The Coffey Lectureship - Heat Shock Protein 90: A Molecular Chaperone As Anti-Cancer Molecular Target

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology;  Genetics;  Clinical Trials / Drug Trials
Article Date: 31 May 2008 - 0:00 PDT

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ORLANDO, FL (UroToday.com) - In a joint meeting of the SBUR and SUO, Dr. Len Neckers discussed Hsp90 as a cancer target. Heat shock proteins are involved in protein synthesis. Early on it was noted that heat increases transcription of HSP genes in the Drosophila. Heat shock proteins were thus identified. HSPs are also referred to molecular chaperones due to their functional role. They act as house-keeping proteins during development and in restoring cellular functions after environmental stress. In 1981 a protein was noted to be involved in the Src pathway and its oncogenic potential. This was an early identification of HSPs in a functional capacity.

The first identified HSP90 inhibitor was Geldanamycin, as its binding to Hsp90 resulted in anti-tumor activity. Derivatives of this are more stable and are now in clinical trials in myeloma. Low throughput screening was used to identify Hsp90 as the molecular target of Geldanamycin. Molecular modifications to it have resulted in a burst of research interest in this area. The consistent observation is that these drugs disrupt the association of a HSP with it molecular "client" such as Src. There are about 100 client proteins, of which many are key components of cell growth and signal transduction pathways. An analysis of these proteins show most are involved and stably activated in cancers. Their stability involves HSPs and disruption of Hsp90 would interfere with many pathways. Dr. Neckers showed that interfering with Hsp90 would then affect multiple cell processes. Non-small cell lung cancer is an example where low expression of Hsp90 correlates with better survival, suggesting that less Hsp90 supports better outcome. In 2008 there are 40 clinical trials using Hsp90 inhibitors in cancer.

He then reviewed the Hsp90 pathway. The Hsp90 chaperone is driven by ATP hydrolysis resulting in dissociation of Hsp90 and ATP activation of the client protein. Hsp90 inhibitors result in dissociation and early ubiquitination of the client protein. As compared to ATP elution by sepharose that shows the release of many client proteins, Geldanamycin elution specifically elutes Hsp90. This supports the specificity of the drug- Hsp90 relationship. He showed data on Geldanamycin inactivation and destabilization of Akt kinase. Transcription and translation of Akt is not effected, he emphasized.

In urologic tumors, the androgen receptor is a client of Hsp90. He showed numerous pathways involving AR, such as Ack kinase activity that depends on Hsp90 activation. Raf-1 stability and signaling are also sensitive to Hsp90 inhibition. Stability of AR itself is sensitive to Hsp90 inhibition in doses that are tolerable in humans. This was shown in cell line with wild-type and mutated AR.

In renal cell and prostate cancer HIF-1α is degraded by Geldanamycin in both normoxia and hypoxia. Geldanamycin interfered with HIF-1α transcriptional activity. Furthermore, Hsp90 is recently show to be expressed on the cell surface and is involved in cell motility. Geldanamycin inhibited tumor migration and invasion. In vivo, treatment with an antibody decreased metastasis.

Presented by Len Neckers, MD, at the Annual Meeting of the American Urological Association (AUA) - May 17 - 22, 2008. Orange County Convention Center - Orlando, Florida, USA.

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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