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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
| Meeting/Date
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Title |
Link |
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ASCO Annual Meeting 2010
June 7, 2010 - Chicago, IL
|
A Phase 1 dose-escalation study of the Hsp90 inhibitor
STA-9090 administered twice weekly in patients with solid tumors.
|
Poster
Abstract |
|
ASCO Annual Meeting 2010
June 5, 2010 - Chicago, IL
|
A Phase 1 dose-escalation study of the Hsp90 inhibitor
STA-9090 administered once weekly in patients with solid tumors.
|
Poster
Abstract |
|
101st AACR Annual Meeting
April 19, 2010 - Washington, DC
|
Hsp90 inhibitor STA-9090 enhances the activity of
standard of care therapies in erlotinib-sensitive and -resistant NSCLC models
|
Poster
Abstract |
|
101st AACR Annual Meeting
April 19, 2010 - Washington, DC
|
Hsp90 inhibitor STA-9090 induces HIF-1a degradation in
the hypoxic regions of solid tumors
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Poster
Abstract |
|
101st AACR Annual Meeting
April 19, 2010 - Washington, DC
|
Multimodal action of the Hsp90 inhibitor STA-9090 in
treating cancer cells with activated JAK/STAT signaling
|
Poster
Abstract |
|
10th Annual Targeted Therapies of Lung Cancer Meeting
February 25, 2010 - Santa Monica, CA
|
STA-9090, A Potent 2nd Generation Hsp90 Inhibitor
|
Presentation |
|
Hematologic Malignancies: Bridging the Gap 2010
February 5-7, 2010 - Singapore City, Singapore
|
Hsp90 Inhibitor STA-9090 Down-Regulates Expression of
Hsp90 Client Protein WT1 in Myeloid Leukemia Cells.
|
Poster
Abstract |
|
AACR-IASLC
Joint Conference on Molecular Origins of Lung Cancer
January 12, 2010 - Coronado, CA
|
Synergy between the novel Hsp90 inhibitor STA-9090 and
taxanes in preclinical models of NSCLC.
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Poster |
AACR-NCI-EORTC
Molecular Targets and Cancer Therapeutics
November 18, 2009 - Boston, MA |
Pharmacodynamic analysis of the Hsp90 inhibitor
STA-9090 in a lung cancer xenograft model supports an infrequent dosing
schedule in the clinic.
|
Poster
Abstract |
AACR-NCI-EORTC
Molecular Targets and Cancer Therapeutics
November 17, 2009 - Boston, MA |
In vitro and in vivo efficacy of the novel Hsp90
inhibitor STA-9090 and its synergy with paclitaxel.
|
Poster
Abstract |
AACR-NCI-EORTC
Molecular Targets and Cancer Therapeutics
November 17, 2009 - Boston, MA |
Hsp90 inhibitor STA-9090 potently suppresses
heterogeneous KIT kinase-domain mutations responsible for gastrointestinal
stromal tumor progression during imatinib therapy.
|
Poster
Abstract |
100th AACR Annual Meeting
April 21, 2009 - Denver, CO |
The novel Hsp90 inhibitor STA-9090 has potent
anticancer activity in in vitro and in vivo models of lung cancer.
|
Poster
Abstract |
99th AACR Annual Meeting
April 14, 2008 - San Diego, CA |
The novel Hsp90 inhibitor STA-9090 exhibits activity
against Kit dependent and independent malignant mast cell tumors.
|
Abstract |
99th AACR Annual Meeting
April 14, 2008 - San Diego, CA |
The novel Hsp90 inhibitor STA-12-1474 exhibits
biologic activity against canine osteosarcoma cell lines.
|
Abstract |
STA-9090 Publications
| Publication
|
Title/Author |
Link |
| International Journal of Cancer 2009.
125:2792-801. |
The novel Hsp90 inhibitor STA-1474 exhibits biologic
activity against osteosarcoma cell lines.
McCleese et al. |
Publication |
Experimental Hematology 2008.
36:1266-77. |
The novel Hsp90 inhibitor STA-9090 exhibits activity
against Kit-dependent and –independent malignant mast cell tumors.
Lin T, et al. |
Publication |
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General Hsp90 References
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Kim, YS, et al.: Update on Hsp90 Inhibitors in Clinical Trials. Curr Top Med
Chem. 2009; 9(15):1479-92.
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Mahalingam, D, et al.: Targeting Hsp90 for cancer therapy. Br J Cancer, 2009;
100(10):1523-9.
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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.
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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.
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Solit, DB, Chiosis, G: Development and application of Hsp90 inhibitors. Drug
Discov Today. 2008; 13(1-2):38-43.
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Workman, P: Altered states: selectively drugging the Hsp90 cancer chaperone.
Trends Mol Med., 2004; 10(2):47-51.
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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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