NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma

Jenna H. Burton, Christina Mazcko, Amy LeBlanc, Joseph M. Covey, Jiuping Ji, Robert J. Kinders, Ralph E. Parchment, Chand Khanna, Melissa Paoloni, Sue Lana, Kristen Weishaar, Cheryl London, William Kisseberth, Erika Krick, David Vail, Michael Childress, Jeffrey N. Bryan, Lisa Barber, E. J. Ehrhart, Michael KentTimothy Fan, Kelvin Kow, Nicole Northup, Heather Wilson-Robles, Joseph Tomaszewski, Julianne L. Holleran, Miguel Muzzio, Julie Eiseman, Jan H. Beumer, James H. Doroshow, Yves Pommier

Research output: Contribution to journalArticle

Abstract

Purpose: Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline noncamptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics. Experimental Design: Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined. Results: The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; gH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744. Conclusions: These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https:// ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.

Original languageEnglish (US)
Pages (from-to)5830-5840
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number23
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Burton, J. H., Mazcko, C., LeBlanc, A., Covey, J. M., Ji, J., Kinders, R. J., Parchment, R. E., Khanna, C., Paoloni, M., Lana, S., Weishaar, K., London, C., Kisseberth, W., Krick, E., Vail, D., Childress, M., Bryan, J. N., Barber, L., Ehrhart, E. J., ... Pommier, Y. (2018). NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma. Clinical Cancer Research, 24(23), 5830-5840. https://doi.org/10.1158/1078-0432.CCR-18-1498