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Article ; Online: Development of a Practical Nomogram for Personalized Anemia Management in Patients Treated with Ataxia Telangiectasia and Rad3-related Inhibitor Camonsertib.

Rosen, Ezra / Yap, Timothy A / Lee, Elizabeth K / Højgaard, Martin / Mettu, Niharika B / Lheureux, Stephanie / Carneiro, Benedito A / Plummer, Ruth / Fretland, Adrian J / Ulanet, Danielle / Xu, Yi / McDougall, Robin / Koehler, Maria / Fontana, Elisa

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 30, Issue 4, Page(s) 687–694

Abstract: Purpose: Camonsertib is a highly selective and potent inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. Dose-dependent anemia is a class-related on-target adverse event often requiring dose modifications. Individual patient risk factors ... ...

Abstract	Purpose: Camonsertib is a highly selective and potent inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. Dose-dependent anemia is a class-related on-target adverse event often requiring dose modifications. Individual patient risk factors for the development of significant anemia complicate the selection of a "one-size-fits-all" ATR inhibitor (ATRi) dose and schedule, possibly leading to suboptimal therapeutic doses in patients at low risk of anemia. We evaluated whether early predictors of anemia could be identified to ultimately inform a personalized dose-modification approach. Patients and methods: On the basis of preclinical observations and a mechanistic understanding of ATRi-related anemia, we identified several potential factors to explore in a multivariable linear regression modeling tool for predicting hemoglobin level ahead of day 22 (cycle 2) of treatment. Results: In patients treated with camonsertib monotherapy (NCT04497116), we observed that hemoglobin decline is consistently preceded by reticulocytopenia, and dose- and exposure-dependent decreases in monocytes. We developed a nomogram incorporating baseline and day 8 hemoglobin and reticulocyte values that predicted the day 22 hemoglobin values of patients with clinically valuable concordance (within 7.5% of observations) 80% of the time in a cross-validation performance test of data from 60 patients. Conclusions: The prediction of future hemoglobin decrease, after a week of treatment, may enable a personalized, early dose modification to prevent development of clinically significant anemia and resulting unscheduled dose holds or transfusions.
MeSH term(s)	Humans ; Ataxia Telangiectasia ; Ataxia Telangiectasia Mutated Proteins ; Nomograms ; Anemia/drug therapy ; Anemia/etiology ; Hemoglobins
Chemical Substances	Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Hemoglobins
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2080
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Article ; Online: Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.

So, Joan / Lewis, Alexander C / Smith, Lorey K / Stanley, Kym / Franich, Rheana / Yoannidis, David / Pijpers, Lizzy / Dominguez, Pilar / Hogg, Simon J / Vervoort, Stephin J / Brown, Fiona C / Johnstone, Ricky W / McDonald, Gabrielle / Ulanet, Danielle B / Murtie, Josh / Gruber, Emily / Kats, Lev M

EMBO molecular medicine

2022 Volume 14, Issue 7, Page(s) e15203

Abstract: The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH ... ...

Abstract	The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
MeSH term(s)	Dihydroorotate Dehydrogenase ; Enzyme Inhibitors/pharmacology ; Humans ; Leukemia, Myeloid, Acute ; Oxidoreductases Acting on CH-CH Group Donors/metabolism ; Protein Biosynthesis ; Pyrimidines/pharmacology
Chemical Substances	Dihydroorotate Dehydrogenase ; Enzyme Inhibitors ; Pyrimidines ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-)
Language	English
Publishing date	2022-05-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202115203
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Article ; Online: Loss of p19(Arf) facilitates the angiogenic switch and tumor initiation in a multi-stage cancer model via p53-dependent and independent mechanisms.

Ulanet, Danielle B / Hanahan, Douglas

PloS one

2010 Volume 5, Issue 8, Page(s) e12454

Abstract: The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence ... ...

Abstract	The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence suggests that, in addition to promoting tumorigenesis via disruptions in the homeostatic balance between cell proliferation and apoptosis of overt cancer cells, genetic alterations leading to tumor suppressor loss of function or oncogene gain of function can also incite tumor development via effects on the tumor microenvironment. In a transgenic mouse model of multi-stage pancreatic neuroendocrine carcinogenesis (PNET) driven by inhibition of the canonical p53 and Rb tumor suppressors with SV40 large T-antigen (Tag), stochastic progression to tumors is limited in part by a requirement for initiation of an angiogenic switch. Despite inhibition of p53 by Tag in this mouse PNET model, concomitant disruption of Arf via genetic knockout resulted in a significantly accelerated pathway to tumor formation that was surprisingly not driven by alterations in tumor cell proliferation or apoptosis, but rather via earlier activation of the angiogenic switch. In the setting of a constitutional p53 gene knockout, loss of Arf also accelerated tumor development, albeit to a lesser degree. These findings demonstrate that Arf loss of function can promote tumorigenesis via facilitating angiogenesis, at least in part, through p53-independent mechanisms.
MeSH term(s)	Animals ; Apoptosis/genetics ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p16/deficiency ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Disease Models, Animal ; Disease Progression ; Gene Knockout Techniques ; Mice ; Mice, Inbred C57BL ; Neoplasm Staging ; Neovascularization, Pathologic/genetics ; Neuroendocrine Tumors/blood supply ; Neuroendocrine Tumors/genetics ; Neuroendocrine Tumors/metabolism ; Neuroendocrine Tumors/pathology ; Pancreatic Neoplasms/blood supply ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Stromal Cells/metabolism ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Cdkn2a protein, mouse ; Cyclin-Dependent Kinase Inhibitor p16 ; Tumor Suppressor Protein p53
Language	English
Publishing date	2010-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0012454
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Loss of p19(Arf) facilitates the angiogenic switch and tumor initiation in a multi-stage cancer model via p53-dependent and independent mechanisms.

Danielle B Ulanet / Douglas Hanahan

PLoS ONE, Vol 5, Iss 8, p e

2010 Volume 12454

Abstract	The Arf tumor suppressor acts as a sensor of oncogenic signals, countering aberrant proliferation in large part via activation of the p53 transcriptional program, though a number of p53-independent functions have been described. Mounting evidence suggests that, in addition to promoting tumorigenesis via disruptions in the homeostatic balance between cell proliferation and apoptosis of overt cancer cells, genetic alterations leading to tumor suppressor loss of function or oncogene gain of function can also incite tumor development via effects on the tumor microenvironment. In a transgenic mouse model of multi-stage pancreatic neuroendocrine carcinogenesis (PNET) driven by inhibition of the canonical p53 and Rb tumor suppressors with SV40 large T-antigen (Tag), stochastic progression to tumors is limited in part by a requirement for initiation of an angiogenic switch. Despite inhibition of p53 by Tag in this mouse PNET model, concomitant disruption of Arf via genetic knockout resulted in a significantly accelerated pathway to tumor formation that was surprisingly not driven by alterations in tumor cell proliferation or apoptosis, but rather via earlier activation of the angiogenic switch. In the setting of a constitutional p53 gene knockout, loss of Arf also accelerated tumor development, albeit to a lesser degree. These findings demonstrate that Arf loss of function can promote tumorigenesis via facilitating angiogenesis, at least in part, through p53-independent mechanisms.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2010-08-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results.

Yap, Timothy A / Fontana, Elisa / Lee, Elizabeth K / Spigel, David R / Højgaard, Martin / Lheureux, Stephanie / Mettu, Niharika B / Carneiro, Benedito A / Carter, Louise / Plummer, Ruth / Cote, Gregory M / Meric-Bernstam, Funda / O'Connell, Joseph / Schonhoft, Joseph D / Wainszelbaum, Marisa / Fretland, Adrian J / Manley, Peter / Xu, Yi / Ulanet, Danielle /

Rimkunas, Victoria / Zinda, Mike / Koehler, Maria / Silverman, Ian M / Reis-Filho, Jorge S / Rosen, Ezra

Nature medicine

2023 Volume 29, Issue 6, Page(s) 1400–1411

Abstract: Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia- ... ...

Abstract	Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d
MeSH term(s)	Female ; Humans ; Ataxia Telangiectasia ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Protein Kinase Inhibitors/pharmacokinetics ; DNA Damage ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism
Chemical Substances	Protein Kinase Inhibitors ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
Language	English
Publishing date	2023-06-05
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02399-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia

Joan So / Alexander C Lewis / Lorey K Smith / Kym Stanley / Rheana Franich / David Yoannidis / Lizzy Pijpers / Pilar Dominguez / Simon J Hogg / Stephin J Vervoort / Fiona C Brown / Ricky W Johnstone / Gabrielle McDonald / Danielle B Ulanet / Josh Murtie / Emily Gruber / Lev M Kats

EMBO Molecular Medicine, Vol 14, Iss 7, Pp n/a-n/a (2022)

2022

Abstract: Abstract The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate‐limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. ...

Abstract	Abstract The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate‐limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.
Keywords	acute myeloid leukemia ; DHODH ; leukemic stem cells ; protein translation ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy.

Ulanet, Danielle B / Ludwig, Dale L / Kahn, C Ronald / Hanahan, Douglas

Proceedings of the National Academy of Sciences of the United States of America

2010 Volume 107, Issue 24, Page(s) 10791–10798

Abstract: The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the ... ...

Abstract	The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic beta cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti-IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti-IGF-1R therapies.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Breast Neoplasms/metabolism ; Breast Neoplasms/therapy ; Cell Line, Tumor ; Female ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/therapy ; Neuroendocrine Tumors/metabolism ; Neuroendocrine Tumors/therapy ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/therapy ; Receptor, IGF Type 1/antagonists & inhibitors ; Receptor, IGF Type 2/metabolism ; Receptor, Insulin/deficiency ; Receptor, Insulin/genetics ; Receptor, Insulin/metabolism ; Signal Transduction
Chemical Substances	Antibodies, Monoclonal ; Receptor, IGF Type 2 ; Receptor, IGF Type 1 (EC 2.7.10.1) ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2010-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0914076107
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Zs.A 1148: Show issues

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Article ; Online: Genetic ablation of Bcl-x attenuates invasiveness without affecting apoptosis or tumor growth in a mouse model of pancreatic neuroendocrine cancer.

Hager, Jeffrey H / Ulanet, Danielle B / Hennighausen, Lothar / Hanahan, Douglas

PloS one

2009 Volume 4, Issue 2, Page(s) e4455

Abstract: Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro- and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of ... ...

Abstract	Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro- and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-x(L), demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic beta-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-x(L) upon exogenous over-expression.
MeSH term(s)	Animals ; Apoptosis ; Cell Movement ; Cell Proliferation ; Disease Models, Animal ; Disease Progression ; GTPase-Activating Proteins/metabolism ; Gene Deletion ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Islets of Langerhans/metabolism ; Islets of Langerhans/pathology ; Mice ; Mice, Knockout ; Neoplasm Invasiveness ; Neuroendocrine Tumors/genetics ; Neuroendocrine Tumors/pathology ; Organ Specificity ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Transcription, Genetic ; Up-Regulation/genetics ; bcl-X Protein/deficiency ; bcl-X Protein/metabolism
Chemical Substances	GTPase-Activating Proteins ; Ralbp1 protein, mouse ; bcl-X Protein
Language	English
Publishing date	2009-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0004455
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

Ulanet, Danielle B / Ludwig, Dale L / Kahn, C. Ronald / Hanahan, Douglas

Proceedings of the National Academy of Sciences of the United States of America. 2010 June 15, v. 107, no. 24

2010

Abstract	The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic Î² cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti-IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti-IGF-1R therapies.
Keywords	animal models ; apoptosis ; breast neoplasms ; carcinogenesis ; gene overexpression ; genes ; humans ; insulin receptors ; insulin-like growth factor I receptor ; insulin-like growth factor II ; monoclonal antibodies ; neoplasm cells ; signal transduction ; therapeutics ; transgenic animals ; tyrosine
Language	English
Dates of publication	2010-0615
Size	p. 10791-10798.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0914076107
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Article ; Online: Genetic ablation of Bcl-x attenuates invasiveness without affecting apoptosis or tumor growth in a mouse model of pancreatic neuroendocrine cancer.

Jeffrey H Hager / Danielle B Ulanet / Lothar Hennighausen / Douglas Hanahan

PLoS ONE, Vol 4, Iss 2, p e

2009 Volume 4455

Abstract	Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro- and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-x(L), demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic beta-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-x(L) upon exogenous over-expression.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2009-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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