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1.
Oncotarget ; 6(29): 28327-40, 2015 Sep 29.
Article in English | MEDLINE | ID: mdl-26334103

ABSTRACT

Advanced Epithelial Ovarian Cancer (EOC) patients frequently relapse by 24 months and develop resistant disease. Research on EOC therapies relies on cancer cell lines established decades ago making Patient Derived Xenografts (PDX) attractive models, because they are faithful representations of the original tumor. We established 35 ovarian cancer PDXs resulting from the original graft of 77 EOC samples onto immuno-compromised mice. PDXs covered the diversity of EOC histotypes and graft take was correlated with early patient death. Fourteen PDXs were characterized at the genetic and histological levels. PDXs reproduced phenotypic features of the ovarian tumors of origin and conserved the principal characteristics of the original copy number change (CNC) profiles over several passages. However, CNC fluctuations in specific subregions comparing the original tumor and the PDXs indicated the oligoclonal nature of the original tumors. Detailed analysis by CGH, FISH and exome sequencing of one case, for which several tumor nodules were sampled and grafted, revealed that PDXs globally maintained an oligoclonal structure. No overgrowth of a particular subclone present in the original tumor was observed in the PDXs. This suggested that xenotransplantation of ovarian tumors and growth as PDX preserved at least in part the clonal diversity of the original tumor. We believe our data reinforce the potential of PDX as exquisite tools in pre-clinical assays.


Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Heterografts/metabolism , Ovarian Neoplasms/genetics , Transplantation, Heterologous/methods , Adult , Aged , Aged, 80 and over , Animals , Clone Cells/metabolism , Clone Cells/pathology , Female , Heterografts/pathology , Humans , Mice, Nude , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Ovarian Neoplasms/pathology , Prognosis , Survival Analysis
2.
Oncotarget ; 5(16): 7138-48, 2014 Aug 30.
Article in English | MEDLINE | ID: mdl-25216528

ABSTRACT

The anti-HER2 antibody pertuzumab inhibits HER2 dimerization and affects HER2/HER3 dimer formation and signaling. As HER3 and its ligand neuregulin are implicated in pancreatic tumorigenesis, we investigated whether HER3 expression could be a predictive biomarker of pertuzumab efficacy in HER2low-expressing pancreatic cancer. We correlated in vitro and in vivo HER3 expression and neuregulin dependency with the inhibitory effect of pertuzumab on cell viability and tumor progression. HER3 knockdown in BxPC-3 cells led to resistance to pertuzumab therapy. Pertuzumab treatment of HER3-expressing pancreatic cancer cells increased HER3 at the cell membrane, whereas the anti-HER3 monoclonal antibody 9F7-F11 down-regulated it. Both antibodies blocked HER3 and AKT phosphorylation and inhibited HER2/HER3 heterodimerization but affected differently HER2 and HER3 homodimers. The pertuzumab/9F7-F11 combination enhanced tumor inhibition and the median survival time in mice xenografted with HER3-expressing pancreatic cancer cells. Finally, HER2 and HER3 were co-expressed in 11% and HER3 alone in 27% of the 45 pancreatic ductal adenocarcinomas analyzed by immunohistochemistry. HER3 is essential for pertuzumab efficacy in HER2low-expressing pancreatic cancer and HER3 expression might be a predictive biomarker of pertuzumab efficacy in such cancers. Further studies in clinical samples are required to confirm these findings and the interest of combining anti-HER2 and anti-HER3 therapeutic antibodies.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/enzymology , Receptor, ErbB-3/metabolism , Animals , Biomarkers, Tumor , Cell Proliferation/drug effects , Female , Humans , Mice , Mice, Nude , Pancreatic Neoplasms/pathology , Random Allocation , Receptor, ErbB-3/antagonists & inhibitors , Signal Transduction , Xenograft Model Antitumor Assays , Pancreatic Neoplasms
3.
Mol Oncol ; 8(2): 431-43, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24394560

ABSTRACT

Patient derived xenografts (PDXs) are increasingly appreciated models in cancer research, particularly for preclinical testing, as they reflect the patient's tumor biology more accurately than cancer cell lines. We have established a collection of 20 breast PDXs and characterized their biological and clinical features, as well as their genetic stability. While most PDXs originated from triple negative breast cancers (70%), our collection comprised five ER + cases (25%). Remarkably, the tumors that produced PDXs derived from a subset of aggressive breast cancers with a high proportion of grade 3 tumors and reduced recurrence-free survival. Consistent with this, we found significant differences between the transcriptomic signatures of tumors that produced a PDX (Take) and those that did not (No Take). The PDXs faithfully recapitulate the histological features of their primary tumors, and retain an excellent conservation of molecular classification assignment and Copy Number Change (CNC). Furthermore, the CNC profiles of different PDXs established from the same tumor overlap significantly. However, a small fraction of CNCs in the primary tumor that correspond to oligoclonal events were gradually lost during sequential passaging, suggesting that the PDXs' genetic structure eventually stabilizes around a dominant clone present in the tumor of origin. Finally, de novo occurring genetic events covering up to 9% of the genome were found in only a minority of the PDXs, showing that PDXs have limited genetic instability. These data show that breast cancer PDXs represent a subset of aggressive tumors prone to relapse, and that despite of an excellent conservation of original features, they remain genetically dynamic elements.


Subject(s)
Breast Neoplasms , Gene Expression Regulation, Neoplastic , Transcriptome , Animals , Breast Neoplasms/classification , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Gene Expression Profiling , Heterografts , Humans , Mice , Mice, Nude , Neoplasm Transplantation
4.
Anticancer Drugs ; 20(10): 932-40, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19741504

ABSTRACT

The success of treatment of advanced non-small-cell lung cancer (NSCLC) remains very poor. The aim of this study was, on a series of NSCLC xenografts, to compare the efficacy of standard cisplatin-based or docetaxel-based chemotherapy. Seven human xenografts were obtained from six patients (two xenografts were derived from primary or metastatic tumors of the same patient). Three xenografts were adenocarcinomas and four were squamous cell carcinomas. All xenografts reproduced the same histology as that of the patient's original tumor. Docetaxel, administered as single-agent chemotherapy, induced a significant response in five of the seven NSCLC xenografts (71%), without significant increase after combination with cisplatin, vinorelbine, or gemcitabine. Relative expression of genes putatively involved in drug response was also studied in all xenografts and did not explain the variability of drug sensitivity. In conclusion, this panel of human NSCLC xenografts reliably reproduces the data obtained in patient tumors and the relative sensitivity to docetaxel reported in NSCLC patients.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/therapeutic use , Lung Neoplasms/drug therapy , Taxoids/therapeutic use , Aged , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/pharmacology , Docetaxel , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic/drug effects , Genes, p53/genetics , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mice , Mice, Nude , Middle Aged , Taxoids/pharmacology , Xenograft Model Antitumor Assays/methods
5.
Tumour Biol ; 28(3): 139-50, 2007.
Article in English | MEDLINE | ID: mdl-17519533

ABSTRACT

Hepatic and lung metastases are the leading causes of mortality and major indicators of aggressiveness in colorectal cancer. The underlying molecular mechanisms contributing to the development of metastasis are still unclear. Here, we designed a novel approach to explore gene expression profiles associated with metastasis in human colorectal cancer (hCRC). A series of ten isogenic tumors from three different hCRC models were orthotopically implanted into nude mice. In these series, we analyzed the contribution of dynamic heterogeneity, independently of any intrinsic gene expression program predictive of metastasis. When screened for the presence of disseminated tumor cells in the lung and liver, as the most common host tissues for hCRC metastases, both high- and low-metastatic efficient tumors were found among these isogenic orthotopic series. The metastasis-specific cDNA macroarray analysis of 96 genes, in both tumor populations for each of the three hCRC models, characterized a common differential gene expression within a small group of genes. Our results suggest that, independently of a gene expression profile predictive of metastasis, the progressive acquisition of additional alterations occurs during hCRC tumorigenesis. This dynamic process might determine tumor progression, namely the metastasis dissemination.


Subject(s)
Colonic Neoplasms/genetics , Gene Expression Profiling , Animals , Colonic Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Heterologous
6.
Int J Cancer ; 120(7): 1579-90, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17205515

ABSTRACT

The epidermal growth factor receptor (EGFR) signaling pathway is often activated in NSCLC, and thus represents a promising therapeutic target. We studied the antitumor activity of gefitinib (Iressa), an orally active EGFR-tyrosine kinase inhibitor, alone and in combination with standard chemotherapy in 5 recently established human NSCLC xenografts with wild-type EGFR. Mice were treated with 2 protocols of chemotherapy based on cisplatin (CDDP) combined with either gemcitabine (GEM) or vinorelbine (VNR). Gefitinib alone significantly inhibited tumor growth (TGI) in 4 of the 5 tumor xenografts (mean TGI of 58%, range: 25-70%). CDDP+VNR alone failed to achieve any significant responses, while CDDP+GEM achieved significant responses in 2 xenografts (TGI of 93 and 47%). Addition of gefitinib to CDDP+GEM potentialized chemotherapy in the 3 CDDP+GEM-resistant xenografts, but did not potentialize the CDDP+VNR combination. The effect of gefitinib treatment on the activity of extra cellular-regulated kinase (Erk), Akt, JNK and p38 kinases was assessed in IC9LC11 and IC1LC131, two NSCLC xenografts selected for their sensitivity and resistance to gefitinib, respectively. In IC9LC11, gefitinib strongly inhibited Erk, Akt and Jnk phosphorylation, but P38 remained active. Inversely, in IC1LC131, Erk and Akt pathways remained active, while Jnk and P38 pathways were inhibited by gefitinib. The data indicate that the antitumor activity of gefitinib in NSCLC, alone or in combination with chemotherapy, is tumor-dependent and is influenced by downstream signaling events independent of EGFR status.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/metabolism , Lung Neoplasms/drug therapy , Signal Transduction , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Gefitinib , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , MAP Kinase Kinase 4/genetics , MAP Kinase Kinase 4/metabolism , Maximum Tolerated Dose , Mice , Mice, Nude , Neoplasm Transplantation , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Quinazolines/administration & dosage , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Transplantation, Heterologous , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , Vinorelbine , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism , Gemcitabine
7.
Cancer Lett ; 215(1): 53-9, 2004 Nov 08.
Article in English | MEDLINE | ID: mdl-15374632

ABSTRACT

We investigated on colon cancer cells the effect of geraniol on thymidylate synthase and thymidine kinase expression, two enzymes related to 5-fluorouracil cytotoxicity. The anti-tumoral efficacy of geraniol and 5-fluorouracil were also evaluated on TC-118 human tumors transplanted in Swiss nu/nu mice. Geraniol (150 microM) but not 5-fluorouracil caused a 2-fold reduction of thymidylate synthase and thymidine kinase expression in cancer cells. In nude mice, the combined administration of 5-fluorouracil (20 mg/kg) and geraniol (150 mg/kg) caused a 53% reduction of the tumor volume, whereas a 26% reduction was obtained with geraniol alone, 5-fluorouracil alone showed no effect.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Colonic Neoplasms/drug therapy , DNA/metabolism , Fluorouracil/therapeutic use , Oils, Volatile , Terpenes/administration & dosage , Acyclic Monoterpenes , Animals , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Drug Therapy, Combination , Female , Humans , Mice , Mice, Nude , Plant Oils , RNA, Messenger/genetics , RNA, Messenger/metabolism , Thymidine Kinase/genetics , Thymidine Kinase/metabolism , Thymidylate Synthase/genetics , Thymidylate Synthase/metabolism , Transplantation, Heterologous , Tumor Cells, Cultured
8.
Oncogene ; 23(9): 1737-44, 2004 Mar 04.
Article in English | MEDLINE | ID: mdl-15001986

ABSTRACT

Mutations in the tumor-suppressor gene p53 have been associated with advanced colorectal cancer (CRC). Irinotecan (CPT-11), a DNA topoisomerase 1 inhibitor, has been recently incorporated to the adjuvant therapy. Since the DNA-damage checkpoint depends on p53 activation, the status of p53 might critically influence the response to CPT-11. We analysed the sensitivity to CPT-11 in the human colon cancer cell line HT29 (mut p53) and its wild-type (wt)-p53 stably transfected subclone HT29-A4. Cell-cycle analysis in synchronised cells demonstrated the activation of transfected wt-p53 and a p21(WAF1/CIP1)-dependent cell-cycle blockage in the S phase. Activated wt-p53 increased apoptosis and enhanced sensitivity to CPT-11. In p53-deficient cells, cDNA-macroarray analysis and western blotting showed an accumulation of the cyclin-dependent kinase (cdk)1/cyclin B complex. Subsequent p53-independent activation of the cdk-inhibitor (cdk-I) p21(WAF1/CIP1) prevented cell-cycle progression. Cdk1 induction was exploited in vivo to improve the sensitivity to CPT-11 by additional treatment with the cdk-I CYC-202. We demonstrate a gain of sensitivity to CPT-11 in a p53-mutated colon cancer model either by restoring wild-type p53 function or by sequential treatment with cdk-Is. Considering that mutations in p53 are among the most common genetic alterations in CRC, a therapeutic approach specifically targeting p53-deficient tumors could greatly improve the treatment outcomes.


Subject(s)
CDC2 Protein Kinase/antagonists & inhibitors , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Enzyme Inhibitors/pharmacology , Tumor Suppressor Protein p53/deficiency , CDC2 Protein Kinase/metabolism , Cell Cycle/drug effects , Cyclin B/metabolism , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Enzyme Activation/drug effects , HT29 Cells , Humans , Irinotecan , Mutation/genetics , Purines/pharmacology , Roscovitine , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
9.
J Urol ; 169(5): 1729-34, 2003 May.
Article in English | MEDLINE | ID: mdl-12686819

ABSTRACT

PURPOSE: Prostate cancer is known to be refractory to chemotherapy with only mitoxantrone showing some benefit. Recent clinical data indicate the antitumoral efficacy of taxanes alone or combined with estramustine phosphate. We compared the response to these treatments of hormone dependent and independent human prostate cancer xenografts. MATERIALS AND METHODS: PAC120, an androgen dependent human prostate cancer xenograft, and several HIDs, which are androgen independent variants, were established in nude mice. Human gene expression was determined by semiquantitative reverse transcriptase-polymerase chain reaction. Androgen deprivation was achieved by surgical castration. Tumor bearing mice received 20 mg./kg. docetaxel on day 2, 1 mg./kg. hydrocortisone on days 1 to 3, 4 mg./kg. estramustine phosphate on days 1 to 4 or 1 mg./kg. mitoxantrone on day 1 by the intraperitoneal route for 3-week cycles. Relative tumor volume and growth delay were evaluated. Histological examination of tumors was done before and after treatment. RESULTS: Mitoxantrone transiently decreased the growth rate of HID xenografts but did not affect that of PAC120. Estramustine phosphate alone inhibited the growth of PAC120 but not that of HID variants. Docetaxel inhibited the growth of all prostate cancer xenografts (PAC120 and HIDs) and increased survival. PAC120 showed distinct response patterns during prolonged treatment. Efficacy was significantly decreased by splitting docetaxel into 2 doses given at a 7-day interval (p = 0.01). The docetaxel effect was potentiated by estramustine phosphate in 1 of the 2 HID variants tested. In castrated mice docetaxel induced a greater growth delay than in intact male mice (p = 0.01). High Her2/neu and beta2-tubulin transcripts were detected in all samples. Prostate specific antigen, androgen receptor and multidrug related protein-1 mRNA did not correlate with the drug response, while CYP3A4 mRNA inversely correlated with the response. Docetaxel treated tumors had an increased number of mitotic cells with centrosome alterations and multinuclei, an increased number of Ki67 labeled cells and a strong decrease in beta-tubulin without evidence of apoptosis. CONCLUSIONS: Docetaxel showed a significant antitumoral effect on hormone dependent and tumors, which was largely superior to that of mitoxantrone. Estramustine phosphate alone had a modest effect. The drug response was associated with high Her2/neu expression, low CYP3A4 expression and the induction of numerous mitotic abnormalities.


Subject(s)
Antineoplastic Agents/administration & dosage , Estramustine/administration & dosage , Mitoxantrone/administration & dosage , Paclitaxel/analogs & derivatives , Paclitaxel/administration & dosage , Prostatic Neoplasms/drug therapy , Taxoids , Androgens/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Docetaxel , Humans , Male , Mice , Mice, Nude , Middle Aged , Neoplasm Transplantation , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery
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