RANKL inhibition may prove effective in treatment of human malignancy, suggests study

AmgenApr 20 2010

Amgen (Nasdaq: AMGN) today announced results of a preclinical study demonstrating a positive response to administration of RANK-Fc against mammary tumor formation in mouse models. OPG-Fc and RANK-Fc bind to and block the action of RANKL. These molecules have a comparable mechanism of action to denosumab.  The study was presented today in a late-breaking abstract at the American Association for Cancer Research (AACR) 101st Annual Meeting 2010 in Washington, D.C.

As denosumab does not recognize rodent RANKL and the pharmacodynamic mechanism of denosumab is aligned with that of OPG-Fc or RANK-Fc, investigations conducted with these molecules in rodents are deemed appropriate to gain further understanding of the mechanism of action of RANKL in cancer.

Using a hormone (MPA) and carcinogen (DMBA)-induced mammary tumor model in wild-type (WT) mice, the study showed that treatment with RANK-Fc at the initiation of DMBA treatment delayed the time to mammary tumor formation vs. control-treated mice (P<0.0001). RANK-Fc treatment also decreased the incidence of palpable mammary tumors at 32 weeks post last DMBA (22 percent in RANK-Fc treated mice vs. 94 percent in control-treated mice).

The study also tested three different doses of zoledronic acid (0.025, 0.2 and 0.5 mg/kg weekly at DMBA initiation) in WT mice for anti-tumor activity. Zoledronic acid had no effect at any dose on time to tumor formation compared to the control. Additionally, zoledronic acid had no effect at any dose on mammary tumor incidence at 32 weeks post last DMBA (92,100 and 95 percent mammary tumor incidence for 0.5 mg/kg, 0.2 mg/kg and 0.025 mg/kg treated groups respectively).

"In this preclinical study, RANKL inhibition reduced mammary tumor formation in hormone-dependent mouse models," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "These studies suggest that RANKL inhibition might also prove effective in the treatment of human malignancy. We are encouraged by these results, which could ultimately prove important for patients with breast cancer."

In previous preclinical studies, RANKL inhibition has been shown to reduce skeletal tumor progression and improve survival of tumor-bearing animals.  The current study demonstrates the additional ability of RANKL inhibition to reduce the development of tumors outside the skeleton in hormone-dependent mammary tumor models.

RANKL and its target receptor RANK are key factors in bone remodeling and bone destruction associated with bone metastasis. Denosumab, a fully human monoclonal antibody that specifically inhibits RANKL, inhibits osteoclastogenesis and osteoclast-mediated bone destruction.