RAP-011, a soluble activin receptor type IIA IgG-Fc fusion protein, is a novel bone anabolic agent that prevents bone loss and skeletal metastases in a mouse model of metastatic breast cancer.

Abstract

Abstract Abstract #1158 Breast cancer cells have a strong propensity to metastasize to bone, resulting in debilitating complications such as intractable bone pain, spinal compression, pathological fractures, or loss of mobility and function. Anti-resorptive agents, such as bisphosphonates, are commonly used to halt the additional loss of bone, but fail to stimulate the formation of new bone to repair lost or damaged bone. Previous data demonstrated that treatment with an activin antagonist, a soluble form of the extracellular domain of the activin type IIA receptor (ActRIIA) fused to a murine IgG-Fc fragment (RAP-011), can restore bone mass in ovariectomized mice with established bone loss and prevent bone loss in a murine model of multiple myeloma.
 To investigate the ability of RAP-011 to prevent skeletal metastases in an experimental model, bioluminescent breast cancer cells (MDA-MB-231-luc-D3H2LN) were administered by intracardiac injection into athymic nude mice that had been pretreated for 2 weeks with RAP-011 (10 mg/kg S.C. twice weekly) or vehicle (VEH). At 3 and 5 weeks post-inoculation, RAP-011 treated mice displayed lower levels of hind limb, mandible and lung metastases compared to VEH-treated mice. RAP-011 treated mice had reduced tumor burden (-70%) and increased overall survival by 11 days compared to VEH-treated mice. It was also shown that RAP-011 preserved bone mineral density and increased both trabecular volume (BV/TV +140%, P<0.001) and trabecular number (+15%, P<0.001), compared to VEH. In the VEH-treated mice, BV/TV was lower in bones with a tumor present (0.191) than bones without a tumor (0.276, p=0.1). However, RAP-011 treated mice increased BV/TV to a similar extent in both bones with a tumor (0.598) and bones without a tumor (0.599, p=0.98) compared to the VEH controls (p<0.001).
 Taken together, these data suggest that inhibition of activin has the potential therapeutic benefit of improving bone health in patients with cancer related bone loss as well as preventing metastasis of breast cancer. Towards this end, ACE-011, the human analog of RAP-011, is currently in clinical development for the treatment of cancer-related bone loss. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1158.