Combined therapy with DR5- targeting antibody-drug conjugate and CDK inhibitors as a novel strategy for advanced MSS and MSI-H colorectal cancer
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PROVIDER: PRJNA1224440 | ENA |
REPOSITORIES: ENA
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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 | GSE288560 | 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 | GSE289746 | GEO
Project description:Combined therapy with DR5- targeting antibody-drug conjugate and CDK inhibitors as a novel strategy for advanced MSS and MSI-H colorectal cancer
| PRJNA1218435 | ENA
Project description:Expression profiling was used to identify genes differentially expressed in MSS (microsatellite stable) and MSI (microsatellite unstable) colon cancer cell lines. Data submitted in support of manuscript entitled Villin expression is frequently lost in poorly differentiated colon cancer, Diego Arango, Sheren Al-Obaidi, David S. Williams, Jose Dopeso, Rocco Mazzolini, Georgia Corner, Do-Sun Byun, Carmel Murone, Lars Tögel, Nikolajs Zeps, Lauri A. Aaltonen, Barry Iacopetta and John M. Mariadason, American Journal of Pathology, 2012. 5 microsatellite stable (MSS) and 5 microsatellite unstable (MSI) colon cancer cell lines profiled. Each cell line grown and arrayed in duplicate, and the duplicates averaged for each cell line before calculating means for MSS and MSI lines.
2012-02-07 | E-GEOD-35566 | biostudies-arrayexpress
Project description:Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response. Experiment Overall Design: Genes differentially expressed between MSI and MSS tumours were identified as follows: (i) gene probe sets were pre-selected for being flagged as ‘PRESENT’ in at least 10 tumour samples (21,324 probe sets); (ii) the probe set signal values on the pre-selected probe sets were used to run a t-test between the two types of tumour samples; (iii) the false discovery rate (FDR) method was applied to the t-test calculated p-values to correct for multiple testing and (iv) a false discovery rate <0.05 and a t-test p-value < 0.01 were chosen as threshold criteria to identify the genes differentially expressed in tumours with and without MSI
2009-01-03 | E-GEOD-13911 | biostudies-arrayexpress
Project description:Expression profiling was used to identify genes differentially expressed in MSS (microsatellite stable) and MSI (microsatellite unstable) colon cancer cell lines. Data submitted in support of manuscript entitled Villin expression is frequently lost in poorly differentiated colon cancer, Diego Arango, Sheren Al-Obaidi, David S. Williams, Jose Dopeso, Rocco Mazzolini, Georgia Corner, Do-Sun Byun, Carmel Murone, Lars Tögel, Nikolajs Zeps, Lauri A. Aaltonen, Barry Iacopetta and John M. Mariadason, American Journal of Pathology, 2012.
2012-02-07 | GSE35566 | GEO
Project description:Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response.
2008-12-18 | GSE13911 | GEO
Project description:Gastric cancer (GC) is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvement, the clinical outcome for patients with advanced GC is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multi-level platform of GC models, comprising 100 Patient-derived xenografts (PDXs), primary cell lines and organoids. Samples were classified according to their histology, microsatellite stability (MS) and Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution and it includes all the GC histologic and molecular types identified by TCGA. PDX histopathological features were consistent with those of patients’ primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number variation of tyrosine kinases/KRAS genes and MSI status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell intrinsic MSI signature, which was efficiently exported to gastric cancer, allowing the identification -among MSS patients- of a subset of MSI-like tumors with common molecular assets and significant better prognosis. We generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel 'druggable' targets and define the best therapeutic strategies. Moreover, transcriptomic analysis of GC PDXs allowed the identification of a cancer cell intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.
2019-10-15 | GSE128459 | GEO
Project description:We compared the expression of genes related to inflammatory cytotoxic functions between MSI and MSS (HLA class I negative and positive) gastrointestinal adenocarcinomas (GIACs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two GIACs were divided into three study groups as a function of HLA class I expression and MSI phenotype. Comparison between eight high-level MSI (MSI-H) and 8 MSS/HLA+ (control) cancers identified 2170 differentially expressed genes (p< 0.05) after microarray analysis on the Affymetrix HG-U133-Plus-PM plate. We grouped genes in Gene Ontology functional categories: apoptotic programme (119 genes, p=5.1·10-7), leukocyte activation (32 genes, p=0.01), T cell activation (20 genes, p= 0.01), and cytokine production (19 genes, p= 0.04). Real-time RT-PCR and immunohistochemical evaluation were used to confirm some microarray data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+ T lymphocytes in the MSI-H group (p<0.001). Finally, tumours with immunohistochemical HLA class I negative pattern were not grouped together but rather in accordance with features of the gene expression profile of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-ABC negative CRCs. In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and differentiate MSI from MSS cancers. The two types of tumours, MSI/HLA- and MSS/HLA-, showed marked differences in the composition and intensity of infiltrating leukocytes, suggesting that their immune escape strategies involve distinct pathways. Case-control study. Samples were selected according to immunological criteria: those with total loss of HLA antigens and those without alterations in the expression of HLA molecules. In addition, the microsatellite instability genotype of all the samples was also analyzed, resulting in microsatellite stability (MSS) and microsatellite instability (MSI) samples. Therefore, three groups of samples were selected: MSS/HLA+, MSS/HLA-, and MSI. The MSS/HLA+ group was used as the control.
2011-02-28 | E-GEOD-27544 | biostudies-arrayexpress
Project description:MSI analysis using blood-derived MSI markers
| PRJEB53321 | ENA