Dataset Information

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047.

ABSTRACT: Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.

SUBMITTER: Kuo WL

PROVIDER: S-EPMC2803786 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047.

Kuo Wen-Lin WL Das Debopriya D Ziyad Safiyyah S Bhattacharya Sanchita S Gibb William J WJ Heiser Laura M LM Sadanandam Anguraj A Fontenay Gerald V GV Hu Zhi Z Wang Nicholas J NJ Bayani Nora N Feiler Heidi S HS Neve Richard M RM Wyrobek Andrew J AJ Spellman Paul T PT Marton Laurence J LJ Gray Joe W JW

BMC medicine 20091214

<h4>Background</h4>Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.<h4>Methods</h4>A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primar ...[more]

PMID: 20003408

Similar Datasets

Project description:PurposePolyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma.MethodsA total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with once weekly intravenous infusions of PG-11047. PG-11047 dose escalation ranged from 50 to 590 mg.ResultsThe maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size.ConclusionsResults of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.

Project description:Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC.

Dataset Information

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047.

Publications

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets