STA-9090, an experimental treatment against advanced gastrointestinal stromal tumours (GIST) has been shown encouraging results, according to Synta Pharmaceuticals Corp.
STA-9090 is a synthetic, small molecule Hsp90 inhibitor with a novel chemical structure.
Synta Pharmaceuticals Corp is initiating a phase 2 clinical study of STA-9090 in patients with advanced gastrointestinal stromal tumours (GIST). This is the sixth clinical study of STA-9090.
The non-randomized, open-label, multi-centre Phase 2 study is designed to characterize the efficacy and safety of STA-9090 in patients with metastatic or unresectable GIST following failure of systemic treatment with imatinib (Gleevec) and sunitinib (Sutent).
The trial will enrol up to approximately 55 patients in a two-stage design. Patients will be stratified according to whether or not they have been exposed to other Hsp90 inhibitors, and STA-9090 will be administered as a single agent on a once-weekly intravenous dosing schedule.
Patients tolerating STA-9090 may continue on treatment until disease progression.
Patients will be assessed for clinical benefit rate per RECIST criteria. Other objectives of the trial are to assess the impact of treatment with STA-9090 on certain biomarkers and to characterize the safety of STA-9090 in this patient population.
“Both imatinib (Gleevec) and sunitinib (Sutent) have proven very effective in helping patients with GIST to live longer; however, the majority of patients will eventually experience disease progression despite treatment with both of those molecularly targeted therapies,” stated George Demetri, M.D., Dana-Farber Cancer Institute.
Once those two standard drugs fail, patients have a poor prognosis and very limited treatment options. Hsp90 inhibition is a promising therapeutic approach for these patients because the mutated kinase proteins that are the cause of resistance to both Gleevec and Sutentdepend upon being chaperoned and protected by the function of Hsp90.
STA-9090 can potently inhibit the Hsp90 function and disrupt the mutant signalling in multidrug-resistant GIST. Based on the preclinical and early clinical results seen to date, STA-9090 has the potential to unlock the true potential of Hsp90 as a therapeutic target in GIST, he added.
Preclinical results related to STA-9090 in GIST were presented at the AACR-NCI-EORTC Conference on Molecular Targets and Cancer Therapeutics in November 2009.
In these studies, STA-9090 was also 5-15 fold more potent than 17-AAG, a first-generation, ansamycin-family Hsp90 inhibitor. Additionally, STA-9090 was active against GIST cells that were resistant to 17-AAG.
Synta expects to report data from the ongoing phase 1 and phase 1/2 trials and initiate studies in multiple other cancer indications in the first half of 2010.
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, melanoma and certain haematologic cancers – as well as potent activity against cancers resistant to imatinib (Gleevec), sunitinib (Sutent), erlotinib (Tarceva), and dasatanib (Sprycel).
In addition to GIST, Synta is currently conducting a Phase 2 trial in non-small cell lung cancer (NSCLC), two Phase 1/2 clinical trials of STA-9090 inhaematologicc cancers and two Phase 1 trials studies of STA-9090 in solidtumour cancers.
Hsp90 is 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 cancer drugs.
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.
What is GIST?
A gastrointestinal stromal tumor (GIST) is a type of cancer that occurs in the gastrointestinal (GI or digestive) tract, including the esophagus, stomach, gallbladder, liver, small intestine, colon, and rectum.
Neraly 4,500 to 6,000 GIST cases are diagnosed each year in the United States, according to the American Cancer Society estimates.
Although these tumors can start anywhere in the GI tract, they occur most often in the stomach (50% to 70%) or the small intestine (20% to 30%).
Synta Pharmaceuticals Corp. is a biopharmaceutical company focused on small molecule drugs.