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Patient-derived primary xenografts in the preclinical development of novel targeted therapies for bladder cancer

ABSTRACT: Purpose: While molecular targeted therapy has revolutionized the treatment of many cancers, little progress has been made in the development of novel therapies for muscle invasive bladder cancer (MIBC). Here we report on the establishment and characterization of patient-derived primary MIBC xenografts

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE67312 | GEO | 2015/03/27

SECONDARY ACCESSION(S): PRJNA279489

REPOSITORIES: GEO

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Patient-derived primary xenografts in the preclinical development of novel targeted therapies for bladder cancer

Project description:Purpose: While molecular targeted therapy has revolutionized the treatment of many cancers, little progress has been made in the development of novel therapies for muscle invasive bladder cancer (MIBC). Here we report on the establishment and characterization of patient-derived primary MIBC xenografts Tumor fragments derived from 7 patients with MIBC were grafted under the renal capsule of NOD-SCID mice and subsequently transplanted to further mice over multiple generations. Patient tumor and xenograft tissue were processed for analysis of , gene expression by microarray, and expression of select potential target pathways by immunohistochemistry (IHC).

2015-03-27 | E-GEOD-67312 | biostudies-arrayexpress

Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies.

Project description:Optimal animal models of muscle invasive bladder cancer (MIBC) are necessary to overcome the current lack of novel targeted therapies for this malignancy. Here we report on the establishment and characterization of patient-derived primary xenografts (PDX). Patient tumors were grafted under the renal capsule of mice and subsequently transplanted over multiple generations. Patient tumor and PDX were processed for analysis of copy number variations by aCGH, gene expression by microarray, and expression of target pathways by immunohistochemistry (IHC). One PDX harbouring an FGFR3 mutation was treated with an inhibitory monoclonal antibody targeting FGFR3. Five PDX were successfully established. Tumor doubling time ranged from 5 to 11 days. Array CGH revealed shared chromosomal aberrations in the patient tumors and PDX. Gene expression microarray and IHC confirmed that PDXs maintain similar patterns to the parental tumors. Tumor growth in the PDX with an FGFR3 mutation was inhibited by the FGFR3 inhibitor. PDXs recapitulate the tumor biology of the patients' primary tumors from which they are derived. Investigations related to tumor biology and drug testing in these models are therefore more likely to be relevant to the disease state in patients. They represent a valuable tool for developing precision therapy in MIBC.

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Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-Sparing Trimodality Therapy for Muscle-Invasive Bladder Cancer

Project description:Background: Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. Objective: To evaluate immune and stromal signatures in MIBC treated with TMT.

2019-03-23 | GSE128701 | GEO

Expression data from bladder tumors and adjacent normal tissues

Project description:miRNAs are involved in cancer development and progression,acting as tumor suppressors or oncogenes. Half of the human miRNAs are located in cancer-associated genomic regions and can function as tumor suppressor genes or oncogenes depending on their targets miRNA profiling was performed on paired bladder cancer tissues and differentially expressed miRNAs were identified in BC and adjacent noncancerous tissues of any disease stage/grade. Ten paired bladder cancer tissues (5 low-grade non-muscle-invasive bladder cancer[NMIBC] and 5 high-grade muscle-invasive bladder cancer[MIBC]) were sent to CapitalBio Corp. (Beijing) for noncoding RNA microarray analysis. The microarray analysis was done as described on the Web site of CapitalBio. NMIBC samples include 07A, 19A, 23A, 24A and T63 while coresponding pairs include 07B, 19B, 23B, 24B and 63. MIBC samples include 10A, 20A, 21A, 34A and 49A while coresponding pairs include 10B, 20B, 21B, 34B and 49B.

2012-07-06 | E-GEOD-39093 | biostudies-arrayexpress

Bladder-RI

Project description:A Cartes dM-^RIdentite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net/). Seven transcriptome datasets corresponding to a new series of 85 MIBC (Muscle-invasive bladder cancer) and six publicly-available series (298 MIBC) were analyzed. Tumors were classified by consensus clustering. Overall survival was determined from Kaplan-Meier curves. The role of the EGFR pathway was investigated by pathway bioinformatics analysis, determination of the expression levels of its components (by microarray, RT-qPCR and western blot) and of EGFR copy number by CGH arrays. A 40-gene transcriptomic classifier was used to identify basal-like cell lines and a basal-like mouse model. Please note M-^QMIBC molecular subtype': tumors classification using consensus clustering.

2014-06-01 | E-MTAB-1803 | biostudies-arrayexpress

Bladder Tumours O-Glycoproteomics

Project description:Bladder carcinogenesis and tumour progression is accompanied by profound alterations in protein glycosylation. These include the presence of short chain O-glycans such as Tn and T antigens and their sialylated counterparts sialyl-Tn(STn) and sialyl-T(ST). The presence of such structures is commonly associated with poor prognosis. In search for prognosis biomarkers and novel therapeutic targets we have screened, using immunohistochemistry, a series of bladder tumours with differing clinicopathology for these short-chain O-glycans. Aiming at identifying protein targets, we have studied the O-glycoproteome of a pool of STn positive tumours from muscle invasive bladder cancer (MIBC) patients.

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Kinome expression profiling of muscle invasive bladder cancer (MIBC) patients

Project description:Muscle invasive bladder cancer (MIBC) is one of the aggressive cancer with limited treatment options. Targeted gene expression profiling in normal and tumor samples from MIBC patients could aid in identification of potential therapeutic targets. Thus we used kinase specific panel to study their expression pattern and to identify targetable genes.

2020-04-20 | GSE130598 | GEO

Long noncoding RNA LNMAT1 promotes lymphatic metastasis in bladder cancer

Project description:Long non-coding RNAs (lncRNAs) are a large class of non-protein-coding transcripts that are over 200nt in length. LncRNAs have emerged as key regulator of biological process involved in the development and progression of bladder cancer. Bladder cancer is one of the most common genitourinary malignancies worldwide, with approximately 429,800 new cases and 165,100 deaths annually in the world. To identify critical lncRNAs that contributes to the progression of bladder cancer, Next generation sequencing (NSG) was performed in five paired high-grade muscle invasive bladder cancer (MIBC) and normal adjacent tissues (NAT), and in five lymph node (LN)-positive and LN-negative bladder cancer tissues. Our results indicate that the differential expressed lncRNAs in both MIBC tissues and LN-positive tissues associated in a variety of biological functions, such as metastasis.

2018-06-01 | GSE106534 | GEO

Nucleocytoplasmic β‐Catenin expression contributes to neuroendocrine differentiation in muscle invasive bladder cancer

Project description:Muscle invasive bladder cancer (MIBC) is highly heterogeneous, both at the molecular level and in terms of clinical progression. Several molecular classifications have been proposed to understand this heterogeneity and contribute to diagnosis and treatment. Although the neuroendocrine-like subtype is the most aggressive and exhibits the worst survival rate when compared to other subtypes, molecular mechanisms underlying neuroendocrine differentiation have not yet been understood. The nuclear localization of β-catenin is known to be associated with the activation of the Wnt/β-catenin pathway, and it is linked to disease progression and aggressiveness in various cancer types. To decipher the mechanisms underlying the neuroendocrine differentiation of bladder cancer, we determined β-catenin expression profiles of 169 T2-stage primary MIBC samples. Immunohistochemistry analysis revealed increased expression of the most widely used NE markers SYP, CGA, and CD56 in β-catenin positive MIBC tumors. As a result of our transcriptomic analysis, we observed higher expression of neuroendocrine differentiation-related genes, and lower expression of basal differentiation and urothelial differentiation-related genes in β-catenin positive MIBC tumors. Furthermore, we applied a molecular consensus classifier to β-catenin positive and negative samples, and the NE score was significantly higher in β-catenin positive MIBC compared to others. By comparing transcriptome proﬁles, we reveal that β-catenin positive MIBC harbor unique gene modules and gene expression profiles that are divergent from the β-catenin negative MIBC. GO term and KEGG pathway analyses showed that various neurogenesis-related pathways as well as regulation of gene expression and chromatin remodeling were significantly enriched at β-catenin positive MIBC. Our results collectively revealed that β-catenin expression contributes to neuroendocrine differentiation of bladder cancer.

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Identification of ADAMTS9-AS2 and MBNL1-AS1 as subtype-specific dysregulated lncRNAs in basal and luminal muscle-invasive bladder cancer via RNA sequencing

Project description:Muscle-invasive bladder cancer (MIBC) is an aggressive disease with high morbidity and mortality that can be divided into basal and luminal subtypes based on genomic characteristics. Due to the complex heterogeneity of MIBC, specific markers are needed to distinguish MIBC subtypes to guide future clinical treatment. In this study, we explore abnormal lncrnas that are specific to the basic and intracavitary subtypes of MIBC, which will provide potential biomarkers for precision therapy of MIBC.

2023-04-14 | GSE229410 | GEO

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