Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Clin Cancer Res. 2017 Oct 15;23(20):6215-6226. doi: 10.1158/1078-0432.CCR-16-3151. Epub 2017 Jul 5.

Abstract

Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins, is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities, or are unable to cross the blood-brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivoExperimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo were assessed in non-tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient-derived GSC xenograft mouse glioma models.Results: Onalespib-mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII, and AKT, disrupted their downstream signaling, and decreased the proliferation, migration, angiogenesis, and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts.Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo, which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas. Clin Cancer Res; 23(20); 6215-26. ©2017 AACR.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology*
  • Blood-Brain Barrier / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacokinetics
  • Dacarbazine / pharmacology
  • Disease Models, Animal
  • Drug Synergism
  • Drug Therapy, Combination
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression
  • Glioma / drug therapy
  • Glioma / metabolism*
  • Glioma / mortality
  • Glioma / pathology*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Isoindoles / pharmacokinetics
  • Isoindoles / pharmacology*
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction / drug effects
  • Survival Rate
  • Temozolomide
  • Xenograft Model Antitumor Assays
  • Zebrafish

Substances

  • Antineoplastic Agents
  • Benzamides
  • HSP90 Heat-Shock Proteins
  • Isoindoles
  • Dacarbazine
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone
  • Temozolomide