Abstract 4022: Combination of PI3K inhibitor BAY 1082439 with radium-223 is a promising treatment of cancer with bone metastases
Authors: Suominen Mari I. , Fagerlund Katja , Stasik Enrico , Haegebarth Andrea , Scholz Arne , Rissanen Jukka P. , Kornacker Martin , Mumberg Dominik , Halleen Jussi M. , Ziegelbauer Karl , Liu Ningshu 
Published: May 2015

Abstract
About 80% of advanced prostate, breast and lung cancer patients develop bone metastases, which cause significant morbidity including chronic pain and pathologic fractures. Patients with bone metastases have a poor prognosis and currently there is no curative treatment. This is largely due to the unique biological microenvironments of bone where a wide range of growth factors promote tumor cell survival and tumor cells stimulate bone remodeling.
Activation of PI3K plays important role in prostate and breast cancer cell proliferation, survival and metastasis. PI3K also mediates critical signaling pathways involving tumor and stromal cell interaction, including cancer-induced bone turnover and osteolysis. BAY 1082439 is a highly selective and potent PI3K inhibitor with balanced activity against PI3kα and PI3Kβ isoforms and currently being evaluated in a phase I clinical trial (N. Liu, et al. AACR 2012 Abstract #2799). Radium-223 dichloride (radium-223), a novel therapy recently approved for treatment of castration-resistant prostate cancer (CRPC) with bone metastases, selectively targets bone and kills metastatic cancer cells by the emission of alpha particles (Parker et al. N Engl J Med. 2013; 369:213).
To identify more effective therapy to treat bone metastases, we evaluated the combination of PI3K inhibitor BAY 1082439 and radium-223 in vitro and in the syngeneic 4T1 metastatic breast cancer model in mice. BAY 1082439 and radium-223 showed synergistic anti-proliferative effects in vitro in both hormone receptor positive (HR+, MCF7 and LNCaP) and negative (4T1 and PC3) breast and prostate tumor cell lines. Pronounced synergistic effects on apoptosis induction were observed in MCF7 and LNCaP cell lines. In vivo, combination of BAY 1082439 at the maximum tolerable dose and radium-223 at the efficacious dose was well tolerated. BAY 1082439 significantly decreased whole body tumor burden as single agent (67% reduction, p=0.00156) and more effectively in combination with radium-223 (81% tumor reduction, p=0.0012), while the effect of radium-223 alone was not statistically significant. Furthermore, BAY 1082439 strongly inhibited tumor-induced osteolysis measured by radiography and led to 53.2% (p=0.16) and 84% (p=0.00698) reduction in total osteolytic area as single agent and in combination with radium-223, respectively. The frequency of soft tissue metastases was also decreased by treatment with BAY 1082439 alone (e.g. 73% reduction in kidney, p=0.012) and more pronounced with radium-223 combination treatment (e.g. complete inhibition of kidney metastasis, p=0.0003). In summary, our data indicate synergistic effects of the PI3K inhibitor BAY 1082439 and radium-223 in inhibiting tumor cell proliferation, survival, total and bone marrow tumor burden, and tumor-induced osteolysis, and warrant further clinical evaluation of this promising combination therapy for the treatment of cancer with bone metastases.
Citation Format: Mari I. Suominen, Katja Fagerlund, Enrico Stasik, Andrea Haegebarth, Arne Scholz, Jukka P. Rissanen, Martin Kornacker, Dominik Mumberg, Jussi M. Halleen, Karl Ziegelbauer, Ningshu Liu. Combination of PI3K inhibitor BAY 1082439 with radium-223 is a promising treatment of cancer with bone metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4022. doi:10.1158/1538-7445.AM2014-4022