STA-9090
Hsp90 Inhibitor

Program Overview

About STA-9090

STA-9090 is a potent, second-generation, small-molecule heat shock protein 90 (Hsp90) inhibitor, being developed for treating multiple solid tumor and hematologic cancers.

STA-9090 was discovered and developed internally at Synta and has a chemical structure unrelated to the first-generation, ansamycin family of Hsp90 inhibitors such as 17-AAG or IPI-504. In preclinical studies, STA-9090 has shown potency up to 100 times greater than the first-generation Hsp90 inhibitors as well as activity against a wider range of kinases. In in vitro and in vivo models, STA-9090 has shown potent activity against a wide range of cancer types, including lung, prostate, colon, breast, gastric, pancreatic, gastrointestinal stromal tumors (GIST), melanoma, AML, chronic myeloid leukemia, Burkitt's lymphoma, diffuse large B-cell lymphoma, and multiple myeloma - as well as potent activity against cancers resistant to imatinib (Gleevec®), sunitinib (Sutent®), erlotinib (Tarceva®), and dasatinib (Sprycel®).

Mechanism of Action

STA-9090 potently inhibits Hsp90, a chaperone protein required for the proper folding and activation of other cellular proteins, particularly kinases. Many of these "client proteins" of Hsp90—such as AKT, BCR-ABL, BRAF, KIT, MET, EGFR, FLT3, HER2, PDGFRA, VEGFR—have been shown to be critical to cancer cell growth, proliferation, and survival and are the targets of clinically validated and approved cancer drugs such as Gleevec, Avastin, Herceptin, Sutent, Nexavar, Tarceva, and Erbitux. In preclinical studies, inhibiting Hsp90 causes the degradation of multiple client proteins and leads to cancer cell death. Because mutated kinases which no longer respond to treatment with kinase inhibitors remain dependent on Hsp90 for their activity, inhibiting Hsp90 offers the potential for treating cancers that have become resistant to targeted therapies such as kinase inhibitors. We believe that inhibiting kinases indirectly, by disrupting the chaperone activities of Hsp90, provides two advantages: first, a means to simultaneously attack multiple cancer-promoting kinases; and second, an ability to kill tumor cells with mutated kinases that have lost responsiveness to a direct kinase inhibitor.

Clinical Trials

Phase 1 Solid Tumor Trials

Two trials are being conducted: one with a once-weekly dosing schedule, one with a twice-weekly dosing schedule. The primary objective of both studies is to identify maximum tolerated dose; secondary objectives are to characterize safety, tolerability, signs of biologic and clinical activity.

Click here to get more information on our once-weekly trial.

Click here to get more information on our twice-weekly trial.

Phase 1/2 Trials in Hematologic Malignancies

Two trials are being conducted: one with a once-weekly dosing schedule, one with a twice-weekly dosing schedule. The primary objective of both studies is to identify maximum tolerated dose; secondary objectives are to characterize safety, tolerability, signs of biologic and clinical activity.

Click here to get more information on our once-weekly trial.

Click here to get more information on our twice-weekly trial.

Phase 2 Trial in Non-Small Cell Lung Cancer

This trial is an open-label, multi-center, multi-cohort Phase 2 study designed to characterize the efficacy and safety of STA-9090 in patients with stage IIIB or IV non-small cell lung cancer, based on a once-weekly dosing schedule. Patients will be assessed for tumor response based on the RECIST criteria. Subjects tolerating STA-9090 may continue on treatment until disease progression. Click here for more information on this trial.

Phase 2 Trial in Gastrointestinal Stromal Tumors

This trial is an open-label, multi-center Phase 2 study designed to characterize the efficacy and safety of STA-9090 in patients with metastatic or unresectable GIST following failure of Gleevec® and Sutent®, based on a once-weekly intravenous dosing schedule. Patients will be assessed for clinical benefit rate per RECIST criteria. Click here for more information on this trial.

Phase 2 Trial in Colorectal Cancer

This is an open-label, investigator-sponsored Phase 2 clinical study being conducted in patients with advanced colon cancer or rectal cancer. Click here for more information on this trial.

Phase 2 Trial in Gastric Cancer

This is an open-label, investigator-sponsored Phase 2 clinical study being conducted in patients with advanced gastric, esophageal, or gastroesophageal cancers. Click here for more information on this trial.

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STA-9090 Presentations

STA-9090 Publications

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General Hsp90 References

• Kim, YS, et al.: Update on Hsp90 Inhibitors in Clinical Trials. Curr Top Med Chem. 2009; 9(15):1479-92.

• Mahalingam, D, et al.: Targeting Hsp90 for cancer therapy. Br J Cancer, 2009; 100(10):1523-9.

• Sawai, A, et al.: Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel. Cancer Res. 2008 Jan; 68(2):589-96.

• Powers, M. V., Workman, P.: Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocrine-Related Cancer 2006; 13(1): S125–S135.

• Solit, DB, Chiosis, G: Development and application of Hsp90 inhibitors. Drug Discov Today. 2008; 13(1-2):38-43.

• Workman, P: Altered states: selectively drugging the Hsp90 cancer chaperone. Trends Mol Med., 2004; 10(2):47-51.

• Xu, W, Neckers, L: Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells. Clin Cancer Res. 2007; 13(6):1625-9.

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