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Article ; Online: Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation.

Singh, Pankaj K / Deorukhkar, Amit A / Venkatesulu, Bhanu P / Li, Xiaolin / Tailor, Ramesh / Bomalaski, John S / Krishnan, Sunil

Molecular cancer therapeutics

2019 Volume 18, Issue 12, Page(s) 2381–2393

Abstract: Distinct metabolic vulnerabilities of cancer cells compared with normal cells can potentially be exploited for therapeutic targeting. Deficiency of argininosuccinate synthetase-1 (ASS1) in pancreatic cancers creates auxotrophy for the semiessential amino ...

Abstract	Distinct metabolic vulnerabilities of cancer cells compared with normal cells can potentially be exploited for therapeutic targeting. Deficiency of argininosuccinate synthetase-1 (ASS1) in pancreatic cancers creates auxotrophy for the semiessential amino acid arginine. We explored the therapeutic potential of depleting exogenous arginine via pegylated arginine deiminase (ADI-PEG20) treatment as an adjunct to radiotherapy. We evaluated the efficacy of treatment of human pancreatic cancer cell lines and xenografts with ADI-PEG20 and radiation via clonogenic assays and tumor growth delay experiments. We also investigated potential mechanisms of action using reverse-phase protein array, Western blotting, and IHC and immunofluorescence staining. ADI-PEG20 potently radiosensitized ASS1-deficient pancreatic cancer cells (MiaPaCa-2, Panc-1, AsPc-1, HPAC, and CaPan-1), but not ASS1-expressing cell lines (Bxpc3, L3.6pl, and SW1990). Reverse phase protein array studies confirmed increased expression of proteins related to endoplasmic reticulum (ER) stress and apoptosis, which were confirmed by Western blot analysis. Inhibition of ER stress signaling with 4-phenylbutyrate abrogated the expression of ER stress proteins and reversed radiosensitization by ADI-PEG20. Independent
MeSH term(s)	Animals ; Arginine/therapeutic use ; Cell Line, Tumor ; Disease Models, Animal ; Humans ; Hydrolases/pharmacology ; Hydrolases/therapeutic use ; Mice ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/radiotherapy ; Polyethylene Glycols/pharmacology ; Polyethylene Glycols/therapeutic use
Chemical Substances	Polyethylene Glycols (3WJQ0SDW1A) ; Arginine (94ZLA3W45F) ; Hydrolases (EC 3.-) ; ADI PEG20 (EC 3.5.3.6)
Language	English
Publishing date	2019-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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-18-0708
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Article ; Online: Targeting inflammatory pathways for tumor radiosensitization.

Deorukhkar, Amit / Krishnan, Sunil

Biochemical pharmacology

2010 Volume 80, Issue 12, Page(s) 1904–1914

Abstract: Although radiation therapy (RT) is an integral component of treatment of patients with many types of cancer, inherent and/or acquired resistance to the cytotoxic effects of RT is increasingly recognized as a significant impediment to effective cancer ... ...

Abstract	Although radiation therapy (RT) is an integral component of treatment of patients with many types of cancer, inherent and/or acquired resistance to the cytotoxic effects of RT is increasingly recognized as a significant impediment to effective cancer treatment. Inherent resistance is mediated by constitutively activated oncogenic, proliferative and anti-apoptotic proteins/pathways whereas acquired resistance refers to transient induction of proteins/pathways following radiation exposure. To realize the full potential of RT, it is essential to understand the signaling pathways that mediate inducible radiation resistance, a poorly characterized phenomenon, and identify druggable targets for radiosensitization. Ionizing radiation induces a multilayered signaling response in mammalian cells by activating many pro-survival pathways that converge to transiently activate a few important transcription factors (TFs), including nuclear factor kappa B (NF-κB) and signal transducers and activators of transcription (STATs), the central mediators of inflammatory and carcinogenic signaling. Together, these TFs activate a wide spectrum of pro-survival genes regulating inflammation, anti-apoptosis, invasion and angiogenesis pathways, which confer tumor cell radioresistance. Equally, radiation-induced activation of pro-inflammatory cytokine network (including interleukin (IL)-1β, IL-6 and tumor necrosis factor-α) has been shown to mediate symptom burden (pain, fatigue, local inflammation) in cancer patients. Thus, targeting radiation-induced inflammatory pathways may exert a dual effect of accentuating the tumor radioresponse and reducing normal tissue side-effects, thereby increasing the therapeutic window of cancer treatment. We review recent data demonstrating the pivotal role played by inflammatory pathways in cancer progression and modulation of radiation response.
MeSH term(s)	Animals ; Cyclooxygenase 2/physiology ; Cytokines/metabolism ; Disease Progression ; Humans ; Inflammation/metabolism ; Inflammation/prevention & control ; Molecular Targeted Therapy ; NF-kappa B/physiology ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/radiotherapy ; Radiation Injuries/prevention & control ; Radiation Tolerance/drug effects ; STAT Transcription Factors/physiology
Chemical Substances	Cytokines ; NF-kappa B ; STAT Transcription Factors ; Cyclooxygenase 2 (EC 1.14.99.1)
Language	English
Publishing date	2010-06-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2010.06.039
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Article ; Online: Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.

Gastroenterology

2022 Volume 162, Issue 7, Page(s) 2018–2031

Abstract: Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, ...

Abstract	Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. Methods: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. Results: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. Conclusions: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
MeSH term(s)	Animals ; Cancer-Associated Fibroblasts/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Humans ; Hypoxia/metabolism ; Immune Checkpoint Inhibitors ; Immunosuppression Therapy ; Mice ; Pancreatic Neoplasms/pathology ; Tumor Microenvironment ; Pancreatic Neoplasms
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2022-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2022.02.024
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Zs.MO 572: Show issues

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Article ; Online: Hypoxia-targeted gold nanorods for cancer photothermal therapy.

Chen, Yuan / Bian, Xiaomei / Aliru, Maureen / Deorukhkar, Amit A / Ekpenyong, Oscar / Liang, Su / John, Jyothy / Ma, Jing / Gao, Xiuqing / Schwartz, Jon / Singh, Pankaj / Ye, Yuanqing / Krishnan, Sunil / Xie, Huan

Oncotarget

2018 Volume 9, Issue 41, Page(s) 26556–26571

Abstract: Tumor hypoxia is a well-recognized driver of resistance to traditional cancer therapies such as chemotherapy and radiation therapy. We describe development of a new nanoconstruct composed of gold nanorods (GNRs) conjugated to carbonic anhydrase IX (CAIX) ...

Abstract	Tumor hypoxia is a well-recognized driver of resistance to traditional cancer therapies such as chemotherapy and radiation therapy. We describe development of a new nanoconstruct composed of gold nanorods (GNRs) conjugated to carbonic anhydrase IX (CAIX) antibody that specifically binds to CAIX, a biomarker of hypoxia, to facilitate targeting tumor hypoxic areas for focused photothermal ablation. Physicochemical characterization studies confirmed the size, shape, monodispersity, surface charge, and serum stability of the GNRs. Enzyme-linked immunosorbent assays and cellular binding and uptake studies confirmed successful conjugation of antibody to the GNRs and specificity for CAIX. Near-infrared irradiation of CAIX-overexpressing cells treated with GNR/anti-CAIX resulted in significantly higher cell death than cells treated with control GNRs.
Language	English
Publishing date	2018-05-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.25492
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Article ; Online: Integrin αvβ3-targeted gold nanoshells augment tumor vasculature-specific imaging and therapy

Huan Xie / Parmeswaran Diagaradjane / Amit A Deorukhkar

International Journal of Nanomedicine, Vol 2011, Iss default, Pp 259-

2011 Volume 269

Abstract: Huan Xie1, Parmeswaran Diagaradjane2, Amit A Deorukhkar2, Beth Goins3, Ande Bao3, William T ...

Abstract	Huan Xie1, Parmeswaran Diagaradjane2, Amit A Deorukhkar2, Beth Goins3, Ande Bao3, William T Phillips3, Zheng Wang4, Jon Schwartz5, Sunil Krishnan21Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA; 2Department of Radiation Oncology, Division of Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Radiology, the University of Texas Health Science Center at San Antonio (UTHSC-San Antonio), San Antonio, TX, USA; 4MPI Research, Inc., Mattawan, MI, USA; 5Nanospectra Biosciences, Inc., Houston, TX, USAPurpose: Gold nanoshells (NSs) have already shown great promise as photothermal actuators for cancer therapy. Integrin αvβ3 is a marker that is specifically and preferentially overexpressed on multiple tumor types and on angiogenic tumor neovasculature. Active targeting of NSs to integrin αvβ3 offers the potential to increase accumulation preferentially in tumors and thereby enhance therapy efficacy.Methods: Enzyme-linked immunosorbent assay (ELISA) and cell binding assay were used to study the in vitro binding affinities of the targeted nanoconjugate NS–RGDfK. In vivo biodistribution and tumor specificity were analyzed using 64Cu-radiolabeled untargeted and targeted NSs in live nude rats bearing head and neck squamous cell carcinoma (HNSCC) xenografts. The potential thermal therapy applications of NS–RGDfK were evaluated by subablative thermal therapy of tumor xenografts using untargeted and targeted NSs.Results: ELISA and cell binding assay confirmed the binding affinity of NS–RGDfK to integrin αvβ3. Positron emission tomography/computed tomography imaging suggested that tumor targeting is improved by conjugation of NSs to cyclo(RGDfK) and peaks at ~20 hours postinjection. In the subablative thermal therapy study, greater biological effectiveness of targeted NSs was implied by the greater degree of tumor necrosis.Conclusion: The results presented in this paper set the stage for the advancement of integrin αvβ3-targeted NSs as therapeutic nanoconstructs for effective cancer therapy.Keywords: nanoparticle, cyclo(RGDfK), cancer, thermal ablation
Keywords	Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Dove Medical Press
Document type	Article ; Online
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Article: A novel N-alkylated prodigiosin analogue induced death in tumour cell through apoptosis or necrosis depending upon the cell type.

Deorukhkar, Amit A / Chander, Ramesh / Pandey, Ruchi / Sainis, Krishna B

Cancer chemotherapy and pharmacology

2008 Volume 61, Issue 3, Page(s) 355–363

Abstract: Purpose: To investigate the mechanism of cell death induced by the N-alkylated prodigiosin analogue, 2,2'-[3-methoxy-1'amyl-5'-methyl-4-(1''-pyrryl)] dipyrryl-methene (MAMPDM) in S-180 and EL-4 tumour cell lines.: Methods: Effect of MAMPDM on cell ... ...

Abstract	Purpose: To investigate the mechanism of cell death induced by the N-alkylated prodigiosin analogue, 2,2'-[3-methoxy-1'amyl-5'-methyl-4-(1''-pyrryl)] dipyrryl-methene (MAMPDM) in S-180 and EL-4 tumour cell lines. Methods: Effect of MAMPDM on cell viability was assessed by MTT dye conversion. Induction of apoptosis was assessed by monitoring caspase 3 activity using a fluorogenic substrate, fragmentation of DNA by gel electrophoresis and sub-diploid DNA containing cells by flowcytometry. Necrosis was estimated by flowcytometric analysis of the uptake of propidium iodide. Results: MAMPDM inhibited the proliferation of murine fibrosarcoma, S-180 cells and induced cell death. Investigations into the mechanism of cell death by MAMPDM in S-180 cells showed absence of hallmarks of apoptotic cell death such as activation of caspase 3, DNA fragmentation and presence of cells with sub-diploid DNA content. However, there was a rapid loss of membrane integrity as assessed by uptake of propidium iodide, which is characteristic of necrosis. In contrast to induction of necrosis in S-180 cells, MAMPDM induced apoptotic cell death in EL-4 cells as evident by activation of caspase 3, fragmentation of DNA and sub-diploid DNA containing cells. Conclusions: MAMPDM could induce cell death by either apoptosis or necrosis depending upon the cell type. This would be of advantage in elimination of tumor cells defective in apoptotic pathway and therefore, refractory to the conventional therapies.
MeSH term(s)	Alkenes/pharmacology ; Alkylation ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Membrane Permeability/drug effects ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; DNA, Neoplasm/biosynthesis ; DNA, Neoplasm/genetics ; Dactinomycin/pharmacology ; Diploidy ; Enzyme Inhibitors/pharmacology ; Lymphoma, T-Cell/drug therapy ; Lymphoma, T-Cell/pathology ; Mice ; Necrosis ; Prodigiosin/analogs & derivatives ; Prodigiosin/pharmacology ; Pyrroles/pharmacology ; Rats ; Sarcoma 180/drug therapy ; Staurosporine/pharmacology ; Tetrazolium Salts ; Thiazoles
Chemical Substances	2,2'-(3-methoxy-1'amyl-5'-methyl-4-(1-pyrryl)) dipyrryl-methene ; Alkenes ; Antineoplastic Agents ; DNA, Neoplasm ; Enzyme Inhibitors ; Pyrroles ; Tetrazolium Salts ; Thiazoles ; Dactinomycin (1CC1JFE158) ; thiazolyl blue (EUY85H477I) ; Staurosporine (H88EPA0A3N) ; Prodigiosin (OL369FU7CJ)
Language	English
Publishing date	2008-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-007-0475-y
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Zs.A 1420: Show issues

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Article ; Online: Gadolinium chloride augments tumor-specific imaging of targeted quantum dots in vivo.

Diagaradjane, Parmeswaran / Deorukhkar, Amit / Gelovani, Juri G / Maru, Dipen M / Krishnan, Sunil

ACS nano

2010 Volume 4, Issue 7, Page(s) 4131–4141

Abstract: Nonspecific sequestration of nanoparticles by the reticulo-endothelial system (RES) results in the degradation of image quality of nanoparticle-based imaging. We demonstrate that gadolinium chloride (GdCl3) pretreatment inactivates RES macrophages, ... ...

Abstract	Nonspecific sequestration of nanoparticles by the reticulo-endothelial system (RES) results in the degradation of image quality of nanoparticle-based imaging. We demonstrate that gadolinium chloride (GdCl3) pretreatment inactivates RES macrophages, thereby increasing circulatory time and amplifying the tumor-specific signal of conjugated nanoparticles in vivo. The experimental results were validated using compartmental modeling, and the rate parameters for the observed kinetics pattern were estimated. This pretreatment strategy could have broad applicability across biomedical applications utilizing theranostic nanoparticles that are sequestered by the RES.
MeSH term(s)	Animals ; Biological Transport/drug effects ; Cell Line, Tumor ; ErbB Receptors/metabolism ; Gadolinium/pharmacology ; Half-Life ; Humans ; Kupffer Cells/drug effects ; Kupffer Cells/metabolism ; Kupffer Cells/pathology ; Liver/pathology ; Male ; Mice ; Models, Biological ; Molecular Imaging/methods ; Molecular Probes/metabolism ; Molecular Probes/pharmacokinetics ; Neoplasms/metabolism ; Quantum Dots ; Reproducibility of Results
Chemical Substances	Molecular Probes ; Gadolinium (AU0V1LM3JT) ; ErbB Receptors (EC 2.7.10.1) ; gadolinium chloride (P7082WY76D)
Language	English
Publishing date	2010-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/nn901919w
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Article ; Online: Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer.

Yu, Meifang / Nguyen, Nicholas D / Huang, Yanqing / Lin, Daniel / Fujimoto, Tara N / Molkentine, Jessica M / Deorukhkar, Amit / Kang, Ya'an / San Lucas, F Anthony / Fernandes, Conrad J / Koay, Eugene J / Gupta, Sonal / Ying, Haoqiang / Koong, Albert C / Herman, Joseph M / Fleming, Jason B / Maitra, Anirban / Taniguchi, Cullen M

JCI insight

2019 Volume 5

Abstract: Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth, however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth, however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit abnormally fragmented mitochondria that are essential to its oncogenicity, but it was unclear if this mitochondrial feature was a valid therapeutic target. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin related protein-1 (Drp1) or through overexpression of mitofusin-2 (Mfn2). Notably, we found that oral leflunomide, an FDA-approved arthritis drug, promoted a two-fold increase in Mfn2 expression in tumors and was repurposed as a chemotherapeutic agent, improving the median survival of mice with spontaneous tumors by 50% compared to vehicle. We found that the chief tumor suppressive mechanism of mitochondrial fusion was enhanced mitophagy, which proportionally reduced mitochondrial mass and ATP production. These data suggest that mitochondrial fusion is a specific and druggable regulator of pancreatic cancer growth that could be rapidly translated to the clinic.
MeSH term(s)	Animals ; CRISPR-Cas Systems ; Carcinoma, Pancreatic Ductal/metabolism ; Disease Models, Animal ; Dynamins/antagonists & inhibitors ; Dynamins/genetics ; Enzyme Inhibitors/pharmacology ; GTP Phosphohydrolases/genetics ; Leflunomide/pharmacology ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Mitochondrial Dynamics/drug effects ; Mitochondrial Dynamics/genetics ; Mitophagy/drug effects ; Mitophagy/genetics ; Oxidative Phosphorylation/drug effects ; Pancreatic Neoplasms/metabolism ; Quinazolinones/pharmacology ; Survival Rate
Chemical Substances	3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone ; Enzyme Inhibitors ; Quinazolinones ; GTP Phosphohydrolases (EC 3.6.1.-) ; Mfn2 protein, mouse (EC 3.6.1.-) ; Dnm1l protein, mouse (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5) ; Leflunomide (G162GK9U4W)
Language	English
Publishing date	2019-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Video-Audio Media
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.126915
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Article ; Online: Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation.

Molkentine, Jessica M / Fujimoto, Tara N / Horvath, Thomas D / Grossberg, Aaron J / Garcia, Carolina J Garcia / Deorukhkar, Amit / de la Cruz Bonilla, Marimar / Lin, Daniel / Samuel, Errol L G / Chan, Wai Kin / Lorenzi, Philip L / Piwnica-Worms, Helen / Dantzer, Robert / Tour, James M / Mason, Kathryn A / Taniguchi, Cullen M

Scientific reports

2019 Volume 9, Issue 1, Page(s) 1949

Abstract: Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation ... ...

Abstract	Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.
MeSH term(s)	Administration, Oral ; Amifostine/metabolism ; Amifostine/pharmacology ; Animals ; Female ; Intestine, Small/drug effects ; Male ; Mercaptoethylamines/metabolism ; Mercaptoethylamines/pharmacology ; Mice ; Mice, Inbred C57BL ; Pancreatic Neoplasms/drug therapy ; Radiation Dosage ; Radiation Protection/methods ; Radiation-Protective Agents/therapeutic use ; Pancreatic Neoplasms
Chemical Substances	Mercaptoethylamines ; Radiation-Protective Agents ; N-(2-mercaptoethyl)-1,3-diaminopropane (05P3K9I49L) ; Amifostine (M487QF2F4V)
Language	English
Publishing date	2019-02-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-37147-9
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Article ; Online: Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer.

Fujimoto, Tara N / Colbert, Lauren E / Huang, Yanqing / Molkentine, Jessica M / Deorukhkar, Amit / Baseler, Laura / de la Cruz Bonilla, Marimar / Yu, Meifang / Lin, Daniel / Gupta, Sonal / Cabeceiras, Peter K / Kingsley, Charles V / Tailor, Ramesh C / Sawakuchi, Gabriel O / Koay, Eugene J / Piwnica-Worms, Helen / Maitra, Anirban / Taniguchi, Cullen M

Cancer research

2019 Volume 79, Issue 9, Page(s) 2327–2338

Abstract: When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ... ...

Abstract	When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiation-induced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56% of mice that received high-dose RT with vehicle control. However, radiation-induced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding,
MeSH term(s)	Animals ; Apoptosis ; Female ; Glycine/analogs & derivatives ; Glycine/pharmacology ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors ; Isoquinolines/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pancreatic Neoplasms/mortality ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/radiotherapy ; Proto-Oncogene Proteins p21(ras)/physiology ; Radiation Injuries/etiology ; Radiation Injuries/mortality ; Radiation Injuries/prevention & control ; Radiation-Protective Agents/pharmacology ; Radiotherapy/adverse effects ; Radiotherapy/mortality ; Transcription Factors/physiology ; Tumor Suppressor Protein p53/physiology
Chemical Substances	Isoquinolines ; Radiation-Protective Agents ; Transcription Factors ; Trp53 protein, mouse ; Tumor Suppressor Protein p53 ; transcription factor PTF1 ; Egln1 protein, mouse (EC 1.14.11.29) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29) ; Hras protein, mouse (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Glycine (TE7660XO1C) ; roxadustat (X3O30D9YMX)
Language	English
Publishing date	2019-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-18-1785
Database	MEDical Literature Analysis and Retrieval System OnLINE

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