Investigational Heat Shock Protein Inhibitor Shows Promise in Lung Cancer

Norra MacReady

July 13, 2010

July 13, 2010 (Los Angeles, California) — An investigational compound that acts as a heat shock protein (HSP) inhibitor has shown promise in the treatment of lung cancer and in many other malignancies, speakers reported here at the 11th International Lung Cancer Conference.

The compound, STA-9090, is under development by Synta Pharmaceuticals.

In a company-funded phase 1, open-label, dose-escalation trial, STA-9090 was associated with a mild to moderate adverse effect profile and encouraging clinical findings in 24 of 53 patients with various types of solid tumors.

HSPs, which are found in a wide variety of organisms (from bacteria to humans), derive their name from the fact that their transcription can be elicited by exposure to extreme heat. However, they are also produced in response to other types of stress, such as infection, toxins, and inflammation, and their concentration is higher in certain kinds of tumor cells than in normal tissue.

HSPs function as "chaperone" proteins that help other proteins (the "client" proteins) attain and maintain the proper conformation for further metabolic interactions. HSP-90 is a chaperone protein for at least 5 client proteins that play a critical role in the pathophysiology of nonsmall-cell lung cancer (NSCLC).

STA-9090 inhibits the action of HSP-90, allowing for the simultaneous targeting of multiple oncogenic signaling pathways. STA-9090 is a second-generation HSP-90 inhibitor that, in early trials, has shown more robust activity than the first-generation inhibitors, 17-AAG and IPI-504.

"HSP-90 regulates many of the tumor membrane signal proteins," Tianhong Li, MD, PhD, assistant professor of hematology and oncology at the University of California, Davis, told Medscape Medical News. "If we can modify those, we may be able to make changes that impact tumor growth."

Toxicity has been the primary concern with the HSP-90 inhibitors, she added. "Compared with the first-generation agents, STA-9090 is a more potent tumor inhibitor and is better tolerated." Dr. Li was not involved in this research.

The patients in this study had advanced or metastatic solid tumors for which no standard therapy existed, or that had proven refractory to other types of treatment. Each participant received STA-9090 in a 4-week cycle, consisting of a 1-hour infusion administered once a week for 3 weeks, followed by a week-long dose-free interval. Dosing began at 7 mg/m2 and escalated to 14, 23, 35, 49, 65, 86, 114, and 150 mg/m2 over subsequent cycles. Escalation continued as appropriate in 20% increments up to 259 mg/m2. Of the 53 patients, 10 had NSCLC, 2 had small-cell lung cancer, and the others had tumors of the colon, prostate, pancreas, esophagus, gastrointestinal stroma, or ovary. There were also 2 cases of melanoma.

Of 42 patients evaluated for a clinical response, 1 with colon cancer achieved a partial response, and 23 others achieved stable disease, including 16 for whom the stability persisted for at least 16 weeks.

All of the patients experienced some type of adverse event, the most common being diarrhea, fatigue, abdominal pain, nausea, and anemia. The maximum tolerated dose for weekly administration was established at 216 mg/m2. Most of the events were considered mild to moderate, and none were associated with the cessation of treatment.

Dr. Li made had disclosed no relevant financial relationships.

11th International Lung Cancer Conference (ILCC): Poster 2: Presented July 10, 2010.