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Mechanisms of Disease: the role of heat-shock protein 90 in genitourinary malignancy

Nature Clinical Practice Urology volume 3, pages 590–601 (2006)Cite this article

Abstract

Insight into the molecular biology of cancer has allowed the development of novel therapeutic strategies that target specific oncogenic pathways. Molecular therapeutic strategies are now part of the armamentarium available against urologic malignancy. Among the many targets of interest in urologic cancer, heat-shock protein 90 (HSP90) shows great promise. This molecule has a major role in prostate as well as in renal malignancy. In contrast to other targets, where cancer might escape inhibition via alternative pathways, HSP90 operates at multiple checkpoints in a cancer cell. Its inhibition could, therefore, prove more difficult for neoplastic cells to overcome. Inhibitors of HSP90, such as geldanamycin and its derivatives (17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, known as 17AAG and 17DMAG, respectively) are available and have shown activity both in vivo and in vitro. 17AAG is currently being tested for efficacy in humans after having completed phase I trials, while 17DMAG is still in phase I evaluation. Phase II trials of HSP90 inhibitors in urologic malignancy are being conducted in kidney and advanced prostate cancer. Beyond monotherapy, HSP90 inhibitors might also prove to be beneficial in combination therapy with other chemotherapeutic agents in advanced disease. Studies being conducted in prostate cancer will hopefully help to define this potential application better.

Key Points

  • HSP90 is a ubiquitous intracellular protein that is essential for the processing of normal proteins as well as oncogenes

  • HSP90 acts on multiple nodal points in cancer pathways, and constitutes a more attractive therapeutic target than individual small molecules

  • Inhibitors of HSP90 have shown antineoplastic activity in vitro and in vivo, have completed phase I trials, and are being tested for efficacy as monotherapy in prostate and kidney cancers

  • Combinations of HSP90 inhibitors with other chemotherapeutic agents have a solid rationale for therapeutic use and might hold promise in prostate as well as kidney cancer

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Figure 1: Schematic structure of HSP90.
Figure 2: HSP90 machinery.
Figure 3: HSP90 inhibitors.
Figure 4: Androgen-receptor signaling in prostate cancer.
Figure 5: The von Hippel–Lindau pathway in clear cell kidney cancer.
Figure 6: C-met signaling in hereditary papillary renal carcinoma.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Clinical Fellow in Urologic Oncology, the Urologic Oncology Branch of the National Cancer Institute, National Institute of Health, Bethesda, MD, USA

    Jean-Baptiste Lattouf

  2. Senior Investigator in Medical Oncology, the Urologic Oncology Branch of the National Cancer Institute, National Institute of Health, Bethesda, MD, USA

    Ramaprasad Srinivasan

  3. Senior Investigator in Urologic Oncology, the Urologic Oncology Branch of the National Cancer Institute, National Institute of Health, Bethesda, MD, USA

    Peter A Pinto

  4. Chief of Urologic Oncology, the Urologic Oncology Branch of the National Cancer Institute, National Institute of Health, Bethesda, MD, USA

    W Marston Linehan

  5. Principal Investigator at the Urologic Oncology Branch of the National Cancer Institute, National Institute of Health, Bethesda, MD, USA

    Leonard Neckers

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Correspondence to Leonard Neckers.

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Lattouf, JB., Srinivasan, R., Pinto, P. et al. Mechanisms of Disease: the role of heat-shock protein 90 in genitourinary malignancy. Nat Rev Urol 3, 590–601 (2006). https://doi.org/10.1038/ncpuro0604

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