Heat Shock Protein 90 Inhibitors Investigated as Therapeutic Agents

THE TOPLINE

  • Fox Chase researchers are exploring heat shock protein 90 as a potential therapeutic target for ovarian cancer, kidney disease, and small cell lung cancer
  • The team believes inhibiting the heat shock protein may disrupt several pathways involved in tumorigenesis

Based on research at Fox Chase that has illuminated heat shock protein 90 (HSP90) as a potentially important therapeutic target in several diseases, translational researchers are launching clinical studies to test the efficacy of therapies that inhibit this protein. HSP90 mediates activity for numerous cell-signaling pathways and transcription factors, and is over-expressed in cancerous cells.

One promising area is recurrent epithelial ovarian cancer (EOC) — a condition particularly resistant to chemotherapy because of its genetic instability and overexpression of multiple growth factors.

As part of the NCI Specialized Programs of Research Excellence (SPORE) in ovarian cancer, Fox Chase researchers Denise C. Connolly, PhD, Erica A. Golemis, PhD, and Lainie P. Martin, MD, along with several colleagues, conducted a meta-analysis of siRNA screens, which systematically eliminate cellular proteins, one by one, in order to assess the consequences for cellular growth properties in different contexts. Their goal was to identify proteins which, when inhibited, made tumors more sensitive to therapeutic drugs. They found that a number of proteins interacted with HSP90, suggesting that inhibiting the heat shock protein might disrupt several pathways involved in tumorigenesis.

MRI-FMT

Shown are magnetic resonance and fluorescent molecular tomography images of mice with ovarian tumors treated with HSP90 inhibitor ganetespib or vehicle. Tumor size and the presence and activity of tumor-associated proteins integrin αvβ3 (blue) and cathepsin proteases (red) are visibly reduced in the mice given ganetespib. (Click image to enlarge)

Researchers assessed the effects of HSP90 inhibitor ganetespib on cultured ovarian carcinoma cells and then in xenograft and transgenic mouse models. As reported in Clinical Cancer Research in July 2013, ganetespib significantly depressed tumor growth and induced cell death in tumor cells, with no overt evidence of detrimental side effects in vivo; it also made cancerous cells more sensitive to standard chemotherapy agents such as cisplatin and paclitaxel.

Ganetespib will now be tested in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer through a new clinical trial that combines the agent with paclitaxel.

In another study published the same month in Proceedings of the National Academy of Sciences, Golemis and another research team investigated the potential of HSP90 inhibitors for treating autosomal dominant polycystic kidney disease (ADPKD). An inherited condition in which fluid-filled cysts gradually replace healthy renal cells, ADPKD leads to loss of kidney function in many patients. HSP90 is expressed more highly in cyst cells than in normal kidney tissue, suggesting that it plays a role in disease progression.

Golemis and colleagues found that weekly dosing with the HSP90 inhibitor STA-2842 slowed the onset of cyst formation in mice primed to develop a disease analogous to human ADPKD. The treatment also improved kidney function and slowed disease progression in mice with established ADPKD.

In this study, HSP90 inhibitors tended to accumulate and persist in diseased tissue, but not in normal tissue—suggesting that they provide an excellent mechanism for targeting cytotoxic agents to tumors without damaging other tissues.

Novel drugs that target HSP90 are also being explored as a potential therapy for small cell lung cancer (SCLC), an aggressively recurrent and usually fatal disease. Golemis and medical oncologist Yanis Boumber, MD, PhD, are working with Synta Pharmaceuticals (makers of ganetespib) to investigate the activity of their HSP90 inhibitor-chemotherapy conjugates. Preliminary studies using human SCLC cell line xenografts and patient-derived xenografts have shown promising results, and the researchers hope to move the study into a Phase I clinical trial. ■

Connolly, Golemis, and Martin’s co-authors on the EOC study include Hanqing Liu, PhD, Fang Xiao, PhD, Ilya G. Serebriiskii, PhD, Shane W. O’Brien, MS, Marisa A. Maglaty, BA, Igor Astsaturov, MD, PhD, Samuel Litwin, PhD, and David A. Proia, PhD. Golemis’ co-authors on the ADPKD study include Tamina Seeger-Nukpezah, MD, David A. Proia, PhD, Brian L. Egleston, PhD, Anna S. Nikonova, PhD, Tatiana Kent, PhD, Kathy Q. Cai, MD, PhD, Harvey H. Hensley, PhD, Weiwen Ying, PhD, Dinesh Chimmanamada, PhD, and Ilya G. Serebriiskii, PhD.