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Article ; Online: SGN-CD228A Is an Investigational CD228-Directed Antibody-Drug Conjugate with Potent Antitumor Activity across a Wide Spectrum of Preclinical Solid Tumor Models.

Mazahreh, Rebecca / Mason, Marsha L / Gosink, John J / Olson, Devra J / Thurman, Robert / Hale, Christopher / Westendorf, Lori / Pires, Thomas A / Leiske, Christopher I / Carlson, Markus / Nguyen, Liem T / Cochran, Julia H / Okeley, Nicole M / Yumul, Roma / Jin, Steven / Stone, Ivan J / Sahetya, Disha / Nesterova, Albina / Allred, Sean /

Hensley, Kelly M / Hu, Rachael / Lawrence, Robert / Lewis, Timothy S / Sandall, Sharsti

Molecular cancer therapeutics

2023 Volume 22, Issue 4, Page(s) 421–434

Abstract: SGN-CD228A is an investigational antibody-drug conjugate (ADC) directed to melanotransferrin (CD228, MELTF, MFI2, p97), a cell-surface protein first identified in melanoma. SGN-CD228A consists of a humanized antibody, hL49, with high specificity and ... ...

Abstract	SGN-CD228A is an investigational antibody-drug conjugate (ADC) directed to melanotransferrin (CD228, MELTF, MFI2, p97), a cell-surface protein first identified in melanoma. SGN-CD228A consists of a humanized antibody, hL49, with high specificity and affinity for CD228 that is stably conjugated to 8 molecules of the clinically validated microtubule-disrupting agent monomethyl auristatin E (MMAE) via a novel glucuronide linker. We performed comprehensive IHC studies, which corroborated published RNA sequencing data and confirmed low CD228 expression in normal tissues and high expression in several cancers, including melanoma, squamous non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), colorectal cancer, and pancreatic cancer. SGN-CD228A was efficiently internalized in various tumor cell types, and its cytotoxic activity was dependent on CD228 expression and internalization and intrinsic sensitivity to the MMAE payload. Compared with the valine-citrulline dipeptide linker, the novel glucuronide linker increased the cellular retention of MMAE in vitro and conferred improved antitumor activity against melanoma cell lines in vitro and in vivo. In addition, SGN-CD228A was active across melanoma, TNBC, and NSCLC cell line- and patient-derived xenograft models with heterogeneous antigen expression. In vivo, CD228 expression was important for response to SGN-CD228A but was not well correlated across all tumor types, suggesting that other factors associated with ADC activity are important. Overall, SGN-CD228A is a CD228-directed, investigational ADC that employs innovative technology and has compelling preclinical antitumor activity. SGN-CD228A is investigated in a Phase I clinical trial (NCT04042480) in patients with advanced solid tumors.
MeSH term(s)	Humans ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carcinoma, Non-Small-Cell Lung ; Cell Line, Tumor ; Glucuronides ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Immunoconjugates/chemistry ; Lung Neoplasms ; Melanoma ; Triple Negative Breast Neoplasms ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Glucuronides ; Immunoconjugates
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-22-0401
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Article ; Online: Ribosomal protein L7/L12 is required for GTPase translation factors EF-G, RF3, and IF2 to bind in their GTP state to 70S ribosomes.

Carlson, Markus A / Haddad, Bassam G / Weis, Amanda J / Blackwood, Colby S / Shelton, Catherine D / Wuerth, Michelle E / Walter, Justin D / Spiegel, Paul Clint

The FEBS journal

2017 Volume 284, Issue 11, Page(s) 1631–1643

Abstract: Ribosomal protein L7/L12 is associated with translation initiation, elongation, and termination by the 70S ribosome. The guanosine 5' triphosphate hydrolase (GTPase) activity of elongation factor G (EF-G) requires the presence of L7/L12, which is ... ...

Abstract	Ribosomal protein L7/L12 is associated with translation initiation, elongation, and termination by the 70S ribosome. The guanosine 5' triphosphate hydrolase (GTPase) activity of elongation factor G (EF-G) requires the presence of L7/L12, which is critical for ribosomal translocation. Here, we have developed new methods for the complete depletion of L7/L12 from Escherichia coli 70S ribosomes to analyze the effect of L7/L12 on the activities of the GTPase factors EF-G, RF3, IF2, and LepA. Upon removal of L7/L12 from ribosomes, the GTPase activities of EF-G, RF3, and IF2 decreased to basal levels, while the activity of LepA decreased marginally. Upon reconstitution of ribosomes with recombinant L12, the GTPase activities of all GTPases returned to full activity. Moreover, ribosome binding assays indicated that EF-G, RF3, and IF2 require L7/L12 for stable binding in the GTP state, and LepA retained > 50% binding. Lastly, an EF-G∆G' truncation mutant possessed ribosome-dependent GTPase activity, which was insensitive to L7/L12. Our results indicate that L7/L12 is required for stable binding of ribosome-dependent GTPases that harbor direct interactions to the L7/L12 C-terminal domains, either through a G' domain (EF-G, RF3) or a unique N-terminal domain (IF2). Furthermore, we hypothesize this interaction is concomitant with counterclockwise ribosomal intersubunit rotation, which is required for translocation, initiation, and post-termination.
MeSH term(s)	Enzyme Activation ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Escherichia coli Proteins/physiology ; Guanosine Triphosphate/metabolism ; Hydrolysis ; Mutagenesis, Site-Directed ; Peptide Elongation Factor G/metabolism ; Peptide Initiation Factors/metabolism ; Peptide Termination Factors/metabolism ; Prokaryotic Initiation Factor-2/metabolism ; Recombinant Proteins/metabolism ; Ribosomal Proteins/deficiency ; Ribosomal Proteins/genetics ; Ribosomal Proteins/physiology ; Ribosomes/metabolism
Chemical Substances	Escherichia coli Proteins ; LepA protein, E coli ; Peptide Elongation Factor G ; Peptide Initiation Factors ; Peptide Termination Factors ; Prokaryotic Initiation Factor-2 ; Recombinant Proteins ; Ribosomal Proteins ; prfC protein, E coli ; rplL protein, E coli ; Guanosine Triphosphate (86-01-1)
Language	English
Publishing date	2017-06
Publishing country	England
Document type	Editorial
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.14067
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Article: Ribosomal protein L7/L12 is required for GTPase translation factors EFâG, RF3, and IF2 to bind in their GTP state to 70S ribosomes

Carlson, Markus A / Amanda J. Weis / Bassam G. Haddad / Catherine D. Shelton / Colby S. Blackwood / Justin D. Walter / Michelle E. Wuerth / Paul Clint Spiegel Jr

FEBS journal. 2017 June, v. 284, no. 11

2017

Abstract: Ribosomal protein L7/L12 is associated with translation initiation, elongation, and termination by the 70S ribosome. The guanosine 5â² triphosphate hydrolase (GTPase) activity of elongation factor G (EFâG) requires the presence of L7/L12, which is ... ...

Abstract	Ribosomal protein L7/L12 is associated with translation initiation, elongation, and termination by the 70S ribosome. The guanosine 5â² triphosphate hydrolase (GTPase) activity of elongation factor G (EFâG) requires the presence of L7/L12, which is critical for ribosomal translocation. Here, we have developed new methods for the complete depletion of L7/L12 from Escherichia coli 70S ribosomes to analyze the effect of L7/L12 on the activities of the GTPase factors EFâG, RF3, IF2, and LepA. Upon removal of L7/L12 from ribosomes, the GTPase activities of EFâG, RF3, and IF2 decreased to basal levels, while the activity of LepA decreased marginally. Upon reconstitution of ribosomes with recombinant L12, the GTPase activities of all GTPases returned to full activity. Moreover, ribosome binding assays indicated that EFâG, RF3, and IF2 require L7/L12 for stable binding in the GTP state, and LepA retained > 50% binding. Lastly, an EFâGâGâ² truncation mutant possessed ribosomeâdependent GTPase activity, which was insensitive to L7/L12. Our results indicate that L7/L12 is required for stable binding of ribosomeâdependent GTPases that harbor direct interactions to the L7/L12 Câterminal domains, either through a Gâ² domain (EFâG, RF3) or a unique Nâterminal domain (IF2). Furthermore, we hypothesize this interaction is concomitant with counterclockwise ribosomal intersubunit rotation, which is required for translocation, initiation, and postâtermination.
Keywords	enzyme activity ; Escherichia coli ; guanosine triphosphate ; guanosinetriphosphatase ; methodology ; mutants ; ribosomal proteins ; ribosomes
Language	English
Dates of publication	2017-06
Size	p. 1631-1643.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	EDITORIAL
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.14067
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Article: Non-Invasive Monitoring of Stromal Biophysics with Targeted Depletion of Hyaluronan in Pancreatic Ductal Adenocarcinoma.

Maloney, Ezekiel / DuFort, Christopher C / Provenzano, Paolo P / Farr, Navid / Carlson, Markus A / Vohra, Ravneet / Park, Joshua / Hingorani, Sunil R / Lee, Donghoon

Cancers

2019 Volume 11, Issue 6

Abstract: Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust physical barrier to the perfusion and diffusion of small molecule therapeutics. The targeted depletion of hyaluronan with a PEGylated recombinant human hyaluronidase (PEGPH20) lowers interstitial gel-fluid pressures and re-expands collapsed intratumoral vasculature, improving the delivery of concurrently administered agents. Here we report a non-invasive means of assessing biophysical responses to stromal intervention with quantitative multiparametric magnetic resonance imaging (MRI) at 14 Tesla (T). We found that spin-spin relaxation time T2 values and glycosaminoglycan chemical exchange saturation transfer (GagCEST) values decreased at 24 h, reflecting depletion of intratumoral HA content, and that these parameters recovered at 7 days concurrent with replenishment of intratumoral HA. This was also reflected in an increase in low-b apparent diffusion coefficient (ADC) at 24 h, consistent with improved tumor perfusion that again normalized at 7 days after treatment. Phantom imaging suggests that the GagCEST signal is driven by changes in HA versus other glycosaminoglycans. Thus, multiparametric magnetic resonance imaging (MRI) can be used as a non-invasive tool to assess therapeutic responses to targeted stromal therapy in PDA and likely other stroma-rich solid tumors that have high levels of hyaluronan and collagen.
Language	English
Publishing date	2019-06-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers11060772
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Article: Photostable Ratiometric Pdot Probe for in Vitro and in Vivo Imaging of Hypochlorous Acid

Wu, Li / Carlson Markus A / Chen Lei / Chiu Daniel T / DuFort Christopher C / Hingorani Sunil R / Kuo Chun-Ting / Qin Yuling / Wu I-Che / Wu Xu / Yu Jiangbo

Journal of the American Chemical Society. 2017 May 24, v. 139, no. 20

2017

Abstract: Developing probes for the detection of reactive oxygen species (ROS), a hallmark of many pathophysiological process, is imperative to both understanding the precise roles of ROS in many life-threatening diseases and optimizing therapeutic interventions. ... ...

Abstract	Developing probes for the detection of reactive oxygen species (ROS), a hallmark of many pathophysiological process, is imperative to both understanding the precise roles of ROS in many life-threatening diseases and optimizing therapeutic interventions. We herein report an all-in-one fluorescent semiconducting polymer based far-red to near-infrared (NIR) Pdot nanoprobe for the ratiometric detection of hypochlorous acid (HOCl). The fabrication takes the advantage of flexible polymer design by incorporating target-sensitive and target-inert fluorophores into a single conjugated polymer to avoid leakage or differential photobleaching problems existed in other nanoprobes. The obtained nanoprobe has improved performance in HOCl sensing, such as high brightness, ideal far-red to NIR optical window, excellent photostability, self-referenced ratiometric response, fast response, and high selectivity. The dual-emission property allows the sensitive imaging of HOCl fluctuations produced in living macrophage cells and peritonitis of living mice with high contrast. This study not only provides a powerful and promising nanoprobe to be potentially used in the investigations of in situ HOCl status of diseases in living systems but also puts forward the design strategy of a new category of ratiometric fluorescent probes facilitating precise and reliable measurement in biological systems.
Keywords	fluorescence ; fluorescent dyes ; image analysis ; macrophages ; mice ; peritonitis ; photobleaching ; photostability ; polymers ; reactive oxygen species
Language	English
Dates of publication	2017-0524
Size	p. 6911-6918.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021%2Fjacs.7b01545
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Article ; Online: Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity.

Stromnes, Ingunn M / Brockenbrough, J Scott / Izeradjene, Kamel / Carlson, Markus A / Cuevas, Carlos / Simmons, Randi M / Greenberg, Philip D / Hingorani, Sunil R

Gut

2014 Volume 63, Issue 11, Page(s) 1769–1781

Abstract: Background: Pancreatic ductal adenocarcinoma (PDA) is characterised by a robust desmoplasia, including the notable accumulation of immunosuppressive cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the ... ...

Abstract	Background: Pancreatic ductal adenocarcinoma (PDA) is characterised by a robust desmoplasia, including the notable accumulation of immunosuppressive cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the malignant cells fail to express high levels of antigens that are sufficiently immunogenic to engender an effector T cell response. Objective: To investigate the predominant subsets of immunosuppressive cancer-conditioned myeloid cells that chronicle and shape the progression of pancreas cancer. We show that selective depletion of one subset of myeloid-derived suppressor cells (MDSC) in an autochthonous, genetically engineered mouse model (GEMM) of PDA unmasks the ability of the adaptive immune response to engage and target tumour epithelial cells. Methods: A combination of in vivo and in vitro studies were performed employing a GEMM that faithfully recapitulates the cardinal features of human PDA. The predominant cancer-conditioned myeloid cell subpopulation was specifically targeted in vivo and the biological outcomes determined. Results: PDA orchestrates the induction of distinct subsets of cancer-associated myeloid cells through the production of factors known to influence myelopoiesis. These immature myeloid cells inhibit the proliferation and induce apoptosis of activated T cells. Targeted depletion of granulocytic MDSC (Gr-MDSC) in autochthonous PDA increases the intratumoral accumulation of activated CD8 T cells and apoptosis of tumour epithelial cells and also remodels the tumour stroma. Conclusions: Neoplastic ductal cells of the pancreas induce distinct myeloid cell subsets that promote tumour cell survival and accumulation. Targeted depletion of a single myeloid subset, the Gr-MDSC, can unmask an endogenous T cell response, disclosing an unexpected latent immunity and invoking targeting of Gr-MDSC as a potential strategy to exploit for treating this highly lethal disease.
MeSH term(s)	Adaptive Immunity ; Animals ; Carcinoma, Pancreatic Ductal/immunology ; Carcinoma, Pancreatic Ductal/pathology ; Disease Models, Animal ; Disease Progression ; Genetic Engineering ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; In Vitro Techniques ; Mice ; Myeloid Cells/immunology ; Myeloid Cells/pathology ; Myelopoiesis/immunology ; Pancreatic Neoplasms/immunology ; Pancreatic Neoplasms/pathology ; Spleen/immunology
Chemical Substances	Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2014-02-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2013-306271
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Article ; Online: Photostable Ratiometric Pdot Probe for in Vitro and in Vivo Imaging of Hypochlorous Acid.

Wu, Li / Wu, I-Che / DuFort, Christopher C / Carlson, Markus A / Wu, Xu / Chen, Lei / Kuo, Chun-Ting / Qin, Yuling / Yu, Jiangbo / Hingorani, Sunil R / Chiu, Daniel T

Journal of the American Chemical Society

2017 Volume 139, Issue 20, Page(s) 6911–6918

Abstract	Developing probes for the detection of reactive oxygen species (ROS), a hallmark of many pathophysiological process, is imperative to both understanding the precise roles of ROS in many life-threatening diseases and optimizing therapeutic interventions. We herein report an all-in-one fluorescent semiconducting polymer based far-red to near-infrared (NIR) Pdot nanoprobe for the ratiometric detection of hypochlorous acid (HOCl). The fabrication takes the advantage of flexible polymer design by incorporating target-sensitive and target-inert fluorophores into a single conjugated polymer to avoid leakage or differential photobleaching problems existed in other nanoprobes. The obtained nanoprobe has improved performance in HOCl sensing, such as high brightness, ideal far-red to NIR optical window, excellent photostability, self-referenced ratiometric response, fast response, and high selectivity. The dual-emission property allows the sensitive imaging of HOCl fluctuations produced in living macrophage cells and peritonitis of living mice with high contrast. This study not only provides a powerful and promising nanoprobe to be potentially used in the investigations of in situ HOCl status of diseases in living systems but also puts forward the design strategy of a new category of ratiometric fluorescent probes facilitating precise and reliable measurement in biological systems.
MeSH term(s)	Fluorescent Dyes/chemistry ; Hypochlorous Acid/analysis ; Molecular Structure ; Photochemical Processes
Chemical Substances	Fluorescent Dyes ; Hypochlorous Acid (712K4CDC10)
Language	English
Publishing date	2017-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.7b01545
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Article ; Online: RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma.

Whittle, Martin C / Izeradjene, Kamel / Rani, P Geetha / Feng, Libing / Carlson, Markus A / DelGiorno, Kathleen E / Wood, Laura D / Goggins, Michael / Hruban, Ralph H / Chang, Amy E / Calses, Philamer / Thorsen, Shelley M / Hingorani, Sunil R

Cell

2015 Volume 161, Issue 6, Page(s) 1345–1360

Abstract: For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular understanding of these distinct disease manifestations can ... ...

Abstract	For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular understanding of these distinct disease manifestations can critically inform patient management. Using genetically engineered mouse models, we show that heterozygous mutation of Dpc4/Smad4 attenuates the metastatic potential of Kras(G12D/+);Trp53(R172H/+) pancreatic ductal adenocarcinomas while increasing their proliferation. Subsequent loss of heterozygosity of Dpc4 restores metastatic competency while further unleashing proliferation, creating a highly lethal combination. Expression levels of Runx3 respond to and combine with Dpc4 status to coordinately regulate the balance between cancer cell division and dissemination. Thus, Runx3 serves as both a tumor suppressor and promoter in slowing proliferation while orchestrating a metastatic program to stimulate cell migration, invasion, and secretion of proteins that favor distant colonization. These findings suggest a model to anticipate likely disease behaviors in patients and tailor treatment strategies accordingly.
MeSH term(s)	Animals ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Core Binding Factor Alpha 3 Subunit/metabolism ; Disease Models, Animal ; Genes, p53 ; Humans ; Mice ; Neoplasm Metastasis/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Smad4 Protein/genetics
Chemical Substances	Core Binding Factor Alpha 3 Subunit ; Runx3 protein, human ; Smad4 Protein ; Smad4 protein, mouse ; Kras2 protein, mouse (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2015-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2015.04.048
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Optical painting and fluorescence activated sorting of single adherent cells labelled with photoswitchable Pdots.

Kuo, Chun-Ting / Thompson, Alison M / Gallina, Maria Elena / Ye, Fangmao / Johnson, Eleanor S / Sun, Wei / Zhao, Mengxia / Yu, Jiangbo / Wu, I-Che / Fujimoto, Bryant / DuFort, Christopher C / Carlson, Markus A / Hingorani, Sunil R / Paguirigan, Amy L / Radich, Jerald P / Chiu, Daniel T

Nature communications

2016 Volume 7, Page(s) 11468

Abstract: The efficient selection and isolation of individual cells of interest from a mixed population is desired in many biomedical and clinical applications. Here we show the concept of using photoswitchable semiconducting polymer dots (Pdots) as an optical ' ... ...

Abstract	The efficient selection and isolation of individual cells of interest from a mixed population is desired in many biomedical and clinical applications. Here we show the concept of using photoswitchable semiconducting polymer dots (Pdots) as an optical 'painting' tool, which enables the selection of certain adherent cells based on their fluorescence, and their spatial and morphological features, under a microscope. We first develop a Pdot that can switch between the bright (ON) and dark (OFF) states reversibly with a 150-fold contrast ratio on irradiation with ultraviolet or red light. With a focused 633-nm laser beam that acts as a 'paintbrush' and the photoswitchable Pdots as the 'paint', we select and 'paint' individual Pdot-labelled adherent cells by turning on their fluorescence, then proceed to sort and recover the optically marked cells (with 90% recovery and near 100% purity), followed by genetic analysis.
MeSH term(s)	Fluorescence ; Humans ; MCF-7 Cells ; Microscopy, Confocal ; Microscopy, Fluorescence ; Molecular Imaging/methods ; Polymers/chemistry ; Quantum Dots ; Semiconductors
Chemical Substances	Polymers
Language	English
Publishing date	2016-04-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms11468
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Article ; Online: Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase.

DuFort, Christopher C / DelGiorno, Kathleen E / Carlson, Markus A / Osgood, Ryan J / Zhao, Chunmei / Huang, Zhongdong / Thompson, Curtis B / Connor, Robert J / Thanos, Christopher D / Scott Brockenbrough, J / Provenzano, Paolo P / Frost, Gregory I / Michael Shepard, H / Hingorani, Sunil R

Biophysical journal

2016 Volume 110, Issue 9, Page(s) 2106–2119

Abstract: Elevated interstitial fluid pressure can present a substantial barrier to drug delivery in solid tumors. This is particularly true of pancreatic ductal adenocarcinoma, a highly lethal disease characterized by a robust fibroinflammatory response, ... ...

Abstract	Elevated interstitial fluid pressure can present a substantial barrier to drug delivery in solid tumors. This is particularly true of pancreatic ductal adenocarcinoma, a highly lethal disease characterized by a robust fibroinflammatory response, widespread vascular collapse, and hypoperfusion that together serve as primary mechanisms of treatment resistance. Free-fluid pressures, however, are relatively low in pancreatic ductal adenocarcinoma and cannot account for the vascular collapse. Indeed, we have shown that the overexpression and deposition in the interstitium of high-molecular-weight hyaluronan (HA) is principally responsible for generating pressures that can reach 100 mmHg through the creation of a large gel-fluid phase. By interrogating a variety of tissues, tumor types, and experimental model systems, we show that an HA-dependent fluid phase contributes substantially to pressures in many solid tumors and has been largely unappreciated heretofore. We investigated the relative contributions of both freely mobile fluid and gel fluid to interstitial fluid pressure by performing simultaneous, real-time fluid-pressure measurements with both the classical wick-in-needle method (to estimate free-fluid pressure) and a piezoelectric pressure catheter transducer (which is capable of capturing pressures associated with either phase). We demonstrate further that systemic treatment with pegylated recombinant hyaluronidase (PEGPH20) depletes interstitial HA and eliminates the gel-fluid phase. This significantly reduces interstitial pressures and leaves primarily free fluid behind, relieving the barrier to drug delivery. These findings argue that quantifying the contributions of free- and gel-fluid phases to hydraulically transmitted pressures in a given cancer will be essential to designing the most appropriate and effective strategies to overcome this important and frequently underestimated resistance mechanism.
MeSH term(s)	Adenocarcinoma/pathology ; Animals ; Extracellular Fluid/drug effects ; Extracellular Fluid/metabolism ; Hyaluronic Acid/pharmacology ; Hydrostatic Pressure ; Mice ; NIH 3T3 Cells ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Viscosity
Chemical Substances	Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2016--10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2016.03.040
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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