Abstract 640: New models of breast and lung cancer bone metastases for preclinical efficacy testing

Abstract

Abstract Introduction Clinically, bone is a very common site of metastatic spread in many cancers. In breast, and in particular cases of advanced estrogen receptor positive (ER+) cancers, the propensity of bone involvement is 85%. Similarly in lung cancer, 30-40% of patients with advanced disease develop bone metastases, and as recent advances in lung cancer therapies improve survival, the number of patients living with bone metastases is expected to increase. At the same time there is a paucity of especially ER+ and osteoblastic animal models available for the nonclinical evaluation of new treatment strategies. We present herein the development of four mouse models of breast and lung cancer suitable for screening of new therapies. Experimental procedures Human breast cancer cell lines BT-474 and MFM-223 and non-small cell lung cancer (NSCLC) cell lines NCI-H226luc and NCI-H322 were used. BT-474 is ER+, i.e. luminal B subtype and MFM-223 is basal subtype with androgen receptor (AR) expression. H226 originates from squamous cell carcinoma and H322 from adenocarcinoma of the lung. The different cell lines were inoculated in the tibia of female nude or NOD.scid mice. Half of the BT-474 inoculated mice had a s.c. slow release 17-beta estradiol pellet implanted. The formation of bone lesions was monitored by X-ray imaging. For H226 transfected with luciferase, tumor growth was also followed by bioluminescence imaging (BLI). Finally, tumor growth and type of bone lesion, i.e. ostelytic or oestoblastic, was confirmed by histology. Results Development of bone lesions was successful in 100% and 90% of animals, with or without hormonal supplementation respectively, four weeks after inoculation of BT-474 cells. Bone lesions were detected earlier in mice with estradiol pellet and were of lytic type. In contrast, bone lesions in mice without hormonal supplementation were strongly osteoblastic. For MFM-223, bone lesions were observed 4-6 weeks after inoculation and the success rate was 60% in nude mice and 70% in NOD.scid mice. For both lung cancer cell lines, 100% of the mice developed bone lesions and were detectable already two weeks after inoculation. H226luc cells developed osteoblastic-mixed lesions and H322 cells induced lytic lesions. Very interestingly, H226luc cells also formed lung metastases in all animals, as evidenced by BLI. Some lung metastases were also found in H322 inoculated mice. Conclusions Two new osteoblastic models are added to the current scarce selection and altogether four new bone lesion models representing different subtypes of breast and lung cancer were successfully established. The different types of bone reaction in these models offer a platform for studying the underlying pathways resulting in response to treatment in osteoblastic vs. osteolytic tumor microenvironment. Citation Format: Mari I. Suominen, Urs B. Hagemann, Yvonne Konkol, Jenni Bernoulli, Katja M. Fagerlund, Roger M. Bjerke, Jenny Karlsson, Jussi M. Halleen, Alan Cuthbertson. New models of breast and lung cancer bone metastases for preclinical efficacy testing. [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 640.