University3, Medical University of Łódź4, Samsung Medical Center5, National Health Service6, Princess Margaret Cancer Centre7, Centre Hospitalier Universitaire de Toulouse8, University of Alberta Hospital9, Spanish National Research Council10, Harvard University11, Celgene12
TL;DR: Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features, and adverse events were consistent with the well-established safety profile of azacItidine.
902 citations