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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 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).

ORGANISM(S): Mus musculus

SUBMITTER: Mohammed Alshalalfa

PROVIDER: E-GEOD-67312 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

2015-03-27 | GSE67312 | GEO

RNA-seq profiling of upper tract urothelial carcinoma: bladder cancer consensus classification relevance, molecular heterogeneity and differential immune signatures

Project description:Analyses of large transcriptomics datasets of muscle-invasive bladder cancer (MIBC) has led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUC) are less known. Our objective was to determine the relevance of consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors.Subtype IHC markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16 and Ki67, MMR proteins, PD-L1 IHC were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3’RNA-seq, including with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression.Most of the 66 patients were men (77.3%), with pT1 (n=23, 34.8%) or pT2-4 stage UTUC (n=43, 65.2%). FGFR3 mutations and dMMR status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as Luminal papillary (LumP). Combining our consensus classification results to that of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUC, which was significantly higher than in MIBC. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular if FGFR3 mutated.

2023-10-10 | GSE244957 | GEO

A genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy

Project description:To determine whether adding Decipher to standard risk stratification tools (CAPRA-S and Stephenson nomogram) improves accuracy in prediction of metastatic disease within 5 years after surgery in men with adverse pathologic features after RP. The study population consisted of 182 patients selected from 2,641 men who underwent RP at the Cleveland Clinic between 1987-2008 who met the following criteria: 1) preoperative PSA>20 ng/mL, stage pT3 or margin positive, or Gleason score >/8; 2) pathologic node negative; 3) undetectable post-RP PSA; 4) no neoadjuvant or adjuvant therapy; and 5) minimum of 5 years follow-up for the controls.

2014-11-21 | E-GEOD-62667 | biostudies-arrayexpress

Pegvisomant-treated mouse prostate epithelium renal grafts

Project description:PTEN-CaP2 mouse prostate cancer cells were grafted under the kidney capsule of immunocompromised mice. After three weeks, mice were treated with 100 mg/kg pegvisomant (provided by Pfizer) or PBS vehicle 3X weekly for three weeks. Grafts were harvested three days after final treatment, flash frozen, and total RNA was extracted for sequencing.

2022-04-01 | GSE188543 | GEO

Identification of Nuclear Export Inhibitor-Based Combination Therapies in Preclinical Models of Triple-Negative Breast Cancer

Project description:An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% will be diagnosed with basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but acquired chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, a set of four human basal-like TNBC cell lines was utilized to determine the cytotoxicity profile of 1,363 unique clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts identified a combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemical studies, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, patient-derived xenografts, and patient tumor samples; within basal-like patients, XPO1 overexpression was associated with greater rates of metastases. These studies identify a promising new combination therapy for patients with basal-like TNBC.

2021-10-20 | GSE174391 | GEO

Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies

Project description:Mutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML samples. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in samples from patient subtypes with FLT3 mutations. These samples also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 inhibitor reduced the number of circulating cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML.

2023-05-03 | PXD032104 | Pride

Molecular Characterization of a Partial Masculinization in Embryonic Ovaries Grafted into Male Nude Mice

Project description:The fetal ovarian grafts under the kidney capsule of adult male mice undergo a partial sex-reversal showing ectopic SOX9-positive Sertoli cell-like cells around 15-20 days post-transplantation. However, the molecular bases of such masculinization of fetal ovaries in the paternal environment were unclear. We examined the temporal changes of the gene expression profiles of the grafted fetal ovaries during the partial masculinizing process in the male nude mice.

2019-02-04 | GSE88797 | GEO

Multi-model preclinical platform predicts clinical response of melanoma to immunotherapy

Project description:Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrates durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to Immune Checkpoint Blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T-cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a Melanocytic Plasticity Signature (MPS) predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify new mechanisms and treatment strategies to improve patient care.

2020-06-01 | GSE144946 | GEO

Preclinical Advances of Therapies for Laminopathies.

Project description:Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.

| S-EPMC8584472 | biostudies-literature

Discovery and validation of a novel expression signature for recurrence in high-risk bladder cancer post-cystectomy

Project description:Purpose: Selecting muscle-invasive bladder cancer patients for adjuvant therapy is currently based on clinical variables with limited power. We hypothesized that genomic-based signatures can outperform clinical models to identify patients at higher risk. Method:Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. A cohort comprised of 225 patients with organ-confined, muscle-invasive (pT2N0M0),extravesical (pT3-4aN0M0), and node-positive (pTanyN1-3M0) UCB who underwent radicalcystectomy at the University of Southern California between 1998 and 2004 was used. Each patient had aminimum two-year follow-up post-cystectomy unless they recurred prior to that date. Patients receiving neoadjuvant chemotherapy, and those with clinical evidence of lymphadenopathy or distant metastasis at diagnosis were excluded.

2014-10-27 | E-GEOD-57933 | biostudies-arrayexpress

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