Drugging the cancer chaperone HSP90: Combinatorial therapeutic exploitation of oncogene addiction and tumor stress Conference Paper
| Authors: | Workman, P.; Burrows, F.; Neckers, L.; Rosen, N. |
| Title: | Drugging the cancer chaperone HSP90: Combinatorial therapeutic exploitation of oncogene addiction and tumor stress |
| Conference Title: | 2nd World Conference on Stress |
| Abstract: | The molecular chaperone HSP90 has emerged as an exciting target for cancer treatment. We review the potential advantages of HSP90 inhibitors, particularly the simultaneous combinatorial depletion of multiple oncogenic "client" proteins, leading to blockade of many cancer-causing pathways and the antagonism of all of the hallmark pathological traits of malignancy. Cancer selectivity is achieved by exploiting cancer "dependencies," including oncogene addiction and the stressed state of malignant cells. The multiple downstream effects of HSP90 inhibitors should make the development of resistance more difficult than with agents having more restricted effects. We review the various classes of HSP90 inhibitor that have been developed, including the natural products geldanamycin and radicicol and also the purine scaffold and pyrazole/isoxazole class of synthetic small molecule inhibitors. A first-in-class HSP90 drug, the geldanamycin analog 17-AAG, has provided proof of concept for HSP90 inhibition in patients at well tolerated doses and therapeutic activity has been seen. Other inhibitors show promise in preclinical and clinical development. Opportunities and challenges for HSP90 inhibitors are discussed, including use in combination with other agents. Most of the current HSP90 inhibitors act by blocking the essential nucleotide binding and ATPase activity required for chaperone function. Potential new approaches are discussed, for example, interference with cochaperone binding and function in the superchaperone complex. Biomarkers for use with HSP90 inhibitors are described. We stress how basic and translational research has been mutually beneficial and indicate future directions to enhance our understanding of molecular chaperones and their exploitation in cancer and other diseases. © 2007 New York Academy of Sciences. |
| Keywords: | unclassified drug; oncoprotein; proto-oncogene proteins; histone deacetylase inhibitor; nonhuman; conference paper; drug targeting; protein function; sensitivity analysis; translation initiation; neoplasms; biological marker; animals; drug inhibition; unindexed drug; protein depletion; antineoplastic combined chemotherapy protocols; protein binding; enzyme activity; cancer therapy; oncogene; drug mechanism; cancer cell; heat shock protein 90 inhibitor; heat shock protein 90; hsp90 heat-shock proteins; stress; therapy effect; tumor; natural product; antineoplastic antibiotic; adenosine triphosphatase; drug tolerance; cell selection; geldanamycin; radicicol; ver 50589; chaperone; inhibitors; scaffold protein; ansamycin derivative; cnf 2024; pu 24fcl; nucleotide binding site; novobiocin; 17 allylamino 17 demethoxygeldanamycin; ver 49009; 17 dimethylaminoethylamino 17 demethoxygeldanamycin; hsp molecular chaperone; 8 arylsulfanyl adenine derivative 37; adenine derivative; cct 018159; celestrol; cf 237; gedunin; ipi 504; nucleotide binding protein; resorcinol derivative |
| Journal Title | Annals of the New York Academy of Sciences |
| Volume: | 1113 |
| Conference Dates: | 2007 Aug 23-26 |
| Conference Location: | Budapest, Hungary |
| ISBN: | 0077-8923 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2007-10-01 |
| Start Page: | 202 |
| End Page: | 216 |
| Language: | English |
| DOI: | 10.1196/annals.1391.012 |
| PUBMED: | 17513464 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Chapter in "Stress Responses in Biology and Medicine: Stress of Life in Molecules, Organisms, and Psychosocial Communities" - "Cited By (since 1996): 160" - "Export Date: 17 November 2011" - "CODEN: ANYAA" - "Source: Scopus" |
