A Trial of SHR-1210 in Combination With AIN457 in Patients With MSS CRC（SHR-1210-AIN457）
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2332316 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Targeted therapies for advanced microsatellite stable (MSS) subtypes of colorectal cancer (CRC) continue to present significant clinical challenges. Death receptor 5 (DR5/TRAIL-R2) is an apoptotic receptor frequently overexpressed in various cancers. Evidence suggests that DR5-targeting antibody drug conjugates (ADC) show promising efficacy in several cancers. In this study, we demonstrated DR5 as a clinically significant target for CRC by analyzing tissue microarrays from advanced CRC cohorts (473 MSS cases and 36 MSI-H cases), as well as data from a TCGA cohort comprising 418 cases. Our novel clinical-stage DR5-targeting ADC, Oba01, designed to deliver the microtubule-disrupting agent MMAE, shows superior therapeutic efficacy across various CRC cell lines, patient-derived xenografts (PDXs), and corresponding organoids (PDXOs), regardless of their MSS or MSI-H status. Importantly, our functional RNAseq and proteomic analysis of the impact of Oba01 on global gene expression revealed that the cell cycle pathway and cyclin-dependent kinases (CDKs) are mechanistically synergistic targets of the drug's effects. Supporting this idea, we presented solid evidence to show Oba01 and abemaciclib, a FDA-approved CDK4/6 inhibitor for metastatic breast cancer, substantially synergize across various clinically relevant models derived from advanced CRC patients with both MSS and MSI-H status, in both in vitro and in vivo settings. The fact that this synergy spans multiple CDK inhibitors further highlights the potential of combining DR5-mediated delivery of MMAE with CDK inhibition as a novel therapeutic strategy for advanced CRC patients, especially those with the challenging to treat MSS subtype.
2025-04-24 | GSE289746 | GEO
Project description:Targeted therapies for advanced microsatellite stable (MSS) subtypes of colorectal cancer (CRC) continue to present significant clinical challenges. Death receptor 5 (DR5/TRAIL-R2) is an apoptotic receptor frequently overexpressed in various cancers. Evidence suggests that DR5-targeting antibody drug conjugates (ADC) show promising efficacy in several cancers. In this study, we demonstrated DR5 as a clinically significant target for CRC by analyzing tissue microarrays from advanced CRC cohorts (473 MSS cases and 36 MSI-H cases), as well as data from a TCGA cohort comprising 418 cases. Our novel clinical-stage DR5-targeting ADC, Oba01, designed to deliver the microtubule-disrupting agent MMAE, shows superior therapeutic efficacy across various CRC cell lines, patient-derived xenografts (PDXs), and corresponding organoids (PDXOs), regardless of their MSS or MSI-H status. Importantly, our functional RNAseq and proteomic analysis of the impact of Oba01 on global gene expression revealed that the cell cycle pathway and cyclin-dependent kinases (CDKs) are mechanistically synergistic targets of the drug's effects. Supporting this idea, we presented solid evidence to show Oba01 and abemaciclib, a FDA-approved CDK4/6 inhibitor for metastatic breast cancer, substantially synergize across various clinically relevant models derived from advanced CRC patients with both MSS and MSI-H status, in both in vitro and in vivo settings. The fact that this synergy spans multiple CDK inhibitors further highlights the potential of combining DR5-mediated delivery of MMAE with CDK inhibition as a novel therapeutic strategy for advanced CRC patients, especially those with the challenging to treat MSS subtype.
2025-04-24 | GSE288560 | GEO
Project description:This is a Phase Ib/II , Open-label , Investigator-initiated Trail of SHR-1210 (an Anti-PD-1 Inhibitor) in Combination With SHR6390 (a CDK4/6 Inhibitor) in Patients With Advanced Colorectal Cancer, Non-small Cell Lung Cancer and Hepatocellular Carcinoma.
The study was designed in two stages, the first stage was the tolerance observation stage, and the second stage was the curative effect expansion stage.
The first part of the study is the Dose-finding Phase designed to establish the safety of SHR-1210 Combination With SHR6390 at different dose Levels(150mg QD or 100mg QD ). The second part of the study is the Expansion Phase designed to generate additional clinical data at specified doses .
This study aims to evaluate the safety and efficacy of SHR-1210 combination with SHR6390 in the treatment of advanced CRC,NSCLC and HCC.
| 2278800 | ecrin-mdr-crc
Project description:The goal was to identify gene expression signatures predictive of early relapse among stage IIA/MSS colon cancer patients. A secondary question addressed was whether the invasion front profiles could generate a competitive signature. 39 whole tumor and 35 matched invasion front profiles were generated (4 samples failed) and grouped into \\"early relapse\\" (relapse within 5 years) and \\"no relapse\\" (no relapse for at least 6 years) categories.
2024-03-25 | E-MTAB-13695 | biostudies-arrayexpress
Project description:Arabidopsis thaliana SHR, SHR [Source:UniProtKB/TrEMBL;Acc:A0A178UYJ6], is differentially expressed in 67 experiment(s);
| AT4G37650 | ExpressionAtlas
Project description:Arabidopsis thaliana SHR, SHR [Source:UniProtKB/TrEMBL;Acc:A0A178UYJ6], is expressed in 15 baseline experiment(s);
| AT4G37650 | ExpressionAtlas
Project description:Transcriptional profiling in the shoot after SHR induction by DEX. We used Affymetrix ATH1 microarrays to identify new target genes of SHR and the effect of SHR on growth and development of the Arabidopsis shoot system by global transcriptome analysis.
2014-11-12 | GSE63207 | GEO
Project description:The goals of this study is to compare the differently expressed genes in abdominal aorta tissue of WKY and SHR as well as differently expressed genes in the abdominal aorta tissue of SHR with or without neferine treatment. The rat (n=15) were randomly divided into 3 groups: WKY,SHR, and SHR + neferine - H (high concentration) groups (n=6 for each group). Rat in WKY and SHR groups were intragastrically with double distilled water (dd H2O); while rat in SHR + SHR + neferine - H groups were intragastrically with 10mg/kg/D of neferine for 10 weeks. Then the abdominal aorta were used to identify differentially expressed genes among different groups.
2022-10-06 | GSE214655 | GEO
Project description:Clinical Significance: Understanding the differences in colorectal cancer (CRC) aggressiveness and clinical outcomes in relation to tumor stage and different molecular subsets is at most important for designing treatment regimens. However, molecular signatures for specific phenotypic subsets that predict the aggressiveness and clinical outcomes of CRC, specifically in advanced disease stage are lacking. Therefore, for the first time, the current study has identified a set of molecular markers that are associated with aggressive Stage III CRCs that exhibited microsatellite stable and mutant p53 phenotypic features. These findings might aid in designing aggressive treatment regimens and help to provide insights into the development of novel therapeutic targets. Results: Increased incidence of p53 mutations in MSS CRCs (58%) was associated with higher CRC-specific mortality than MSS-p53 wild-type phenotypes (log-rank, P=0.025; and hazard ratio, 2.52; 95% confidence interval, 1.25-5.08). Of 49 down-regulated genes, LPAR6, PDLIM3 and PLAT and of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8, were confirmed by qNPA, qRT-PCR, and IHC platforms. Conclusions: p53 mutations are associated with poor prognosis of Stage III microsatellite stable CRCs. p53 wild type vs. mutant tumor samples
2012-01-26 | E-GEOD-27157 | biostudies-arrayexpress
Project description:Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC) (Picard et al., 2020). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORgt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51 by ketoconazole, a clinically approved drug, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel immune-modulation mechanism of oncometabolites and an invention strategy for the difficult-to-treat MSS CRC.
2023-12-02 | GSE249124 | GEO