Comparative Oncology Assessment of a Novel Inhibitor of Valosin-Containing Protein in Tumor-Bearing Dogs
| Autor: | Amy K. LeBlanc, Christina N. Mazcko, Timothy M. Fan, David M. Vail, Brian K. Flesner, Jeffrey N. Bryan, Shan Li, Feng Wang, Scott Harris, Jesse D. Vargas, Jeevan P. Govindharajulu, Soumya Jaganathan, Francesca Tomaino, Apurva K. Srivastava, Tsui-Fen Chou, Gordon M. Stott, Joseph M. Covey, Barbara Mroczkowski, James H. Doroshow |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-22-0167 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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