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Comparative Oncology Assessment of a Novel Inhibitor of Valosin-Containing Protein in Tumor-Bearing Dogs

LeBlanc, Amy K. and Mazcko, Christina N. and Fan, Timothy M. and Vail, David M. and Flesner, Brian K. and Bryan, Jeffrey N. and Li, Shan and Wang, Feng and Harris, Scott and Vargas, Jesse D. and Govindharajulu, Jeevan P. and Jaganathan, Soumya and Tomaino, Francesca and Srivastava, Apurva K. and Chou, Tsui-Fen and Stott, Gordon M. and Covey, Joseph M. and Mroczkowski, Barbara and Doroshow, James H. (2022) Comparative Oncology Assessment of a Novel Inhibitor of Valosin-Containing Protein in Tumor-Bearing Dogs. Molecular Cancer Therapeutics, 21 (10). pp. 1510-1523. ISSN 1535-7163. PMCID PMC9538592. doi:10.1158/1535-7163.mct-22-0167. https://resolver.caltech.edu/CaltechAUTHORS:20221107-998820100.20

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Abstract

Pet dogs with naturally occurring cancers play an important role in studies of cancer biology and drug development. We assessed tolerability, efficacy, and pharmacokinetic/pharmacodynamic relationships with a first-in-class small molecule inhibitor of valosin-containing protein (VCP/p97), CB-5339, administered to 24 tumor-bearing pet dogs. Tumor types assessed included solid malignancies, lymphomas, and multiple myeloma. Through a stepwise dose and schedule escalation schema, we determined the maximum tolerated dose to be 7.5 mg/kg when administered orally on a 4 days on, 3 days off schedule per week for 3 consecutive weeks. Adverse events were minimal and mainly related to the gastrointestinal system. Pharmacokinetic/pharmacodynamic data suggest a relationship between exposure and modulation of targets related to induction of the unfolded protein response, but not to tolerability of the agent. An efficacy signal was detected in 33% (2/6) of dogs with multiple myeloma, consistent with a mechanism of action relating to induction of proteotoxic stress in a tumor type with abundant protein production. Clinical trials of CB-5339 in humans with acute myelogenous leukemia and multiple myeloma are ongoing.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1158/1535-7163.MCT-22-0167DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9538592PubMed CentralArticle
ORCID:
AuthorORCID
LeBlanc, Amy K.0000-0001-7656-9859
Mazcko, Christina N.0000-0002-2543-7781
Fan, Timothy M.0000-0003-2510-7050
Vail, David M.0000-0002-1964-3693
Flesner, Brian K.0000-0002-2459-7054
Bryan, Jeffrey N.0000-0002-6820-9850
Li, Shan0000-0002-0829-1821
Wang, Feng0000-0003-4742-2668
Harris, Scott0000-0002-0400-9905
Vargas, Jesse D.0000-0002-3671-6778
Govindharajulu, Jeevan P.0000-0002-3705-4120
Jaganathan, Soumya0000-0001-8763-0109
Tomaino, Francesca0000-0001-8991-5415
Srivastava, Apurva K.0000-0002-6390-7553
Chou, Tsui-Fen0000-0003-2410-2186
Stott, Gordon M.0000-0002-9148-6100
Covey, Joseph M.0000-0002-5696-8999
Mroczkowski, Barbara0000-0002-6107-2580
Doroshow, James H.0000-0002-4463-1790
Additional Information:Canine SPE and IF assays were conducted at the Colorado State University Veterinary Clinical Pathology Laboratory, with special thanks to Dr. Russell Moore. NCI-Frederick is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the “Guide for Care and Use of Laboratory Animals (National Research Council; 1996; National Academy Press; Washington, DC).” This project has been funded in whole or in part with federal funds from the NCI, NIH, under Contract Nos. HHSN261201500003 and 75N91019D00024 and Task Order No. 75N091019F00129. This work was supported by the Intramural Program of the NCI, NIH (Z01-BC006161). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funders:
Funding AgencyGrant Number
NIHHHSN261201500003
NIH75N91019D00024
NIH75N091019F00129
NIHZ01-BC006161
Issue or Number:10
PubMed Central ID:PMC9538592
DOI:10.1158/1535-7163.mct-22-0167
Record Number:CaltechAUTHORS:20221107-998820100.20
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20221107-998820100.20
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:117750
Collection:CaltechAUTHORS
Deposited By: Research Services Depository
Deposited On:18 Nov 2022 18:41
Last Modified:18 Nov 2022 21:13

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