3D Tissue Engineering Bone Marrow Culture (3DTEBM)
In cancer drug development, despite promising results in vitro tissue culture models, many therapies fail to show the same efficacy in clinical trials in patients. The main reasons that can explain the discrepancy are the lack of tumor microenvironment and 3D aspects (such as hypoxia and drug gradients) in the classic tissue culture models, as well as the patient heterogeneity that cannot be reflected by limited number of cell lines in vitro.
We have developed an ex-vivo 3D-tissue engineered bone marrow model (3DTEBM) that includes all cells in the tumor microenvironment, demonstrated 3D aspects of the tumor, and is patient-derived (not cell lines). The 3DTEBM is the only available patient-derived model that allows proliferation of primary cancer (Myeloma, AML, CML, and ALL) cells ex vivo, which includes the cancer cells and all the accessory cells in the TME in the BM. Moreover, the 3DTEBM recreates 3D aspects of the tumor BM niche including hypoxic, low-proliferative, stroma-rich “endosteal niche”-like lower layer; along with an oxygenated, highly-proliferative, endothelial cell-rich “vascular niche”-like upper layer. These properties nominate the 3DTEBM as an optimal model to predict clinical therapeutic response in cancer patients.
Unlike classic tissue culture models, the ex vivo efficacious concentration (IC50) in the 3DTBM model directly correlated with the clinical efficacious concentrations (Css) of novel myeloma therapies. Consequently, ex vivo drug treatment in the 3DTEBM model retrospectively predicted the clinical response to novel therapies in 89% of the relapsed/refractory Myeloma patient cohort. Moreover, the 3DTEBM recapitulated the tumor immune-microenvironment. We have also shown the the 3DTEBM can be developed from the bone marrow of leukemia and lymphoma patients.
We are focused on using this model for better understanding of the interaction of cancer cells and the tumor microenvironment, for drug development, and for development of precision medicine strategies in malignancies involving the bone marrow.
