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A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma
Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this...
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| Published in: | PloS one 2014-05, Vol.9 (5), p.e95404 |
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| cites | cdi_FETCH-LOGICAL-c692t-36b96c6fbca88a6c8f51dcbb2fbc4b50c9a3c5c89e6a470bef3e6b3c78d44fd83 |
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| container_issue | 5 |
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| container_title | PloS one |
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| creator | Habineza Ndikuyeze, Georges Gaurnier-Hausser, Anita Patel, Reema Baldwin, Albert S May, Michael J Flood, Patrick Krick, Erika Propert, Kathleen J Mason, Nicola J |
| description | Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of |
| doi_str_mv | 10.1371/journal.pone.0095404 |
| format | article |
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Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0095404</identifier><identifier>PMID: 24798348</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Apoptosis ; B cells ; B-cell lymphoma ; B-Lymphocytes - metabolism ; B-Lymphocytes - pathology ; Binding ; Biological effects ; Biology and Life Sciences ; Cancer therapies ; Cell proliferation ; Chemical properties ; Clinical trials ; Comparative analysis ; Cyclin D ; Cytotoxicity ; Disease ; Dog Diseases - drug therapy ; Dog Diseases - metabolism ; Dog Diseases - pathology ; Dogs ; Gene expression ; Health aspects ; Hematology ; Humans ; I-kappa B Kinase ; Intravenous administration ; Kinases ; Lymph nodes ; Lymphocytes B ; Lymphoma ; Lymphoma, Large B-Cell, Diffuse - drug therapy ; Lymphoma, Large B-Cell, Diffuse - metabolism ; Lymphoma, Large B-Cell, Diffuse - pathology ; Lymphoma, Large B-Cell, Diffuse - veterinary ; Medicine and Health Sciences ; Metabolism ; Mutation ; NF-kappa B - metabolism ; NF-κB protein ; Non-Hodgkin's lymphomas ; Peptides ; Peptides - pharmacokinetics ; Peptides - pharmacology ; Pharmacokinetics ; Pharmacology ; Protein Structure, Tertiary ; Research and Analysis Methods ; Sentinel Lymph Node Biopsy ; Signal Transduction - drug effects ; Signaling ; Studies ; Tissues ; Toxicity ; Veterinary colleges ; Veterinary medicine</subject><ispartof>PloS one, 2014-05, Vol.9 (5), p.e95404</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Habineza Ndikuyeze et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Habineza Ndikuyeze et al 2014 Habineza Ndikuyeze et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-36b96c6fbca88a6c8f51dcbb2fbc4b50c9a3c5c89e6a470bef3e6b3c78d44fd83</citedby><cites>FETCH-LOGICAL-c692t-36b96c6fbca88a6c8f51dcbb2fbc4b50c9a3c5c89e6a470bef3e6b3c78d44fd83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1521000262/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1521000262?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24798348$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Climent, Jose Angel Martinez</contributor><creatorcontrib>Habineza Ndikuyeze, Georges</creatorcontrib><creatorcontrib>Gaurnier-Hausser, Anita</creatorcontrib><creatorcontrib>Patel, Reema</creatorcontrib><creatorcontrib>Baldwin, Albert S</creatorcontrib><creatorcontrib>May, Michael J</creatorcontrib><creatorcontrib>Flood, Patrick</creatorcontrib><creatorcontrib>Krick, Erika</creatorcontrib><creatorcontrib>Propert, Kathleen J</creatorcontrib><creatorcontrib>Mason, Nicola J</creatorcontrib><title>A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. 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drug therapy</subject><subject>Lymphoma, Large B-Cell, Diffuse - metabolism</subject><subject>Lymphoma, Large B-Cell, Diffuse - pathology</subject><subject>Lymphoma, Large B-Cell, Diffuse - veterinary</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mutation</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Non-Hodgkin's lymphomas</subject><subject>Peptides</subject><subject>Peptides - pharmacokinetics</subject><subject>Peptides - pharmacology</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Protein Structure, Tertiary</subject><subject>Research and Analysis Methods</subject><subject>Sentinel Lymph Node Biopsy</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Studies</subject><subject>Tissues</subject><subject>Toxicity</subject><subject>Veterinary colleges</subject><subject>Veterinary medicine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9-K1DAUxoso7rr6BqIBQfBixqRN2_RGGJdVB1YX_Hcb0uS0zZg2tUlH51l8WTNOd5iCggSScPL7vhxOcqLoMcFLkuTk5caOQyfMsrcdLDEuUorpneicFEm8yGKc3D3Zn0UPnNtgnCYsy-5HZzHNC5ZQdh79WqG-EQ7QGkmjOy2FQX7QYbYVcjvnod3HzA4pMHoLAyj04er9DSp1p3RXI2VboTvUQ--1AhS2ytYO_dC-QS7k5kUHdnRISK-3wgf564UEY5DR3wApXVVjuN2IoYbjya7tm2D7MLpXCePg0bReRF_eXH2-fLe4vnm7vlxdL2RWxH6RZGWRyawqpWBMZJJVKVGyLOMQoWWKZSESmUpWQCZojkuoEsjKROZMUVopllxETw--vbGOT3V1nKQxwRjHWRyI9YFQVmx4P-hWDDtuheZ_AnaouRi8lgY4hbQEyHKQqqSCJiVOmWQiB0IYIwQHr1fTbWPZgpLQ-UGYmen8pNMNr-2WUxzUxT7dZ5PBYL-P4Pw_Up6oWoSsdFfZYCZb7SRfUcJynOeYBmr5FyoMtX_38LMqHeIzwYuZIDAefvpajM7x9aeP_8_efJ2zz0_YBoTxjbNm9Np2bg7SAygH69wA1bFyBPN9Y9xWg-8bg0-NEWRPTqt-FN12QvIb1YALvA</recordid><startdate>20140505</startdate><enddate>20140505</enddate><creator>Habineza Ndikuyeze, Georges</creator><creator>Gaurnier-Hausser, Anita</creator><creator>Patel, Reema</creator><creator>Baldwin, Albert S</creator><creator>May, Michael J</creator><creator>Flood, Patrick</creator><creator>Krick, Erika</creator><creator>Propert, Kathleen J</creator><creator>Mason, Nicola J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140505</creationdate><title>A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma</title><author>Habineza Ndikuyeze, Georges ; Gaurnier-Hausser, Anita ; Patel, Reema ; Baldwin, Albert S ; May, Michael J ; Flood, Patrick ; Krick, Erika ; Propert, Kathleen J ; Mason, Nicola J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-36b96c6fbca88a6c8f51dcbb2fbc4b50c9a3c5c89e6a470bef3e6b3c78d44fd83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - 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Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24798348</pmid><doi>10.1371/journal.pone.0095404</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-05, Vol.9 (5), p.e95404 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1521000262 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | Animals Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Apoptosis B cells B-cell lymphoma B-Lymphocytes - metabolism B-Lymphocytes - pathology Binding Biological effects Biology and Life Sciences Cancer therapies Cell proliferation Chemical properties Clinical trials Comparative analysis Cyclin D Cytotoxicity Disease Dog Diseases - drug therapy Dog Diseases - metabolism Dog Diseases - pathology Dogs Gene expression Health aspects Hematology Humans I-kappa B Kinase Intravenous administration Kinases Lymph nodes Lymphocytes B Lymphoma Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - pathology Lymphoma, Large B-Cell, Diffuse - veterinary Medicine and Health Sciences Metabolism Mutation NF-kappa B - metabolism NF-κB protein Non-Hodgkin's lymphomas Peptides Peptides - pharmacokinetics Peptides - pharmacology Pharmacokinetics Pharmacology Protein Structure, Tertiary Research and Analysis Methods Sentinel Lymph Node Biopsy Signal Transduction - drug effects Signaling Studies Tissues Toxicity Veterinary colleges Veterinary medicine |
| title | A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T20%3A24%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20phase%20I%20clinical%20trial%20of%20systemically%20delivered%20NEMO%20binding%20domain%20peptide%20in%20dogs%20with%20spontaneous%20activated%20B-cell%20like%20diffuse%20large%20B-cell%20lymphoma&rft.jtitle=PloS%20one&rft.au=Habineza%20Ndikuyeze,%20Georges&rft.date=2014-05-05&rft.volume=9&rft.issue=5&rft.spage=e95404&rft.pages=e95404-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0095404&rft_dat=%3Cgale_plos_%3EA418707704%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c692t-36b96c6fbca88a6c8f51dcbb2fbc4b50c9a3c5c89e6a470bef3e6b3c78d44fd83%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1521000262&rft_id=info:pmid/24798348&rft_galeid=A418707704&rfr_iscdi=true |