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

Fingerprint

Topoisomerase I Inhibitors
Canidae
Lymphoma
Camptothecin
irinotecan
NSC 724998
Dogs
Neoplasms
Diarrhea
Pharmacokinetics
Topotecan
Pets
Drug Resistance
Pharmaceutical Preparations
Toxicology
Research Design
Bone Marrow
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma. / Burton, Jenna H.; Mazcko, Christina; LeBlanc, Amy; Covey, Joseph M.; Ji, Jiuping; Kinders, Robert J.; Parchment, Ralph E.; Khanna, Chand; Paoloni, Melissa; Lana, Sue; Weishaar, Kristen; London, Cheryl; Kisseberth, William; Krick, Erika; Vail, David; Childress, Michael; Bryan, Jeffrey N.; Barber, Lisa; Ehrhart, E. J.; Kent, Michael; Fan, Timothy; Kow, Kelvin; Northup, Nicole; Wilson-Robles, Heather; Tomaszewski, Joseph; Holleran, Julianne L.; Muzzio, Miguel; Eiseman, Julie; Beumer, Jan H.; Doroshow, James H.; Pommier, Yves.

In: Clinical Cancer Research, Vol. 24, No. 23, 01.12.2018, p. 5830-5840.

Research output: Contribution to journalArticle

Burton, JH, Mazcko, C, LeBlanc, A, Covey, JM, Ji, J, Kinders, RJ, Parchment, RE, Khanna, C, Paoloni, M, Lana, S, Weishaar, K, London, C, Kisseberth, W, Krick, E, Vail, D, Childress, M, Bryan, JN, Barber, L, Ehrhart, EJ, Kent, M, Fan, T, Kow, K, Northup, N, Wilson-Robles, H, Tomaszewski, J, Holleran, JL, Muzzio, M, Eiseman, J, Beumer, JH, Doroshow, JH & Pommier, Y 2018, 'NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma', Clinical Cancer Research, vol. 24, no. 23, pp. 5830-5840. https://doi.org/10.1158/1078-0432.CCR-18-1498
Burton, Jenna H. ; Mazcko, Christina ; LeBlanc, Amy ; Covey, Joseph M. ; Ji, Jiuping ; Kinders, Robert J. ; Parchment, Ralph E. ; Khanna, Chand ; Paoloni, Melissa ; Lana, Sue ; Weishaar, Kristen ; London, Cheryl ; Kisseberth, William ; Krick, Erika ; Vail, David ; Childress, Michael ; Bryan, Jeffrey N. ; Barber, Lisa ; Ehrhart, E. J. ; Kent, Michael ; Fan, Timothy ; Kow, Kelvin ; Northup, Nicole ; Wilson-Robles, Heather ; Tomaszewski, Joseph ; Holleran, Julianne L. ; Muzzio, Miguel ; Eiseman, Julie ; Beumer, Jan H. ; Doroshow, James H. ; Pommier, Yves. / NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 23. pp. 5830-5840.
@article{58d462c0e1fd44599d5e5336aa05994d,
title = "NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma",
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.",
author = "Burton, {Jenna H.} and Christina Mazcko and Amy LeBlanc and Covey, {Joseph M.} and Jiuping Ji and Kinders, {Robert J.} and Parchment, {Ralph E.} and Chand Khanna and Melissa Paoloni and Sue Lana and Kristen Weishaar and Cheryl London and William Kisseberth and Erika Krick and David Vail and Michael Childress and Bryan, {Jeffrey N.} and Lisa Barber and Ehrhart, {E. J.} and Michael Kent and Timothy Fan and Kelvin Kow and Nicole Northup and Heather Wilson-Robles and Joseph Tomaszewski and Holleran, {Julianne L.} and Miguel Muzzio and Julie Eiseman and Beumer, {Jan H.} and Doroshow, {James H.} and Yves Pommier",
year = "2018",
month = "12",
day = "1",
doi = "10.1158/1078-0432.CCR-18-1498",
language = "English (US)",
volume = "24",
pages = "5830--5840",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "23",

}

TY - JOUR

T1 - NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma

AU - Burton, Jenna H.

AU - Mazcko, Christina

AU - LeBlanc, Amy

AU - Covey, Joseph M.

AU - Ji, Jiuping

AU - Kinders, Robert J.

AU - Parchment, Ralph E.

AU - Khanna, Chand

AU - Paoloni, Melissa

AU - Lana, Sue

AU - Weishaar, Kristen

AU - London, Cheryl

AU - Kisseberth, William

AU - Krick, Erika

AU - Vail, David

AU - Childress, Michael

AU - Bryan, Jeffrey N.

AU - Barber, Lisa

AU - Ehrhart, E. J.

AU - Kent, Michael

AU - Fan, Timothy

AU - Kow, Kelvin

AU - Northup, Nicole

AU - Wilson-Robles, Heather

AU - Tomaszewski, Joseph

AU - Holleran, Julianne L.

AU - Muzzio, Miguel

AU - Eiseman, Julie

AU - Beumer, Jan H.

AU - Doroshow, James H.

AU - Pommier, Yves

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85056267420&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056267420&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-1498

DO - 10.1158/1078-0432.CCR-18-1498

M3 - Article

AN - SCOPUS:85056267420

VL - 24

SP - 5830

EP - 5840

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 23

ER -