Bone marrow (BM) metastases are an important problem in metastatic breast cancer. Metastatic-relapse occurs even decades after the first diagnosis and can show different clinical features compared to the primary disease. The cross-talk between cancer cells and the microenvironment influences tumor behaviour and impinges on therapeutic efficiency.

To uncover new targets for the inhibition of BM metastases, we performed a transcriptional analysis of BM stromal cells using in-vivo models of breast cancer bone metastases. We identified IL6, and its downstream JAK kinases pathway, as major up-regulated signals in the bone stroma of tumor-bearing mice. Moreover, we found that a significant proportion of BM metastases from breast cancer patient biopsies are positive for pSTAT3 staining, attesting to activation of JAK-STAT signaling. These results provide a rational to investigate the therapeutic potential of a JAK inhibition in bone metastases. We evaluated the effect of two JAK inhibitors: the BSK805, a JAK2 inhibitor, and ruxolitinib a JAK1-JAK2 inhibitor currently in clinical trials for metastatic breast cancer. In pre-clinical models of breast cancer metastases (the triple negative MDA-MB231 SCP1833 and the ER+ EO771), treatment with the JAK inhibitors decreased pSTAT3 signaling in the bone, but surprisingly increased metastastic tumor burden.

Considering the importance of the JAK-STAT pathway as a therapeutic target, we are investigating the possible bystander effects of blocking JAK kinases. Analysis of the BM stoma showed that JAK inhibition decreased TRAP+ osteoclasts and affected the mesenchymal compartment, with a significant increase in the BM fat compartment in tumor-bearing animals. The reasons for and the consequences of these changes in the bone stroma are under investigation. As the JAK-STAT signaling pathway is also a key regulator of the hematopoietic compartment, we are studying how JAK inhibitors influence the immune response in tumor bearing mice. Further dissection of the immunomodulatory effect of JAK inhibition and how this influences tumor dissemination and expansion is warranted.

Citation Format: Alessia Bottos, Jason Gill, Thomas Radimerski, Alexandar Tzankov, Aleksandra Wodnar-Filipowicz, Nancy E Hynes. Effects of JAK pathway inhibition in pre-clinical models of breast cancer bone marrow metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-19.