A Molecular Profile of Colorectal Cancer to Guide Therapy [HMEC]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE51242 | GEO | 2016/12/31
SECONDARY ACCESSION(S): PRJNA221801
REPOSITORIES: GEO
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Project description:The ability to dissect heterogeneity in colorectal cancer (CRC) is a critical step in developing predictive biomarkers. The goal of this study was to develop a gene expression based molecular subgrouping model, which predicts the likelihood that patients will respond to specific therapies. Using microarray data compiled from 848 CRC patients, we developed a subgrouping model based on 23 activated oncogenic pathway expression signatures. Stability of the model was validated in two independent data sets. To test the capacity of our model to predict patient response to specific targeted therapies and to determine the sensitivity of the subgroups to chemotherapy in vivo, we treated patient-derived colorectal cancer explants (PDCCEs) predicted to have high mTOR pathway activity with everolimus or oxaliplatin. Results: A molecular profile of the discovery dataset revealed 8 molecular subgroups of colorectal cancer (MSCC). Both validation sets also exhibited 8 MSCC and demonstrated significant similarities to the discovery dataset. MSCC predicted to have active mTOR pathway signaling were more sensitive to everolimus compared to MSCC predicted to have low mTOR pathway activity (p=0.016). Furthermore, MSCCs displayed differential sensitivities to oxaliplatin (p<0.05). The ability to predict oncogenic signaling pathway activation is a powerful tool that may be used to sub-classify CRCs into clinically relevant MSCCs. Patterns of pathway activation may be used to target specific therapies in CRC patients and identification of sensitivities of MSCC to specific drugs can be a powerful approach to guide therapy for CRC patients.
2016-12-31 | GSE41568 | GEO
Project description:<p>One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.</p>
| phs000535 | dbGaP
Project description:Glomerular podocytes are highly differentiated cells that are key components of the kidney filtration units. The podocyte cytoskeleton builds the basis for the dynamic podocyte cytoarchitecture and plays a central role for proper podocyte function. Recent studies implicate that immunosuppressive agents including the mTOR-inhibitor everolimus have a protective role directly on the stability of the podocyte cytoskeleton. To elucidate mechanisms underlying mTOR-inhibitor mediated cytoskeletal rearrangements, we carried out microarray gene expression studies to identify target genes and corresponding pathways in response to everolimus. We analyzed the effect of everolimus in a puromycin aminonucleoside experimental in vitro model of podocyte injury. Upon treatment with puromycin aminonucleoside, microarray analysis revealed gene clusters involving cytoskeletal-associated pathways, adhesion, migration and extracellular matrix composition to be affected. Everolimus is capable of protecting podocytes from injury, both on the transcriptome and protein level. Rescued genes included TUBB2B and DCDC2, both involved in microtubule structure formation in neuronal cells but not identified in podocytes so far. Confirming gene expression data, Western-blot analysis in cultured podocytes showed an increase of TUBB2B and DCDC2 protein after everolimus treatment, and immunohistochemistry in healthy control kidneys confirmed a podocyte-specific expression. Microtubule-inhibitor experiments led to a maldistribution of TUBB2B and DCDC2 as well as an aberrant reorganization of the actin cytoskeleton. Tubb2bbrdp/brdp mice showed a delay in glomerular podocyte and capillary development. Taken together, our study suggests that off-target, non-immune mediated effects of the mTOR-inhibitor everolimus on the podocyte cytoskeleton might involve regulation of microtubules, revealing a potential novel role of TUBB2B and DCDC2 in glomerular podocyte development We analyzed the effect of everolimus on gene expression in a puromycin aminonucleoside experimental in vitro model of podocyte injury using microarrays
2015-09-09 | E-GEOD-66107 | biostudies-arrayexpress
Project description:Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and the development of acquired resistance to PI3K-AKT-mTOR inhibitors remain major challenges for successful patient treatment. Here, we show that MYC activation is a central and clinically relevant mechanism of resistance to mTOR inhibitors (mTORi) in breast cancer. Multi-omic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent focal Myc amplification in tumors that acquire resistance to the mTORi AZD8055. The gained MYC activity was significantly associated with biological processes linked to mTORi response. Specifically, MYC counteracted the translation inhibitory effect induced by mTORi by promoting the translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred resistance to AZD8055 as well as the clinically approved mTORi everolimus, both in mouse models of ILC and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by synergistic growth inhibition using mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant determinant of mTORi resistance that may guide the selection of breast cancer patients for mTOR targeted therapies.
2023-05-02 | PXD041927 | Pride
Project description:Research has shown that anti-angiogenic agents can be effective therapies to treat cancer. Anti-angiogenic agents target the blood vessels required for tumors to grow. Vascular endothelial growth factor (VEGF) is one of the cell pathways used for this blood vessel growth. When the investigators interfere with the VEGF pathway, the investigators inhibit this blood vessel growth which is required by tumors. One of the study drugs being used, tivozanib (AV-951), selectively interferes with the VEGF pathway. The second study drug being used, everolimus (RAD001) interferes with the mTOR pathway. The mTOR pathway is another pathway involved in blood vessel and tumor cell growth. By combining these two drugs the investigators hope to slow or reverse tumor cell growth in patients whose tumors have become resistant to other therapies for their disease.
| 2084165 | ecrin-mdr-crc
Project description:Rapamycin is a natural antifungal, immunosuppressive, and antiproliferative compound allosterically inhibiting mTOR complex 1. The ubiquitin-proteasome system (UPS) responsible for protein turnover is usually not listed among the pathways affected by mTOR signaling; however, a number of reports indicated the interplay between UPS and mTOR. It is also reported that rapamycin and analogs can allosterically inhibit the proteasome itself. We studied the molecular effect of rapamycin and its analogs (rapalogs), everolimus, and temsirolimus by expression chemical proteomics on A549 cell line. The analysis revealed that the cellular response to everolimus differs dramatically from that of rapamycin and temsirolimus. In cluster analysis the effect of everolimus was similar to that of bortezomib, a well-established proteasome inhibitor. UPS-related pathways were enriched in the cluster of proteins specifically up-regulated upon everolimus and bortezomib treatments, suggesting that both compounds have similar proteasome inhibition effects. In particular, the total amount of ubiquitin was significantly elevated in the samples treated with everolimus and bortezomib, and the analysis of the polyubiquitination patterns revealed elevated intensities of the ubiquitin peptide with a GG modification at K48 residue, consistent with a bottleneck in the proteasomal protein degradation. Moreover, everolimus treatment resulted in both ubiquitin phosphorylation and a significant amount of semi-tryptic peptides illustrating the induction of protease activity. These observations suggest that everolimus affects the ubiquitin-proteasome system in a unique way and its mechanism of action is strikingly different from that of its close chemical analogs, rapamycin and temsirolimus.
2024-02-09 | PXD045774 | Pride
Project description:We report mTOR inhibitor (mTORi) is synergistic with BET inhibitor (BETi) in controlling tumor growth and inducing apoptosis in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models. In this study, we studied impact of different treatment on whole-genome mRNA transcriptome in SCLC PDX tumors. Four different treatments (vehicle control, NHWD870 [BETi; 1.5mg/kg], everolimus [mTORi; 2mg/kg], and the combo [NHWD870 1mg/kg and everolimus 1.5mg/kg] were administered daily for one week in a small cell lung cancer PDX LX-95 model. Tumor cells were isolated from PDX tumors using a magnetic-activated cell sorting method to enrich human tumor cells and total RNA was extracted using the RNeasy Mini Kit (Qiagen). mRNA libraries were constructed and pair-ended sequenced using Illumina high-throughput sequencing technology. The length of sequence reads was 150 bp.The samples have 12 to 129 million pass filter reads with more than 90% of bases above the quality score of Q30. We found BET inhibitor increases expression of RPS6KA2, a gene that mediates crosstalk between MAPK and mTOR pathway.
2020-09-01 | GSE155923 | GEO
Project description:<p>One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.</p>
| phs000535.v1.p1 | EGA
Project description:There is growing evidence that uncontrolled activation of the PI3K/Akt/mTOR pathway contributes to the development and progression of breast cancer. Inhibition of this pathway has antitumour effects in preclinical studies and efficacy in combination with other agents in breast cancer patients. The aim of this study is to characterise the effects of pre-operative everolimus treatment in primary breast cancer patients and to identify potential molecular predictors of response. Twenty-seven patients with oestrogen receptor (ER)-positive breast cancer completed 11–14 days of neoadjuvant treatment with 5-mg everolimus. Core biopsies were taken before and after treatment and analysed using Illumina HumanRef-8 v2 Expression BeadChips. Changes in proliferation (Ki67) and phospho-AKT were measured on diagnostic core biopsies/resection samples embedded in paraffin by immunohistochemistry to determine response to treatment. Patients that responded to everolimus treatment with significant reductions in proliferation (fall in % Ki67 positive cells) also had significant decreases in the expression of genes involved in cell cycle (P = 8.70E−09) and p53 signalling (P = 0.01) pathways. Highly proliferating tumours that have a poor prognosis exhibited dramatic reductions in the expression of cell cycle genes following everolimus treatment. The genes that most clearly separated responding from non-responding pre-treatment tumours were those involved with protein modification and dephosphorylation, including DYNLRB2, ERBB4, PTPN13, ULK2 and DUSP16. The majority of ER-positive breast tumours treated with everolimus showed a significant reduction in genes involved with proliferation, these may serve as markers of response and predict which patients will derive most benefit from mTOR inhibition.
2018-08-30 | GSE119262 | GEO
Project description:We present transcriptome profiling of 786-0 renal cell carcinoma cell lines both with and without Everolimus, an mTOR inhibitorhbn
2022-12-01 | GSE99875 | GEO