ZFIN ID: ZDB-PUB-170707-8
Efficacy of Onalespib a Long-acting Second Generation HSP90 Inhibitor as a Single Agent and in Combination with Temozolomide Against Malignant Gliomas
Canella, A., Welker, A.M., Yoo, J.Y., Xu, J., Abbas, F.S., Kesanakurti, D., Nagarajan, P., Beattie, C.E., Sulman, E.P., Liu, J.L., Gumin, J., Lang, F.F., Gurcan, M., Kaur, B., Sampath, D., Puduvalli, V.K.
Clinical cancer research : an official journal of the American Association for Cancer Research
Cell Line, Tumor
Cell Movement/drug effects
Cell Proliferation/drug effects
Dacarbazine/analogs & derivatives*
Disease Models, Animal
Drug Therapy, Combination
Extracellular Signal-Regulated MAP Kinases/metabolism
HSP90 Heat-Shock Proteins/antagonists & inhibitors*
HSP90 Heat-Shock Proteins/genetics
HSP90 Heat-Shock Proteins/metabolism
Neoplastic Stem Cells/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Ribosomal Protein S6 Kinases/metabolism
Signal Transduction/drug effects
Xenograft Model Antitumor Assays
Full text @ Clin. Cancer Res.
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 vivo Experimental 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
were assessed in non-tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed
using zebrafish and patient-derived GSC xenograft mouse glioma models.
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
and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts.
Our results demonstrate the long-acting effects of onalespib against gliomas
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