Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma: Preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates

D. I. Staquicini, S. D'Angelo, F. Ferrara, K. Karjalainen, G. Sharma, T. L. Smith, C. A. Tarleton, D. E. Jaalouk, A. Kuniyasu, W. B. Baze, B. K. Chaffee, P. W. Hanley, K. F. Barnhart, E. Koivunen, S. Marchiò, R. L. Sidman, J. E. Cortes, H. M. Kantarjian, W. Arap, R. Pasqualini

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.

Original languageEnglish (US)
Pages (from-to)436-443
Number of pages8
JournalPharmacogenomics Journal
Volume18
Issue number3
DOIs
StatePublished - May 22 2018

Fingerprint

Peptidomimetics
Primates
Investigational New Drug Application
Rodentia
Lymphoma
Leukemia
Neoplasm Metastasis
Bone and Bones
Glucose
Membranes
Toxicology
Proteins
Macaca fascicularis
United States Food and Drug Administration
Therapeutics
Macaca mulatta
Acute Myeloid Leukemia
Pharmaceutical Preparations
Clinical Trials
Cell Line

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Medicine
  • Pharmacology

Cite this

Staquicini, D. I. ; D'Angelo, S. ; Ferrara, F. ; Karjalainen, K. ; Sharma, G. ; Smith, T. L. ; Tarleton, C. A. ; Jaalouk, D. E. ; Kuniyasu, A. ; Baze, W. B. ; Chaffee, B. K. ; Hanley, P. W. ; Barnhart, K. F. ; Koivunen, E. ; Marchiò, S. ; Sidman, R. L. ; Cortes, J. E. ; Kantarjian, H. M. ; Arap, W. ; Pasqualini, R. / Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma : Preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates. In: Pharmacogenomics Journal. 2018 ; Vol. 18, No. 3. pp. 436-443.
@article{83fb7e5fd5ce4c31a1c32b2861aaa268,
title = "Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma: Preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates",
abstract = "Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.",
author = "Staquicini, {D. I.} and S. D'Angelo and F. Ferrara and K. Karjalainen and G. Sharma and Smith, {T. L.} and Tarleton, {C. A.} and Jaalouk, {D. E.} and A. Kuniyasu and Baze, {W. B.} and Chaffee, {B. K.} and Hanley, {P. W.} and Barnhart, {K. F.} and E. Koivunen and S. Marchi{\`o} and Sidman, {R. L.} and Cortes, {J. E.} and Kantarjian, {H. M.} and W. Arap and R. Pasqualini",
year = "2018",
month = "5",
day = "22",
doi = "https://doi.org/10.1038/tpj.2017.46",
language = "English (US)",
volume = "18",
pages = "436--443",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",
number = "3",

}

Staquicini, DI, D'Angelo, S, Ferrara, F, Karjalainen, K, Sharma, G, Smith, TL, Tarleton, CA, Jaalouk, DE, Kuniyasu, A, Baze, WB, Chaffee, BK, Hanley, PW, Barnhart, KF, Koivunen, E, Marchiò, S, Sidman, RL, Cortes, JE, Kantarjian, HM, Arap, W & Pasqualini, R 2018, 'Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma: Preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates', Pharmacogenomics Journal, vol. 18, no. 3, pp. 436-443. https://doi.org/10.1038/tpj.2017.46

Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma : Preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates. / Staquicini, D. I.; D'Angelo, S.; Ferrara, F.; Karjalainen, K.; Sharma, G.; Smith, T. L.; Tarleton, C. A.; Jaalouk, D. E.; Kuniyasu, A.; Baze, W. B.; Chaffee, B. K.; Hanley, P. W.; Barnhart, K. F.; Koivunen, E.; Marchiò, S.; Sidman, R. L.; Cortes, J. E.; Kantarjian, H. M.; Arap, W.; Pasqualini, R.

In: Pharmacogenomics Journal, Vol. 18, No. 3, 22.05.2018, p. 436-443.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma

T2 - Preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates

AU - Staquicini, D. I.

AU - D'Angelo, S.

AU - Ferrara, F.

AU - Karjalainen, K.

AU - Sharma, G.

AU - Smith, T. L.

AU - Tarleton, C. A.

AU - Jaalouk, D. E.

AU - Kuniyasu, A.

AU - Baze, W. B.

AU - Chaffee, B. K.

AU - Hanley, P. W.

AU - Barnhart, K. F.

AU - Koivunen, E.

AU - Marchiò, S.

AU - Sidman, R. L.

AU - Cortes, J. E.

AU - Kantarjian, H. M.

AU - Arap, W.

AU - Pasqualini, R.

PY - 2018/5/22

Y1 - 2018/5/22

N2 - Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.

AB - Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.

UR - http://www.scopus.com/inward/record.url?scp=85039424783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039424783&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/tpj.2017.46

DO - https://doi.org/10.1038/tpj.2017.46

M3 - Article

C2 - 29205207

VL - 18

SP - 436

EP - 443

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

IS - 3

ER -