Cancer Testbeds for Bone Metastasis Therapeutics

Worldwide over a million deaths occur each year from breast and prostate cancer bone metastasis. Majority of the deaths due to breast and prostate cancer are attributed to metastasis, the process of migration of cancers from the primary site to a remote location which happens to be bone for breast and prostate cancer. Bone metastasis of cancer often causes skeletal failures that become the cause of death in patients. The anticancer drugs available are ineffective for bone metastasis treatment. The inefficacy of anticancer drugs and failure of animal models necessitates the need for reliable in vitro models. We have developed a novel nanoclay tissue engineering scaffold that enables development of a remodeling stage fetal bone, a preferred niche for breast and prostate cancer metastasis. The bone mimetic scaffold utilizes modification of the clay galleries with amino acids to allow biomimetic mineralization of hydroxyapatite inside clay galleries. The bone scaffold is further sequentially seeded with commercial and patient derived cell lines of prostate and breast cancer to generate invitro models of bone metastasis in breast and prostate cancer. A specially designed horizontal flow bioreactor enables physiologically relavant fluid flow through the scaffolds thus creating a realistic testbed of bone metastasis. The cancer testbed servs as a useful platform to investigate new biomarkers using FTIR spectroscopy, RAMAN imaging and nanomechanical investigations. We have developed unique mechanics-based biomarkers that use direct nanoindentation to evaluate thew change in elastic modulus, mechanical plasticity and viscoelasticity of cancer cells as a measure of metastasis progression. We have developed unique FTIR based spectroscopic biomarkers with the help of the testbed that also demonstrate the use of FTIR in developing markers for progression of metastasis⁹. Since clinical observations indicate extensive skeletal problems and failures in bone metastasis patients, we use the testbed to evaluate the mechanisms of influence of cancer cells on the Wnt b catenin pathway an important osteogenesis pathways. We observe the specific role of cancer cell factors DKK and ET-1 on influence osteogenesis at the bone site. Lastly we demonstrate the use of testbed for screening new drugs and plant-based compounds for efficacy in treatment of bone metastasis. Overall the cancer testbed presented here is a useful in vitro system for development of new metastasis therapies and personized medicine.