Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers

Paul G. Richardson, Constantine S. Mitsiades, Jacob P. Laubach, Sagar Lonial, Asher A Chanan Khan, Kenneth C. Anderson

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and stabilizes client proteins involved in cell cycle control and proliferative/anti-apoptotic signalling. HSP90 is overexpressed in a range of cancers, and may contribute to tumour cell survival by stabilizing aberrant signalling proteins and by interfering with apoptosis. Tanespimycin, an HSP90 inhibitor, reduces tumour cell survival in vitro. In multiple myeloma (MM), HSP90 inhibition affects multiple client proteins that contribute to tumour cell survival, including the IGF1 receptor and the IL-6 receptor, and elements of the PI3/Akt, STAT3, and MAPK signalling pathways. HSP90 inhibition also abrogates the protective effect of bone marrow stromal cells and inhibits angiogenesis and osteoclastogenesis. Tanespimycin acts synergistically with the proteasome inhibitor bortezomib in MM cells and tumour explants, possibly reducing their ability to resist bortezomib-induced stress to the endoplasmic reticulum. The combination of tanespimycin and bortezomib has demonstrated significant and durable responses with acceptable toxicity in a phase I/II study in patients with relapsed and relapsed/refractory MM. HSP90 inhibition is a promising strategy in MM especially in combination with bortezomib; additional studies will further evaluate optimal dosings of candidate drugs and schedules, as well as confirm efficacy in comparative phase III trials.

Original languageEnglish (US)
Pages (from-to)367-379
Number of pages13
JournalBritish Journal of Haematology
Volume152
Issue number4
DOIs
StatePublished - Feb 2011
Externally publishedYes

Fingerprint

HSP90 Heat-Shock Proteins
tanespimycin
Multiple Myeloma
Neoplasms
Cell Survival
Therapeutics
Interleukin-6 Receptors
Proteins
Proteasome Inhibitors
Endoplasmic Reticulum Stress
Molecular Chaperones
Cell Cycle Checkpoints
Mesenchymal Stromal Cells
Osteogenesis
Appointments and Schedules
Apoptosis
Bortezomib
Pharmaceutical Preparations

Keywords

  • Cancer
  • Heat shock protein 90
  • Myeloma
  • Peripheral neuropathy
  • Tanespimycin

ASJC Scopus subject areas

  • Hematology

Cite this

Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers. / Richardson, Paul G.; Mitsiades, Constantine S.; Laubach, Jacob P.; Lonial, Sagar; Chanan Khan, Asher A; Anderson, Kenneth C.

In: British Journal of Haematology, Vol. 152, No. 4, 02.2011, p. 367-379.

Research output: Contribution to journalArticle

Richardson, Paul G. ; Mitsiades, Constantine S. ; Laubach, Jacob P. ; Lonial, Sagar ; Chanan Khan, Asher A ; Anderson, Kenneth C. / Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers. In: British Journal of Haematology. 2011 ; Vol. 152, No. 4. pp. 367-379.
@article{e8dcf16ce28d48a2b77b231b95f234e9,
title = "Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers",
abstract = "Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and stabilizes client proteins involved in cell cycle control and proliferative/anti-apoptotic signalling. HSP90 is overexpressed in a range of cancers, and may contribute to tumour cell survival by stabilizing aberrant signalling proteins and by interfering with apoptosis. Tanespimycin, an HSP90 inhibitor, reduces tumour cell survival in vitro. In multiple myeloma (MM), HSP90 inhibition affects multiple client proteins that contribute to tumour cell survival, including the IGF1 receptor and the IL-6 receptor, and elements of the PI3/Akt, STAT3, and MAPK signalling pathways. HSP90 inhibition also abrogates the protective effect of bone marrow stromal cells and inhibits angiogenesis and osteoclastogenesis. Tanespimycin acts synergistically with the proteasome inhibitor bortezomib in MM cells and tumour explants, possibly reducing their ability to resist bortezomib-induced stress to the endoplasmic reticulum. The combination of tanespimycin and bortezomib has demonstrated significant and durable responses with acceptable toxicity in a phase I/II study in patients with relapsed and relapsed/refractory MM. HSP90 inhibition is a promising strategy in MM especially in combination with bortezomib; additional studies will further evaluate optimal dosings of candidate drugs and schedules, as well as confirm efficacy in comparative phase III trials.",
keywords = "Cancer, Heat shock protein 90, Myeloma, Peripheral neuropathy, Tanespimycin",
author = "Richardson, {Paul G.} and Mitsiades, {Constantine S.} and Laubach, {Jacob P.} and Sagar Lonial and {Chanan Khan}, {Asher A} and Anderson, {Kenneth C.}",
year = "2011",
month = "2",
doi = "10.1111/j.1365-2141.2010.08360.x",
language = "English (US)",
volume = "152",
pages = "367--379",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers

AU - Richardson, Paul G.

AU - Mitsiades, Constantine S.

AU - Laubach, Jacob P.

AU - Lonial, Sagar

AU - Chanan Khan, Asher A

AU - Anderson, Kenneth C.

PY - 2011/2

Y1 - 2011/2

N2 - Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and stabilizes client proteins involved in cell cycle control and proliferative/anti-apoptotic signalling. HSP90 is overexpressed in a range of cancers, and may contribute to tumour cell survival by stabilizing aberrant signalling proteins and by interfering with apoptosis. Tanespimycin, an HSP90 inhibitor, reduces tumour cell survival in vitro. In multiple myeloma (MM), HSP90 inhibition affects multiple client proteins that contribute to tumour cell survival, including the IGF1 receptor and the IL-6 receptor, and elements of the PI3/Akt, STAT3, and MAPK signalling pathways. HSP90 inhibition also abrogates the protective effect of bone marrow stromal cells and inhibits angiogenesis and osteoclastogenesis. Tanespimycin acts synergistically with the proteasome inhibitor bortezomib in MM cells and tumour explants, possibly reducing their ability to resist bortezomib-induced stress to the endoplasmic reticulum. The combination of tanespimycin and bortezomib has demonstrated significant and durable responses with acceptable toxicity in a phase I/II study in patients with relapsed and relapsed/refractory MM. HSP90 inhibition is a promising strategy in MM especially in combination with bortezomib; additional studies will further evaluate optimal dosings of candidate drugs and schedules, as well as confirm efficacy in comparative phase III trials.

AB - Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and stabilizes client proteins involved in cell cycle control and proliferative/anti-apoptotic signalling. HSP90 is overexpressed in a range of cancers, and may contribute to tumour cell survival by stabilizing aberrant signalling proteins and by interfering with apoptosis. Tanespimycin, an HSP90 inhibitor, reduces tumour cell survival in vitro. In multiple myeloma (MM), HSP90 inhibition affects multiple client proteins that contribute to tumour cell survival, including the IGF1 receptor and the IL-6 receptor, and elements of the PI3/Akt, STAT3, and MAPK signalling pathways. HSP90 inhibition also abrogates the protective effect of bone marrow stromal cells and inhibits angiogenesis and osteoclastogenesis. Tanespimycin acts synergistically with the proteasome inhibitor bortezomib in MM cells and tumour explants, possibly reducing their ability to resist bortezomib-induced stress to the endoplasmic reticulum. The combination of tanespimycin and bortezomib has demonstrated significant and durable responses with acceptable toxicity in a phase I/II study in patients with relapsed and relapsed/refractory MM. HSP90 inhibition is a promising strategy in MM especially in combination with bortezomib; additional studies will further evaluate optimal dosings of candidate drugs and schedules, as well as confirm efficacy in comparative phase III trials.

KW - Cancer

KW - Heat shock protein 90

KW - Myeloma

KW - Peripheral neuropathy

KW - Tanespimycin

UR - http://www.scopus.com/inward/record.url?scp=78851472038&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78851472038&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2141.2010.08360.x

DO - 10.1111/j.1365-2141.2010.08360.x

M3 - Article

C2 - 21219297

AN - SCOPUS:78851472038

VL - 152

SP - 367

EP - 379

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 4

ER -