The Experts below are selected from a list of 3132 Experts worldwide ranked by ideXlab platform
Michael Mullendore - One of the best experts on this subject based on the ideXlab platform.
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an orally bioavailable small molecule inhibitor of hedgehog signaling inhibits Tumor initiation and metastasis in pancreatic cancer
Molecular Cancer Therapeutics, 2008Co-Authors: Georg Feldmann, Collins Karikari, Volker Fendrich, Karen Mcgovern, Djahida Bedja, Savita Bisht, Hector Alvarez, Jan Bart M Koorstra, Nils Habbe, Michael MullendoreAbstract:Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch, as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary Tumor volume. The only discernible phenotype observed within the treated primary Tumor was a significant reduction in the population of aldehyde dehydrogenase-bright cells, which we have previously identified as a clonogenic Tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase-bright cells with IPI-269609 was accompanied by significant reduction in Tumor Engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with Tumor-initiating ("cancer stem cell") properties.
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an orally bioavailable small molecule inhibitor of hedgehog signaling inhibits Tumor initiation and metastasis in pancreatic cancer
Molecular Cancer Therapeutics, 2008Co-Authors: Georg Feldmann, Collins Karikari, Volker Fendrich, Karen Mcgovern, Djahida Bedja, Savita Bisht, Hector Alvarez, Jan Bart M Koorstra, Nils Habbe, Michael MullendoreAbstract:Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch , as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary Tumor volume. The only discernible phenotype observed within the treated primary Tumor was a significant reduction in the population of aldehyde dehydrogenase–bright cells, which we have previously identified as a clonogenic Tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase–bright cells with IPI-269609 was accompanied by significant reduction in Tumor Engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with Tumor-initiating (“cancer stem cell”) properties. [Mol Cancer Ther 2008;7(9):2725–35]
Georg Feldmann - One of the best experts on this subject based on the ideXlab platform.
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an orally bioavailable small molecule inhibitor of hedgehog signaling inhibits Tumor initiation and metastasis in pancreatic cancer
Molecular Cancer Therapeutics, 2008Co-Authors: Georg Feldmann, Collins Karikari, Volker Fendrich, Karen Mcgovern, Djahida Bedja, Savita Bisht, Hector Alvarez, Jan Bart M Koorstra, Nils Habbe, Michael MullendoreAbstract:Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch, as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary Tumor volume. The only discernible phenotype observed within the treated primary Tumor was a significant reduction in the population of aldehyde dehydrogenase-bright cells, which we have previously identified as a clonogenic Tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase-bright cells with IPI-269609 was accompanied by significant reduction in Tumor Engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with Tumor-initiating ("cancer stem cell") properties.
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an orally bioavailable small molecule inhibitor of hedgehog signaling inhibits Tumor initiation and metastasis in pancreatic cancer
Molecular Cancer Therapeutics, 2008Co-Authors: Georg Feldmann, Collins Karikari, Volker Fendrich, Karen Mcgovern, Djahida Bedja, Savita Bisht, Hector Alvarez, Jan Bart M Koorstra, Nils Habbe, Michael MullendoreAbstract:Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch , as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary Tumor volume. The only discernible phenotype observed within the treated primary Tumor was a significant reduction in the population of aldehyde dehydrogenase–bright cells, which we have previously identified as a clonogenic Tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase–bright cells with IPI-269609 was accompanied by significant reduction in Tumor Engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with Tumor-initiating (“cancer stem cell”) properties. [Mol Cancer Ther 2008;7(9):2725–35]
Collins Karikari - One of the best experts on this subject based on the ideXlab platform.
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Tumor Engraftment in nude mice and enrichment in stroma related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer
Clinical Cancer Research, 2011Co-Authors: Ignacio Garridolaguna, Maria Uson, N V Rajeshkumar, Elizabeth De Oliveira, Collins Karikari, Maria C Villaroel, Ana Salomon, Gretchen E Taylor, Rajni SharmaAbstract:Purpose: The goal of this study was to evaluate prospectively the Engraftment rate, factors influencing Engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts. Experimental Design: Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of Tumor were implanted in nude mice. The status of the SMAD4 gene and content of Tumor-generating cells were determined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array. Patients were followed for progression and survival. Results: A total of 94 patients with PDA were resected, 69 Tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression for patients who received treatment with gemcitabine for metastatic disease ( n = 7) was double in patients with xenografts sensitive to gemcitabine. Conclusion: A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better Engraftment rate. Engraftment is a poor prognosis factor, and engrafted Tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways. Clin Cancer Res; 17(17); 5793–800. ©2011 AACR .
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an orally bioavailable small molecule inhibitor of hedgehog signaling inhibits Tumor initiation and metastasis in pancreatic cancer
Molecular Cancer Therapeutics, 2008Co-Authors: Georg Feldmann, Collins Karikari, Volker Fendrich, Karen Mcgovern, Djahida Bedja, Savita Bisht, Hector Alvarez, Jan Bart M Koorstra, Nils Habbe, Michael MullendoreAbstract:Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch, as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary Tumor volume. The only discernible phenotype observed within the treated primary Tumor was a significant reduction in the population of aldehyde dehydrogenase-bright cells, which we have previously identified as a clonogenic Tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase-bright cells with IPI-269609 was accompanied by significant reduction in Tumor Engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with Tumor-initiating ("cancer stem cell") properties.
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an orally bioavailable small molecule inhibitor of hedgehog signaling inhibits Tumor initiation and metastasis in pancreatic cancer
Molecular Cancer Therapeutics, 2008Co-Authors: Georg Feldmann, Collins Karikari, Volker Fendrich, Karen Mcgovern, Djahida Bedja, Savita Bisht, Hector Alvarez, Jan Bart M Koorstra, Nils Habbe, Michael MullendoreAbstract:Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch , as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary Tumor volume. The only discernible phenotype observed within the treated primary Tumor was a significant reduction in the population of aldehyde dehydrogenase–bright cells, which we have previously identified as a clonogenic Tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase–bright cells with IPI-269609 was accompanied by significant reduction in Tumor Engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with Tumor-initiating (“cancer stem cell”) properties. [Mol Cancer Ther 2008;7(9):2725–35]
Raimon Duranstruuck - One of the best experts on this subject based on the ideXlab platform.
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development of a transplantable gfp b cell lymphoma Tumor cell line from mhc defined miniature swine potential for a large animal Tumor model
Frontiers in Oncology, 2019Co-Authors: Marian Schenk, Abraham J Matar, Isabel Hanekamp, Robert J Hawley, Christene A Huang, Raimon DuranstruuckAbstract:The lack of a reliable and reproducible large animal Tumor model for the study of hemolymphatic malignancies limits the ability to explore the underlying pathophysiology and testing of novel therapies. The goal of this study was to develop an aggressive, trackable swine Tumor cell line in mice for adoptive transfer into MHC matched swine. Two Tumor cell lines, post-transplant lymphoproliferative disease (PTLD) 13271 and chronic myelogenous leukemia (CML) 14736, were previously established from the Massachusetts General Hospital (MGH) miniature swine herd. PTLD 13271 is a swine B-cell lymphoma line originating from an animal that developed PTLD following hematopoietic cell transplantation (HCT), while CML 14736 was generated from a swine that spontaneously developed CML. In order to select for aggressive Tumor variants, both lines were passage into NOD/SCID IL-2 receptor γ−/− (NSG) mice. Tumor induced mortality in mice injected with {"type":"entrez-protein","attrs":{"text":"CML14736","term_id":"888610597","term_text":"CML14736"}}CML14736 was 68% while 100% of mice injected with PTLD 13271 succumbed to PTLD by day 70. Based on aggressiveness, PTLD 13271 was selected for further development and re-passage into NSG mice resulting in increased Tumor burden and metastasis. Transduction of the PTLD 13271 cell line with a green fluorescent protein (GFP)-expressing lentivirus facilitated Tumor tracking when re-passaged in mice. Utilizing a tolerance induction strategy, GFP+ Tumors were injected into an MHC matched miniature swine and successfully followed via flow cytometry for 48 h in circulation, although Tumor Engraftment was not observed. In summary, we report the development of an aggressive GFP+B-cell lymphoma cell line which has the potential for facilitating development of a large animal Tumor model.
Peter Carmeliet - One of the best experts on this subject based on the ideXlab platform.
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anti placental growth factor reduces bone metastasis by blocking Tumor cell Engraftment and osteoclast differentiation
Cancer Research, 2010Co-Authors: Lieve Coenegrachts, Christa Maes, Sophie Torrekens, Riet Van Looveren, Massimiliano Mazzone, Theresa A Guise, Roger Bouillon, Jean Marie Stassen, Peter CarmelietAbstract:Treatment of bone metastases is largely symptomatic and is still an unmet medical need. Current therapies mainly target the late phase of Tumor-induced osteoclast activation and hereby inhibit further metastatic growth. This treatment method is, however, less effective in preventing initial Tumor Engraftment, a process that is supposed to depend on the bone microenvironment. We explored whether bone-derived placental growth factor (PlGF), a homologue of vascular endothelial growth factor-A, regulates osteolytic metastasis. Osteogenic cells secrete PlGF, the expression of which is enhanced by bone-metastasizing breast Tumor cells. Selective neutralization of host-derived PlGF by anti-mouse PlGF (alphaPlGF) reduced the incidence, number, and size of bone metastases, and preserved bone mass. alphaPlGF did not affect metastatic Tumor angiogenesis but inhibited osteoclast formation by preventing the upregulation of the osteoclastogenic cytokine receptor activator of NF-kappaB ligand in osteogenic cells, as well as by blocking the autocrine osteoclastogenic activity of PlGF. alphaPlGF also reduced the Engraftment of Tumor cells in the bone and inhibited their interaction with matrix components in the metastatic niche. alphaPlGF therefore inhibits not only the progression of metastasis but also the settlement of Tumor in the bone. These findings identify novel properties of PlGF and suggest that alphaPlGF might offer opportunities for adjuvant therapy of bone metastasis.
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anti placental growth factor reduces bone metastasis by blocking Tumor cell Engraftment and osteoclast differentiation
Cancer Research, 2010Co-Authors: Lieve Coenegrachts, Christa Maes, Sophie Torrekens, Massimiliano Mazzone, Theresa A Guise, Roger Bouillon, Jean Marie Stassen, Riet Van Looveren, Peter CarmelietAbstract:Treatment of bone metastases is largely symptomatic and is still an unmet medical need. Current therapies mainly target the late phase of Tumor-induced osteoclast activation and hereby inhibit further metastatic growth. This treatment method is, however, less effective in preventing initial Tumor Engraftment, a process that is supposed to depend on the bone microenvironment. We explored whether bone-derived placental growth factor (PlGF), a homologue of vascular endothelial growth factor-A, regulates osteolytic metastasis. Osteogenic cells secrete PlGF, the expression of which is enhanced by bone-metastasizing breast Tumor cells. Selective neutralization of host-derived PlGF by anti-mouse PlGF (αPlGF) reduced the incidence, number, and size of bone metastases, and preserved bone mass. αPlGF did not affect metastatic Tumor angiogenesis but inhibited osteoclast formation by preventing the upregulation of the osteoclastogenic cytokine receptor activator of NF-κB ligand in osteogenic cells, as well as by blocking the autocrine osteoclastogenic activity of PlGF. αPlGF also reduced the Engraftment of Tumor cells in the bone and inhibited their interaction with matrix components in the metastatic niche. αPlGF therefore inhibits not only the progression of metastasis but also the settlement of Tumor in the bone. These findings identify novel properties of PlGF and suggest that αPlGF might offer opportunities for adjuvant therapy of bone metastasis. Cancer Res; 70(16); 6537–47. ©2010 AACR.
