Effects of a soluble activin type 2B receptor Fc fusion protein (STM 217) in TOV-21G, a mouse xenograft model of clear cell ovarian cancer.

Abstract

2541 Background: Response rate and survival with the clear cell subtype of ovarian cancer is has not been improved by the introduction of platinum and taxane chemotherapy. Elevated serum activin is associated with inferior ovarian cancer survival, suggesting that activin inhibition may provide a new treatment strategy. STM 217 (recombinant hu-sActR2B-Fc) is a potent (IC50 < 1nM) inhibitor of activin and myostatin signaling that was tested for anti-ovarian tumor activity. Methods: Athymic nude mice received TOV-21g (clear cell ovarian cancer model) xenografts in the abdominal flank region and after 14 days, weekly subcutaneous STM 217 was administered alone or in combination with 5-fluorouracil (5-FU). Mice were monitored for body weight and tumor volume. Results: After 52 days from tumor cell injection, STM 217 treatment resulted in a statistically significant 43% (p<0.0001) tumor growth reduction, versus the vehicle-treated tumor bearing group tested using ANOVA. In the combination efficacy experiment, 5-FU monotherapy resulted in a 47% (p<0.0001) tumor growth reduction, and the combination of STM217 and 5-FU together resulted in a 73% (p<0.0001) tumor growth reduction. During the course of the study, body weight of the mice receiving STM 217 increased by 26%, mice receiving STM 217 and 5-FU increased by 22%, while control tumor bearing mice receiving vehicle exhibited a 10% body weight loss. Conclusions: Our study demonstrates that inhibition of activin signaling by use of a ligand trap results in antitumor activity, both as a monotherapy, and that additive activity was observed in combination with chemotherapy. Increases in body weight were not impaired by concomitant administration of 5-FU chemotherapy. This study suggests that a phase 1 clinical trial of activin inhibition in metastatic ovarian cancer is warranted.