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 Scopus citations

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
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • 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. (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, 18(3), 436-443. https://doi.org/10.1038/tpj.2017.46