Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.

<h4>Background</h4>The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-...

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Autores principales:	Cheryl A London, Luis Feo Bernabe, Sandra Barnard, William C Kisseberth, Antonella Borgatti, Mike Henson, Heather Wilson, Kiersten Jensen, Daisuke Ito, Jaime F Modiano, Misty D Bear, Michael L Pennell, Jean-Richard Saint-Martin, Dilara McCauley, Michael Kauffman, Sharon Shacham
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/46cc1f6fa5e540ad9ed44f8818e7d073
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spelling	oai:doaj.org-article:46cc1f6fa5e540ad9ed44f8818e7d0732021-11-18T08:34:02ZPreclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.1932-620310.1371/journal.pone.0087585https://doaj.org/article/46cc1f6fa5e540ad9ed44f8818e7d0732014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24503695/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability.<h4>Methods and findings</h4>Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35-256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities.<h4>Conclusions</h4>This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.Cheryl A LondonLuis Feo BernabeSandra BarnardWilliam C KisseberthAntonella BorgattiMike HensonHeather WilsonKiersten JensenDaisuke ItoJaime F ModianoMisty D BearMichael L PennellJean-Richard Saint-MartinDilara McCauleyMichael KauffmanSharon ShachamPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e87585 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cheryl A London Luis Feo Bernabe Sandra Barnard William C Kisseberth Antonella Borgatti Mike Henson Heather Wilson Kiersten Jensen Daisuke Ito Jaime F Modiano Misty D Bear Michael L Pennell Jean-Richard Saint-Martin Dilara McCauley Michael Kauffman Sharon Shacham Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
description	<h4>Background</h4>The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability.<h4>Methods and findings</h4>Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35-256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities.<h4>Conclusions</h4>This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.
format	article
author	Cheryl A London Luis Feo Bernabe Sandra Barnard William C Kisseberth Antonella Borgatti Mike Henson Heather Wilson Kiersten Jensen Daisuke Ito Jaime F Modiano Misty D Bear Michael L Pennell Jean-Richard Saint-Martin Dilara McCauley Michael Kauffman Sharon Shacham
author_facet	Cheryl A London Luis Feo Bernabe Sandra Barnard William C Kisseberth Antonella Borgatti Mike Henson Heather Wilson Kiersten Jensen Daisuke Ito Jaime F Modiano Misty D Bear Michael L Pennell Jean-Richard Saint-Martin Dilara McCauley Michael Kauffman Sharon Shacham
author_sort	Cheryl A London
title	Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
title_short	Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
title_full	Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
title_fullStr	Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
title_full_unstemmed	Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.
title_sort	preclinical evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (sine) kpt-335 in spontaneous canine cancer: results of a phase i study.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/46cc1f6fa5e540ad9ed44f8818e7d073
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Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.

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