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

• Published in: British journal of haematology Vol. 152; no. 4; pp. 367 - 379
• Main Authors: Richardson, Paul G., Mitsiades, Constantine S., Laubach, Jacob P., Lonial, Sagar, Chanan‐Khan, Asher A., Anderson, Kenneth C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2011; Blackwell
• Subjects: AKT protein; Angiogenesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Benzoquinones - pharmacology; Benzoquinones - therapeutic use; Biological and medical sciences; Bone marrow; Bortezomib; Cancer; Cell cycle; Cell survival; Chaperones; Clinical trials; Drug development; Drug Screening Assays, Antitumor - methods; Drugs; Endoplasmic reticulum; Explants; heat shock protein 90; Heat shock proteins; Hematologic and hematopoietic diseases; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - physiology; Hsp90 protein; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Insulin-like growth factor I; Interleukin 6 receptors; Lactams, Macrocyclic - pharmacology; Lactams, Macrocyclic - therapeutic use; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; MAP kinase; Medical sciences; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - physiopathology; myeloma; Osteoclastogenesis; peripheral neuropathy; proteasome inhibitors; Signal transduction; Stat3 protein; Stress; stromal cells; tanespimycin; Toxicity; Antineoplastic agent; Immunopathology; Nervous system diseases; Hematology; B cell neoplasm; Malignant hemopathy; Malignant tumor; Lymphoid neoplasm; Myeloma; peripheral neuropathy; Tanespimycin; Treatment; Immunoglobulinopathy; Lymphoproliferative syndrome; Heat shock protein; Inhibitor; Peripheral nerve disease; Cancer; Heat shock protein 90
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2010.08360.x

Summary 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.