Pharmacological Inhibition of Signaling through the Activin Receptor Type IIa Prevents Primary Tumor Growth and Skeletal Metastases in Mouse Models of Breast Cancer.

Abstract

Abstract 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 loss of bone, but do not stimulate the formation of new bone. Previous data demonstrated that treatment with an activin antagonist, a soluble form of the extracellular domain of the activin receptor type IIA (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.The goal of the current studies was to establish the ability of RAP-011 to directly inhibit breast cancer cell proliferation, delay primary tumor growth and prevent skeletal metastases. Bioluminescent breast cancer cells (MCF-7-luc and MDA-MB-231-luc-D3H2LN) were administered orthotopically to establish a primary tumor model or by intracardiac injection to establish a metastatic breast cancer model. Both studies were performed using athymic nude mice that had been pretreated for 2 weeks with RAP-011 (10 mg/kg S.C. twice weekly) or vehicle (VEH).In vitro studies demonstrated that activin A stimulated proliferation of some tumor cell lines, while the addition of soluble ActRIIa blocked the stimulation. In the orthotopic models of breast cancer RAP-011 treated mice had significantly smaller primary tumors as early as 3 weeks post-inoculation. RAP-011 treated mice had tumors that remained significantly smaller for the duration of the 10 week study (-60%, p<0.02).In the model of metastatic breast cancer, 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%, p<0.001), fewer osteolytic lesions (-45%, p<0.05) and increased overall survival by 11 days compared to VEH-treated mice. DXA scanning of the mice revealed RAP-011 treated mice had a significant increase in bone mineral density compared to the VEH treated mice (+10%, p<0.05), reflecting the decreased levels of osteolytic metastases. Histological analysis of the femur and tibia confirmed increased levels of tumor growth and osteolytic lesions, as well as decreased levels of trabecular bone volume in VEH treated mice.These data support the role of Activin in the establishment and growth of tumors and that the use of a soluble ActRIIA receptor can prevent primary tumor growth and inhibit metastases in patients with breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5058.