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Winning Abstracts from the 2008 Medical Student Abstract Competition: Targeting The HSP90 Co-chaperone CDC37 Causes Growth Arrest And Sensitizes Prostate Cancer Cells To Chemotherapy And Radiation

Authors: Phillip J. Gray, Jr.; Stuart K. Calderwood.Johns Hopkins University School of Medicine, Baltimore, Maryland and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Introduction
Prostate cancer affects over 200,000 men each year and nearly 30,000 will die of their disease. While early-stage prostate cancer is highly treatable, there are very few options for men who present with metastatic disease. The development of novel therapies will require a better understanding of the inner workings of the cancer cell. The HSP90 (heat shock protein 90) chaperone system is a ubiquitous intracellular protein control system which we hope to exploit to aid in the development of these novel treatments for this devastating disease.

Methods
We utilized lentivirally delivered short hairpin RNA plasmids targeted at Cdc37, a known HSP90 co-chaperone in order to study its function in the cell. By utilizing a combination of clonogenic survival assays, Western blot, quantitative PCR, flow cytometry and luciferase reporter assays we analyzed the downstream effects of Cdc37 knockdown on a wide variety of prostate cancer cell types. We also compared the effects of combining Cdc37 knockdown with cytotoxic drugs and ionizing radiation.

Results
Knockdown of Cdc37 induced an irreversible total growth arrest in all of the tested prostate cancer cell lines. This effect was mediated by an inhibition of multiple signaling pathways within the cell including the Akt, Erk, mTOR and androgen receptor pathways. Combining Cdc37 knockdown with the chemotherapeutic drug Paclitaxel showed supra-additive cytotoxic effects on cell survival (IC50 2.68 vs. 5.82 nM) mediated by accelerated apoptosis induction. Cdc37 knockdown also combined well with ionizing radiation (DER25: 1.59)and led to inappropriate advancement through cellular checkpoints resulting in cell death. We also demonstrate that Cdc37 inhibition sensitizes cancer cells to the HSP90-inhibiting drug 17AAG by nearly a full log (IC50 13 vs 125nM). Cdc37 inhibition greatly enhances the protein destabilizing effects of 17AAG and inhibits the upregulation of HSP70, thought to be the major cause of acquired resistance to HSP90-targeted drugs.

Conclusion
Cdc37 is a novel and promising molecular target for the treatment of prostate and other cancers. Its strength as a potential therapeutic tool lies in its ability to simultaneously inhibit numerous kinase signaling pathways commonly dysregulated in cancer. Furthermore, its synergistic interactions with other accepted agents would lead to reduced toxicity and reduced development of resistance when targeted clinically.

This could be your winning abstract. Deadline to submit for the 2009 competition is December 8, 2008. For more information and the link to submit, please click here.

Back to November 2008 Issue of IMpact

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