Integrated Genomics of Ovarian Xenograft Tumor Progression and Chemotherapy Response
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE23616 | GEO | 2011/03/01
SECONDARY ACCESSION(S): PRJNA129933
REPOSITORIES: GEO
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Project description:Xenograft ovarian tumors are useful model to test therapeutic candidates in vivo. We used microarrays to gain insight into the expression changes during tumor growth and induced by the vitamin D analog, MT19C at multiple time points. SKOV-3 cells were grown in 10% FBS/DMEM before injection into mice. Total RNA was collected using standard methods.
2011-03-01 | E-GEOD-23616 | biostudies-arrayexpress
Project description:BackgroundOvarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c.MethodsIn order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth.ResultsThese data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival.ConclusionsWe have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy.
| S-EPMC3155912 | biostudies-literature
Project description:Antitumor efficacy of vitamin D analog in a patient-derived xenograft
| PRJNA1008143 | ENA
Project description:Determine the molecular pathways underlying the antitumor effect of vitamin D analog on xenografts from a patient with docetaxel resistant CRPC.
2024-07-18 | GSE241426 | GEO
Project description:We treated PTENpe-/- mice, in which PTEN is selectively ablated in prostatic epithelial cells, with a Vitamin D analog. We extracted RNA from the prostate of oil (vehicle) and Vitamin D analog-treated mice.
2021-08-04 | GSE164855 | GEO
Project description:Ovarian cancer is the most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo-resistant disease after initial response to standard-of-care treatment with platinum-based therapies. HER2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER2 inhibitors have been poor. Next generation sequencing technologies in conjunction with testing using patient-derived xenografts (PDX) allow validation of personalized treatments. Using a whole-genome mate-pair next generation sequencing (MPseq) protocol, we identified several high grade serous ovarian cancers (HGS-OC) with DNA alterations in genes encoding members of the ERBB2 pathway. The efficiency of anti-HER2 therapy was tested in three different PDX lines with the identified alterations and high levels of HER2 protein expression. Treatment responses to pertuzumab or pertuzumab/trastuzumab were compared in each PDX line WITH standard carboplatin and paclitaxel combination treatment. In all three PDX models, HER2-targeted therapy resulted in significant inhibition of tumor growth compared with untreated controls. However, the responses in each case were inferior to those to chemotherapy, even for chemo-resistant lines. When chemotherapy and HER2-targeted therapy were administered together, a significant regression of tumor was observed after 6 weeks of treatment compared with chemotherapy alone. Post-treatment analysis of these tissues revealed that inhibition of the ERBB2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated ERBB2 pathway alone in HGS-OC results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and HER2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to HER2-targeted therapy.
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Project description:Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated. Gene expression profiling experiments were conducted for 25 patient-derived xenograft glioblastoma samples using Affymetrix Human Gene 1.0 ST arrays according to manufacturer's protocol.
2014-06-12 | E-GEOD-58400 | biostudies-arrayexpress
Project description:High grade serous ovarian carcinoma (HGSC) is the most common and lethal subtype of gynecologic malignancy in women. The current standard of treatment combines cytoreductive surgery and chemotherapy. Despite the efficacy of initial treatment, most patients develop cancer recurrence, and 70% of patients die within 5-years of initial diagnosis. CA125 is the current FDA-approved biomarker used in the clinic to monitor response to treatment and recurrence. Although increasing levels of CA125 precede clinical symptoms of recurrence, often second-look surgeries often reveal microscopic and macroscopic tumors present during remission. Here, we describe a novel strategy for the discovery of serum biomarkers aimed at earlier detection of cancer recurrence. We combined HGSC patient-derived xenograft models, chemoproteomic enrichment of N-glycosylated peptides and systematic development of targeted proteomics assays for rapid biomarker identification and orthogonal verification. The verification of candidates in two independent, longitudinal serum cohorts from HGSC patients (n=96 serum samples) identified four novel biomarker candidates for earlier detection of HGSC recurrence.
2018-08-27 | MSV000082853 | MassIVE
Project description:In this study, we identified prognostic biomarkers in ovarian carcinoma by integrating multi-omics DNA copy number variation (CNV) and methylation variation (MET) data. CNV, MET, and messenger RNA (mRNA) expression were examined in 351 ovarian carcinoma patients. Genes for which expression was correlated with DNA copy-number or DNA methylation were identified; three ovarian carcinoma gene subtypes were defined based on these correlations. Overall survival and B cell scores were lower, while the macrophage cell score was higher, in the DNA imprinting centre 1 (iC1) subtype than in the iC2 and iC3 subtypes. Comparison of CNV, MET, and mRNA expression among the subtypes identified two genes, ubiquitin B (UBB) and interleukin 18 binding protein (IL18BP), that were associated with prognosis. Mutation spectrum results based on subtype indicated that UBB and IL18BP expression may be influenced by mutation loci. Mutation levels were higher in iC1 samples than in iC2 or iC3 samples, indicating that the iC1 subtype is associated with disease progression. This integrated multi-omics analysis of genomics, epigenomics, and transcriptomics provides new insight into the molecular mechanisms of ovarian carcinoma and may help identify biomolecular markers for early disease diagnosis.
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