One out of every eight women will develop breast cancer during her lifetime. Of those women who progress to an advanced stage of disease, over 80% will develop bone metastases. Breast cancer cells preferentially metastasize to bone and typically result in osteoblastic lesions. In the late stages of disease, however, osteolytic lesions are observed. The mechanisms of breast cancer bone metastasis are still unclear, but relationships between the breast cancer cells and the bone tissue elements are suspected of being more complex than initially thought. Far from being an innocent bystander, the bone participates actively in the metastatic process and provides the cancer cells with growth factors and a fertile environment. Among the various cells in the bone environment, osteoblasts have a central role through their bidirectional interactions with the breast cancer cells. Bone metastases are currently incurable and therefore better treatments need to be developed.
We aim to understand the interaction between breast cancer and bone by co-culturing breast cancer cells together with bone osteoblasts. We postulate that there is a bidirectional interaction between these cells mediated by hormones, cytokines and growth factors, which are either immobilized within the extracellular matrix, formed by bone cells or secreted in soluble form, are essential for bone metastasis.
Oncogenic thyrosine kinases have been identified as central targets in molecular cancer therapy. However, drugs designed to inhibit these kinases have been plagued with cardiotoxic side effects. For instance, the powerful anti-cancer drug imatinib, which targets c-Kit kinase in gastrointestinal stromal tumors (GIST) and chronic myelogenous leukemia (CML), no only promotes apoptosis but also heart damage by inhibiting Bcr-Abl kinase. In a strategy to re-design imatinib a new drug was developed to eliminate the Bcr-Abl kinase inhibition, while inhibiting both c-Kit and the JNK pathway, which leads to cardiotoxicity. This drug has been tested in GIST and ovarian cancer cell lines and tested in SCID mice. Although this approach resulted in an apparent more effective drug the mechanisms responsible for such an event are not clearly understood.
There is an urgent need for novel approaches in rational drug design to achieve the goal of new drugs without side effects, fulfilling the promises of personalized medicine. The long-term objective of this research is to identify potential drug targets using an efficient and cost-effective data-mining approach.
This study is aimed at the identification of biological networks as the first step toward a systems-level understanding of the biology of oncogenic tyrosine kinases with the inhibition of c-Kit as a model system. Compared to functional genomics, which requires a priori information about the identity or function of targets, a systems-level understanding of the oncogenic kinases will allow us to identify targets based on their key roles in networks.
