Synta Presents Preclinical Data on Next Generation Hsp90 Inhibitor, STA-9090
- Broad anti-cancer activity as a single agent and in combination
- Strong potency against highly resistant cancers
- Superior profile to first generation Hsp90 inhibitors
“Taken together, the preclinical results presented at this conference
demonstrate the potency, safety and broad activity profile of STA-9090,
both as a single agent and in combination,” said
STA-9090 is currently in four Phase 1 and Phase 1/2 trials. Synta expects to report data from these studies and initiate new trials across multiple tumor types later this year and in the first half of 2010.
Three posters related to STA-9090 were presented at the Conference:
STA-9090 is 5-15 fold more potent than 17-AAG in Gleevec-resistant GIST
Poster Presentation
Title: Hsp90
inhibitor STA-9090 potently suppresses heterogeneous KIT kinase-domain
mutations responsible for gastrointestinal stromal tumor progression
during imatinib therapy.
Permanent Abstract Number: B184
GIST is a rare cancer affecting the digestive tract or nearby structures
within the abdomen. Approximately 5,000 new cases of GIST are diagnosed
in
“Metastases taken from gastrointestinal stromal tumor patients whose
cancers had progressed after treatment with imatinib are remarkably
heterogeneous, displaying as many as eight distinct imatinib-resistance
mutations in the KIT oncoprotein in different metastases taken from a
single patient," said
STA-9090 is effective in multiple cancer models both as a single agent and in combination with paclitaxel
Poster Presentation
Title: In vitro
and in vivo efficacy of the novel Hsp90 inhibitor STA-9090 and
its synergy with paclitaxel.
Permanent Abstract Number: B199
In in vitro studies, STA-9090 demonstrated on average approximately 30-fold greater potency than 17-AAG in 60 solid and hematologic cancer cell lines. Importantly, STA-9090 maintained its potency in cell lines of cancers which were resistant to kinase inhibitors such as Tarceva and Gleevec. In vivo studies of STA-9090 demonstrated strong single agent activity in cancers such as non-small cell lung cancer, gastric carcinoma and melanoma and hematologic malignancies such as acute myeloid leukemia, B-cell lymphoma, chronic myeloid leukemia and multiple myeloma. Activity was demonstrated in models that are particularly resistant to treatment, such as leukemias with the BCR-ABL T315I mutation. STA-9090 also demonstrated both in vitro and in vivo synergy with paclitaxel, including lung cancer models that were resistant to Tarceva, with no evidence of drug-drug interactions between the two agents.
STA-9090 in lung cancer supports infrequent dosing
Poster Presentation
Title:
Pharmacodynamic analysis of the Hsp90 inhibitor STA-9090 in a lung
cancer xenograft model supports an infrequent dosing schedule in the
clinic.
Permanent Abstract Number: C91
Hsp90 inhibition induces rapid client protein degradation, cell cycle arrest and apoptosis, however it has been hypothesized that frequent drug dosing in the clinic may be required to achieve optimal efficacy.
In vitro exposure to STA-9090 for as little as 5 minutes, however, was found to induce long-lasting cell growth inhibition and death, suggesting that even brief drug exposure in vivo may be sufficient to affect tumor growth. Consistent with this, STA-9090 has shown very broad in vivo efficacy in mouse cancer models. In particular, in a lung cancer model STA-9090 was found to be significantly more efficacious than 17-AAG, and pharmacodynamic studies demonstrated that a single drug dose was able to inhibit tumor cell proliferation and increased cell death up to several days after a single drug dose. These effects were correlated with long-lasting decreases in important signaling proteins regulated by Hsp90, such as EGFR, HER2, MET and RAF1. The studies also show that STA-9090 accumulated preferentially in tumors, with a tumor half-life of 58 hours, versus a half-life of 3-5 hours in the normal liver, lung and plasma. These results suggest that an infrequent dosing schedule may be effective in the clinic. These preclinical data are further supported by early clinical results, where once-a-week single agent dosing in solid tumors has resulted in responses in patients who have failed multiple prior therapies as well as instances of prolonged stable disease and a favorable safety profile.
About Hsp90
Hsp90 is a protein that maintains the function of numerous signaling proteins – known as ‘client proteins’ – associated with cancer cell survival and proliferation. Many cancers result from specific mutations in, or aberrant expression of, these client proteins. Examples of cancer-associated client proteins of Hsp90 include KIT in gastrointestinal stromal tumors, epidermal growth factor receptor (EGFR) in lung cancer, and BCR-ABL in chronic myelogenous leukemia. In preclinical studies, inhibiting Hsp90 causes the degradation of these proteins and cancer cell death. Inhibiting Hsp90 has also proven effective in killing cancer cells that have developed resistance to targeted therapies such as tyrosine kinase inhibitors.
About STA-9090
In preclinical studies, STA-9090 has shown the ability to inhibit multiple tyrosine kinases with comparable potency to, and a broader activity profile than specific inhibitors such as Gleevec, Sutent, and Tarceva. In addition, STA-9090 has shown potency up to 100 times greater than the ansamycin family of Hsp90 inhibitors such as 17-AAG, as well as activity against a wider range of kinases. In in vivo models, STA-9090 has shown strong efficacy in a wide range of cancer types, including cancers resistant to Gleevec, Sutent, Tarceva, and 17-AAG. STA-9090 is currently in four Phase 1 and Phase 1/2 trials. Synta expects to report data from these studies and initiate new trials across multiple tumor types later this year and in the first half of 2010.
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References
1.
Source:
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125