GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (123)
  • 1
    Online Resource
    Online Resource
    Abstract LB-122: A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-122-LB-122
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-122-LB-122
    Abstract: The family of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) plays a critical role in cell proliferation and survival. A variety of genetic alterations (e.g. amplifications, mutations, and translocations) of these receptors and ligands have been found in diverse types of tumors. NVP-BGJ398 is a potent, selective, and orally bioavailable inhibitor of the FGFR tyrosine kinases. It inhibits the proliferation of various FGFR-dependent cell lines at nano-molar concentrations including breast and lung cancers harboring FGFR1 amplification, FGFR2-amplified gastric cancer cell lines and FGFR3-mutated bladder cancers. Objectives of the study: The purpose of this phase I-First In Human dose-escalation study is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD) of NVP-BGJ398 when administered orally to adult patients with advanced solid tumors. Secondary objectives include safety, tolerability, pharmacokinetics and preliminary anti-tumor activity in FGFR-dependent cancer. Methods: Patients received BGJ398 daily in a 28-day cycle in escalating dose cohorts starting from 5mg once daily. After cohort 3, patients had to have FGFR1 or FGFR2 amplification or FGFR3 mutation. Dose limiting toxicities (DLTs) were pre-defined and included both severe events and those resulting in significant dosing delays. Preliminary data: 26 patients have been treated, including 10 patients with FGFR1-amplified breast and 3 patients with FGFR1-amplified squamous cell lung cancer. The dose was escalated from 5 mg to 150 mg over 7 dose cohorts. One DLT of delayed dose occurred following a grade 3 AST/ALT event at 100 mg. Adverse events (AE) were generally grade 1-2. The most frequently observed AEs were diarrhea (37%) fatigue (37%) and nausea (32%) Hyperphosphatemia was observed, with increasing frequency at higher doses of NVP-BGJ398, and could be managed with phosphate binders and diuretics. One lung cancer patient with an FGFR1/CEP8 ratio of 2.6 by FISH analysis responded to 100 mg of NVP-BGJ398 with a 33% reduction in target lesions by CT scan at 8 weeks, confirmed at 12 weeks, and a substantial SUV decrease on PET. These observations provide early evidence that inhibition of the FGFR pathway is effective in patients with FGFR dependent cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-122. doi:1538-7445.AM2012-LB-122
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-LB-122
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract B44: When murine tumors are thought to be human: A drawback of patient derived xenografts.
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 16_Supplement ( 2016-08-15), p. B44-B44
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 16_Supplement ( 2016-08-15), p. B44-B44
    Abstract: The use of preclinical models is essential in every aspect of translational cancer research, from the biologic understanding of the disease to the development of new treatments. Patient Derived Xenograft (PDX) models are increasingly used in translational cancer research due to their advantages over other preclinical models. However, although it has been widely demonstrate that these kind of models are predictive of clinical outcome, there are also some drawbacks when working with them. Analyzing our PDX model collection, we have observed that there is a small percentage of cases in which a murine tumor is developed instead of the original human one by a process that has been called horizontal oncogenesis. This process was already observed and described in the early 80´s, however, it is still not well understood and the molecular mechanisms by which it happens remain unknown. In order to determine the origin of the different murine tumors observed in our mice, we performed immunohistochemistry characterization of our altered models and found two different types of murine tumors: murine fibrosarcomas, which were observed in Colorectal and Pancreatic Ductal Adenocarcinoma PDX models; and murine lymphomas, that were observed mainly in Lung PDX models when they were implanted in Nod-scid mice. We also found a case in which a human lymphoproliferation grew in the animals instead of the sample from the small cell lung cancer obtained from the patient. As these murine tumors grow in the same place where the human donor tumor was implanted, it is important to have a quick and effective method to identify them before performing any study with these altered models. In this regard, we have implemented a simple technique based on PCR analysis with primers that recognize K-Ras. We have designed an estrategy in which we can obtain amplicons of different sizes depending on their human or murine origin. Although we still have to analize some of our PDX models, using this methodology we have confirmed that murine tumors appear in a very low percentage of cases (less than 5% to date). However, even with this low incidence we consider that is essential to identify those murine tumors as soon as possible in order to avoid wasting time, money and resources. Citation Format: Camino Menéndez, Beatriz Salvador, Manuel Muñoz, Natalia Baños, Francesca Sarno, Pedro P López-Casas, Manuel Hidalgo. When murine tumors are thought to be human: A drawback of patient derived xenografts.. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B44.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.PDX16-B44
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Discovery of New Targets to Control Metastasis in Pancreatic Cancer by Single-cell Transcriptomics Analysis of Circulating Tumor Cells
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Therapeutics Vol. 19, No. 8 ( 2020-08-01), p. 1751-1760
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 19, No. 8 ( 2020-08-01), p. 1751-1760
    Abstract: Metastasis development is the leading cause of cancer-related mortality in pancreatic ductal adenocarcinoma (PDAC) and yet, few preclinical systems to recapitulate its full spreading process are available. Thus, modeling of tumor progression to metastasis is urgently needed. In this work, we describe the generation of highly metastatic PDAC patient-derived xenograft (PDX) mouse models and subsequent single-cell RNA-sequencing (RNA-seq) of circulating tumor cells (CTC), isolated by human HLA sorting, to identify altered signaling and metabolic pathways, as well as potential therapeutic targets. The mouse models developed liver and lung metastasis with a high reproducibility rate. Isolated CTCs were highly tumorigenic, had metastatic potential, and single-cell RNA-seq showed that their expression profiles clustered separately from those of their matched primary and metastatic tumors and were characterized by low expression of cell-cycle and extracellular matrix–associated genes. CTC transcriptomics identified survivin (BIRC5), a key regulator of mitosis and apoptosis, as one of the highest upregulated genes during metastatic spread. Pharmacologic inhibition of survivin with YM155 or survivin knockdown promoted cell death in organoid models as well as anoikis, suggesting that survivin facilitates cancer cell survival in circulation. Treatment of metastatic PDX models with YM155 alone and in combination with chemotherapy hindered the metastatic development resulting in improved survival. Metastatic PDX mouse model development allowed the identification of survivin as a promising therapeutic target to prevent the metastatic dissemination in PDAC.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-19-1166
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Abstract B42: Patient-derived metastatic models of pancreatic cancer: An in-vivo system for modeling metastasis and preclinical drug screening
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 16_Supplement ( 2016-08-15), p. B42-B42
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 16_Supplement ( 2016-08-15), p. B42-B42
    Abstract: So far, there are few preclinical models that can recapitulate the full metastatic process of pancreatic cancer, therefore modeling of tumor progression to metastasis is urgently needed. In our laboratory, we established patient-derived cancer xenograft (PDX) metastatic models of pancreatic ductal adenocarcinoma (PDA) by orthotopic transplantation of human pancreatic tumor specimens into immunodeficient NOD/SCID/IL2λ-receptor null (NSG) mouse. Importantly, these preclinical orthotopic models preserve the histological and genetic characteristics of donor tumor and provide successful tumor growth with subsequent distal spread to the mouse liver and lung, which are the common metastatic sites of PDA patients. Furthermore, we found that in one of the PDX metastatic models, Gemcitabine and albumin-bound paclitaxel (Nab-paclitaxel) showed significant increase in survival of treated mice, compared to control group, as well as Nab-paclitaxel resulted in reducing the number of mice affected with metastasis. Currently, we are focused on identification and characterization of circulating tumor cells (CTCs) derived from PDX metastatic models, hypothesizing that CTCs population contain cells with clonal capacity to initiate distant metastases. To identify and isolate CTCs from PDX metastatic models of pancreatic cancer, we developed a magnetic separation assay using anti-human antibodies specific to the MHC-class1-surface antigens HLA-ABC, which allowed us to enumerate human tumor cells in mouse peripheral tissues. The molecular characterization of the human CTCs population at single cell level is performed via microfluidics-based platform (Fluidigm) for multiplex gene expression analysis in individual cells. This system allows us to study the simultaneous expression of groups of genes by RNAseq and resolve cellular diversity during pancreatic cancer metastasis by comparing gene expression signatures of the human tumor cells derived from orthotopic tumor, mouse metastatic organs and peripheral blood. We expect that this single cell gene expression analysis will help us to characterize the metastasis-initiating cell sub-clones within the whole heterogeneous tumor population and subsequently identify potential therapeutic targets to trigger the metastatic spread. In summary, our preclinical data provides a rationale for further use of these PDX metastatic models of pancreatic cancer for studying the molecular mechanisms involved in metastatic process, preclinical drug screening and personalized medicine strategies. Citation Format: Spas Dimitrov, Manuel Muñoz, Natalia Baños, Camino Menéndez, Victoria Bonilla, Yolanda Duran, Rodrigo Toledo, Francesca Sarno, Javier Perales-Patón, Fátima Al-Shahrour, Pedro P Lopez-Casas, Manuel Hidalgo. Patient-derived metastatic models of pancreatic cancer: An in-vivo system for modeling metastasis and preclinical drug screening. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B42.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.PDX16-B42
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 5 ( 2018-05-01), p. 966-976
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 5 ( 2018-05-01), p. 966-976
    Abstract: In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy in vitro. Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina in vivo. Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits in vitro human colorectal carcinoma cell proliferation; however, in vivo experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in & gt;30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. Mol Cancer Ther; 17(5); 966–76. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-17-0193
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Abstract 1493: 18F-misonidazole PET (FMISO-PET) monitors vascular normalization (VN) and predicts benefit from antiangiogenic treatment plus chemotherapy in pancreas cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1493-1493
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1493-1493
    Abstract: Antiangiogenic agents’ effects are elicited by VN, a process that improves tumor oxygenation and chemotherapy delivery, factors implicated in chemo-sensitivity. A biomarker that allowed monitoring this process non-invasively could help guiding individual therapeutic decisions. As hypoxia can be tracked with FMISO-PET, and hypoxia is influenced by vessel abnormality, we reasoned that a dynamic FMISO-PET monitoring of tumors treated with antiangiogenics at early timepoints could be informative of VN. Three pancreas cancer PDXs, (Panc215, Panc 286 and Panc219) were studied. Animals (athymic nude mice) were randomized to a window-of-opportunity (WOP) short course (4 days) of the multikinase inhibitor antiangiogenic agent dovitinib (DOV, a VEGFR1-3, PDGFRA/B and FGFR inhibitor) or vehicle. The WOP was preceded and followed by FMISO-PET and FDG-PET, as well as tumor sampling in order to assess vessel architecture and density (CD31 and confocal acquisition), 10Kda-dextran extravasation (vessel abnormality), tumor necrosis (H & E), and hypoxia staining (pimomidazole immunohistochemistry, in order to study the correspondence between FMISO-PET and tissue hypoxia evolution). After the WOP, animals were randomized to the addition of GEM or vehicle to their treatment. Tumor growth inhibition (TGI) was the parameter under study, comparing for each PDX the TGI of GEM, DOV or the combination versus vehicle. DOV did not exert significant TGI in any of the three models. FMISO-PET SUV levels evolved during the WOP: the SUV increased 53% and 72% for Panc286 and Panc219 when treated with vehicle, but remained unchanged during WOP for Panc215. The SUV changes were modulated by DOV: administered during the WOP, FMISO-PET SUV in Panc215 remained stable, but abrogated the increase in Panc219, and induced a 10% decrease in Panc285. FDG-PET showed that the areas that turned FMISO-PET-negative with DOV were still viable in the three models, confirmed by histologic examination (no significant change in the percentage of necrotic area surface). DOV did not add TGI effect to GEM in Panc215 but it improved TGI an additional & gt;80% and 75% compared to GEM alone in Panc286 and Panc219 (p = 0.02 and 0.001). Dovitinib reduced vessel tortuosity and dextran extravasation in Panc286 and Panc219, whereas did not change these parameters in Panc215 during the WOP. FMISO-PET mirrored pimomidazole staining evolution during the WOP. Intratumor gemcitabine concentration increased & gt;2fold after DOV vs. vehicle during the WOP in Panc286 and Panc219, whereas did not change in Panc215. In conclusion, FMISO-PET accurately monitors the changes following VN induced by DOV: hypoxia and vessel leakage reversal, and increased interstitial concentration of GEM. FMISO-PET monitoring during the WOP detect in which tumors antiangiogenic treatment exerts positive effects added to chemotherapy. Citation Format: Tamara Mondejar, Elena Hernadez-Agudo, Marisa Soto-Montenegro, Diego Megias, David Cebrian, Jesus Sanchez, Francisca Mulero, Ramon Colomer, Manuel Hidalgo, Manuel Desco, Miguel Quintela-Fandino. 18F-misonidazole PET (FMISO-PET) monitors vascular normalization (VN) and predicts benefit from antiangiogenic treatment plus chemotherapy in pancreas cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1493. doi:10.1158/1538-7445.AM2015-1493
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-1493
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Abstract B033: Transcriptional dissection and therapeutic modulation of metastasis development in pancreatic cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B033-B033
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B033-B033
    Abstract: Pancreatic cancer (PDAC) is a highly metastatic disease, and up to 70% of patients who are diagnosed with early-stage disease recur with metastatic disease despite treatment with chemotherapy. The development of metastasis remains the leading cause of cancer-related mortality in this disease, and little is known about the molecular mechanisms that drive the spreading of the primary tumor cells to the metastatic niche. Therefore, there is an urgent need to discover druggable antimetastatic targets. To generate a robust model of PDAC metastasis we implanted PDAC patient-derived samples orthotopically in NOD scid gamma (NSG) mice. We observed recurrent dissemination to distant organs, liver, and lung that resulted in animal death with a median of 50 days. We obtained human cancer single-cell suspensions at the primary location (graft), the mouse blood, and the metastatic lesions by using magnetic methods and an anti-HLA-ABC antibody, which recognized the human cells. Next, we captured single-cells by utilizing the Fluidigm technology and performed RNA-seq on each isolated cell. Using bioinformatic tools, we analyzed the transcriptional landscape of the cells isolated from the three compartments to search for potential druggable metastatic drivers. The data show that PDAC circulating tumor cells (CTCs) keep high tumorigenic and metastatic capability and that CTC-derived tumors preserve the morphologic characteristics of parental tumor. The metastatic disease of pancreatic cancer is a well-organized evolutionary process, in which the primary tumor cells, metastatic cells, and CTCs are transcriptionally divergent. The transcriptional heterogeneity between these three biological emerges from three biologic hallmarks including extracellular matrix interaction and focal adhesion, cell cycle, and ribosome biogenesis. The analysis of transcriptionally overexpressed genes identified BIRC5 (Survivin), a key regulator of mitosis and apoptosis, as one of the highest expressed genes in CTCs as well as the most promising target. Intriguingly, in vivo targeting of BIRC5 with YM155, a small molecule described as transcriptional repressor of BIRC5, aborted the metastatic process and significantly increased the survival of treated mice compared to control. Citation Format: Pedro P. Lopez-Casas, Spas Dimitrov, Javier Perales-Patón, Natalia Baños, Manuel Muñoz, Ana Dopazo, Fátima Al-Shahrour, Manuel Hidalgo. Transcriptional dissection and therapeutic modulation of metastasis development in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B033.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B033
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 8 ( 2008-04-15), p. 2841-2849
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 8 ( 2008-04-15), p. 2841-2849
    Abstract: The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development. [Cancer Res 2008;68(8):2841–9]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-5200
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Abstract LB-61: Targeting cancer cell metabolism in pancreatic cancer: p53, a key regulator of glycolysis and a major factor deciding the outcome of targeting the Warburg effect
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-61-LB-61
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-61-LB-61
    Abstract: Background and Aim: Tumor cells depend on metabolic alterations for their continued growth and survival, and such changes make cancer cells peculiarly addicted to the rapacious uptake of glucose. The Warburg effect is such a metabolic feature of cancers that helps to preferentially metabolize pyruvate via glycolytic pathway to lactate by lactate dehydrogenase A (LDHA). Our recent findings indicated that LDHA is required not only for tumor initiation but for tumor maintenance and progression (Le et al., PNAS, 2010). Here, we investigated the therapeutic potential of LDHA inhibition in pancreatic cancer, and attempt to delineate the factors responsible for tumor response. Methods: We evaluated the in vivo efficacy of FX11, a small molecule inhibitor of LDHA, in a panel of pancreatic cancer xenografts with annotated mutational status. Non-invasive quantitative assessment of lactate production was measured by real-time hyperpolarization experiments with 1-13C-labeled pyruvate using a DNP polarizer (HyperSense). [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET) combined with computed tomography (CT) imaging was conducted to evaluate the effect of FX11 treatment on glucose metabolism. Liquid chromatography - mass spectrometry (LC-MS) was used to quantify the tumor metabolites. Ki-67 and TUNEL staining were performed to determine the effect of FX11 treatment on apoptosis and tumor cell proliferation. Results: p53-deficient pancreatic cancer xenografts showed higher baseline metabolic activity and FX11 treatment down-regulated the tumor metabolic activity. Real-time imaging of pyruvate to lactate conversion using nuclear magnetic resonance (NMR) spectroscopy revealed that FX11 treatment inhibits pyruvate to lactate conversion in p53-deficient pancreatic cancer xenografts. Importantly, p53 promotes the expression of TP53-induced glycolysis regulator (TIGAR) and loss of p53 in tumors results in reduced TIGAR levels. The metabolic profiles of p53-deficient versus p53-proficient pancreatic cancer xenografts were remarkably different. FX11 treatment attenuates tumor progression, induces apoptosis and reduces tumor cell proliferation, preferentially in p53-deficient pancreatic cancer xenografts. Conclusions: Because the Warburg effect is characteristic of virtually all cancers and p53 is frequently mutated in vast majority of human cancers, our finding that p53, a key regulator of glycolysis and a major factor deciding the therapeutic outcome of targeting the Warburg effect may have broad clinical implications. Our findings may help to identify patient subsets that may be particularly responsive to LDHA targeted agents in clinical trials. Acknowledgement: Stand Up To Cancer-AACR Dream Team Translational Cancer Research Grant No. SU2C-AACR DT0509. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-61. doi:1538-7445.AM2012-LB-61
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-LB-61
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Homozygous deletions of methylthioadenosine phosphorylase in human biliary tract cancers
    American Association for Cancer Research (AACR) ; 2005
    In:  Molecular Cancer Therapeutics Vol. 4, No. 12 ( 2005-12-01), p. 1860-1866
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 4, No. 12 ( 2005-12-01), p. 1860-1866
    Abstract: The p16INK4A/CDKN2A gene on chromosome 9p21 is a site of frequent allelic loss in human cancers, and in a subset of cases, homozygous deletions at this locus encompass the telomeric methylthioadenosine phosphorylase (MTAP) gene. The MTAP gene product is the principal enzyme involved in purine synthesis via the salvage pathway, such that MTAP-negative cancers are solely dependent on de novo purine synthesis mechanisms. Inhibitors of the de novo pathway can then be used to selectively blockade purine synthesis in cancer cells while causing minimal collateral damage to normal cells. In this study, we determine that 10 of 28 (35%) biliary tract cancers show complete lack of Mtap protein expression. In vitro analysis using a selective inhibitor of the de novo purine synthesis pathway, l-alanosine, shows robust growth inhibition in MTAP-negative biliary cancer cell lines CAK-1 and GBD-1 accompanied by striking depletion of intracellular ATP and failure to rescue this depletion via addition of exogenous methylthioadenosine, the principal substrate of the MTAP gene product; in contrast, no significant effects were observed in MTAP-expressing HuCCT1 and SNU308 cell lines. Colony formation studies confirmed that l-alanosine reduced both number and size of CAK-1 colonies in soft agar assays. Knockdown of Mtap protein by RNA interference in l-alanosine-resistant HuCCT1 cells conferred sensitivity to this agent, confirming that intracellular Mtap protein levels determine response to l-alanosine. Inhibitors of de novo purine synthesis can be a potential mechanism-based strategy for treatment of biliary tract cancers, one third of which show complete loss of MTAP function. [Mol Cancer Ther 2005;4(12):1860–6]
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-05-0103
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...