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Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma (DDLS) part 2

ABSTRACT: Analysis of DNA copy number variations in two DDLS tumor-derived cell lines DDLS8817 and LPS141 growing in culture in basal conditions The goal of this DNA copy number analysis was to determine if genes used in signaling network modeling in DDLS were amplified or deleted Genomic DNA was isolated from asynchronously growing DDLS8817 and LPS141 cultures growing in basal conditions using the Qiagen DNAy kit.

ORGANISM(S): Homo sapiens

SUBMITTER: Martin Miller

PROVIDER: E-GEOD-50750 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma (DDLS) part 1

Project description:Analysis of gene expression levels in two DDLS tumor-derived cell lines DDLS8817 and LPS141 growing in culture in basal conditions The goal of this gene transcript study was to determine the expression level of genes used in signaling network modeling in DDLS RNA was isolated from asynchronously growing DDLS8817 and LPS141 cultures growing in basal conditions using the Qiagen RNEasy kit. Three replicates of each cell line

2013-09-24 | E-GEOD-50749 | biostudies-arrayexpress

Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma (DDLS) part 2

Project description:Analysis of DNA copy number variations in two DDLS tumor-derived cell lines DDLS8817 and LPS141 growing in culture in basal conditions The goal of this DNA copy number analysis was to determine if genes used in signaling network modeling in DDLS were amplified or deleted

2013-09-24 | GSE50750 | GEO

Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma (DDLS)

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-09-24 | E-GEOD-50751 | biostudies-arrayexpress

Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma (DDLS) part 1

2013-09-24 | GSE50749 | GEO

Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma (DDLS)

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-09-24 | GSE50751 | GEO

Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets.

Project description:Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.

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Scattered genomic amplification in dedifferentiated liposarcoma.

Project description:BackgroundAtypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes.ResultsThe present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q.ConclusionsThe observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i.e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis.

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Adipogenesis induces growth inhibition of dedifferentiated liposarcoma.

Project description:Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common types of liposarcoma. Although WDLPS and DDLPS patients receive intensive treatment including radical surgery and systemic therapy, their overall 5-year survival rates are 90% and 30%, respectively, indicating that DDLPS is clinically more aggressive. We examined whether adipogenic stimulation induces adipogenesis in human WDLPS/DDLPS cells by using dexamethasone, indomethacin, insulin, and 3-isobutyl-1-methylxanthine (IBMX), all putative medications or drugs. Functional in vitro experiments showed that treatment with these four compounds induced adipogenic potency by transcriptional and translational upregulation of genes related to the maintenance of stemness and adipogenic differentiation. Using in vivo xenograft models, we found that the induction of stemness and adipogenesis inhibited the tumorigenic potency of DDLPS. This study suggests a potential application of drug repositioning in which adipogenesis-inducing compounds could be used to treat DDLPS patients in a clinical setting.

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Integrated exome and RNA sequencing of dedifferentiated liposarcoma.

Project description:The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management.

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Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma.

Project description:Dedifferentiated liposarcoma (DDLPS) is an aggressive adipogenic cancer with poor prognosis. DDLPS tumors are only modestly sensitive to chemotherapy and radiation, and there is a need for more effective therapies. Genetically, DDLPS is characterized by a low tumor mutational burden and frequent chromosomal structural abnormalities including amplification of the 12q13-15 chromosomal region and the MDM2 gene, which are defining features of DDLPS. The MDM2 protein is an E3 ubiquitin ligase that targets the tumor suppressor, p53, for proteasomal degradation. MDM2 amplification or overexpression in human malignancies is associated with cell-cycle progression and worse prognosis. The MDM2-p53 interaction has thus garnered interest as a therapeutic target for DDLPS and other malignancies. MDM2 binds p53 via a hydrophobic protein interaction that is easily accessible with synthetic analogues. Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Preclinical in vitro and animal models have shown promising results with MDM2 inhibition, resulting in robust p53 reactivation and cancer cell death. However, multiple early-phase clinical trials have failed to show a benefit with MDM2 pathway inhibition for DDLPS. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS.

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