Abstract 381: PI3K inhibitor BAY 1082439 and radium-223 dichloride decrease tumor burden and tumor-induced bone formation in an established bone metastatic prostate cancer model in mice
Authors: Suominen Mari I. , Morko Jukka , Fagerlund Katja M. , Alhoniemi Esa , Mumberg Dominik , Ziegelbauer Karl , Halleen Jussi M. , Scholz Arne , Liu Ningshu 
Published: July 2016

Abstract
Background and objective: Bone is the most common site of metastasis in prostate cancer (PCa) and results in significant morbidity and poor prognosis. Disseminated PCa cells conquer hematopoietic stem cell niches, and during outgrowth they induce osteoblasts to form new, disorganized bone. Also osteoclasts are activated at a varying degree. PI3K activation has important role in survival and proliferation of PCa cells, mediating critical signaling pathways involving tumor and stromal cell interaction in the bone microenvironment. BAY 1082439 is a highly selective and potent PI3K inhibitor currently in Phase I, with equipotent activity against PI3Kα and PI3Kβ isoforms. Radium-223 dichloride (ra-223/Xofigo) is alpha-emitting calcium mimetic that via efficient osteoaffinity provides targeted radiation therapy against bone metastases. We have previously reported that BAY 1082439 and ra-223 showed synergistic anti-proliferative and apoptosis-inductive effects in vitro in LNCaP PCa cells (Suominen et al, AACR Annual Meeting 2014). Here, we investigated the effects of BAY 1082439 and ra-223 as single agents and in combination in the osteoblastic LNCaP tumors in tibia of male nod.scid mice.
Methods: Tumors were established 6 weeks after inoculation of LNCaP cells. Mice were randomized into four treatment groups (vehicle, ra-223; BAY 1082439 and ra-223 + BAY 1082439) based on serum PSA and bone lesion score. Treatments were continued for six weeks and the efficacy was assessed by the following endpoints biweekly and/or at the end of the study: PSA, bone formation marker PINP, bone lesions and bone volume (measured by microCT), and tumor and bone area by histological analysis.
Results: Both ra-223 and BAY 1082439 monotherapies inhibited tumor growth (reduction 67.9%, p = 0.029 and 67.4%, p = 0.009, respectively). Furthermore, BAY 1082439 monotherapy treatment group displayed 68.8% of necrotic tumor, compared to 6.5% in the control group (p = 0.009). In the combination group, tumor growth was further suppressed (tumor reduction 89%, p = 0.005) and it is noteworthy that 60% of animals had no detectable tumors in histology. All treatments inhibited the tumor-induced bone formation compared to vehicle, and the combination treatment inhibited progression of bone lesions nearly completely. In conclusion, BAY 1082439 and ra-223 as monotherapies decreased tumor burden and tumor-induced bone reaction, and the observed effects were further enhanced by the combination treatment.
Citation Format: Mari I. Suominen, Jukka Morko, Katja M. Fagerlund, Esa Alhoniemi, Dominik Mumberg, Karl Ziegelbauer, Jussi M. Halleen, Arne Scholz, Ningshu Liu. PI3K inhibitor BAY 1082439 and radium-223 dichloride decrease tumor burden and tumor-induced bone formation in an established bone metastatic prostate cancer model in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 381.