Abstract B08: Biomimetic Culture Platform for Ex Vivo Preservation of Patient-Derived Multiple Myeloma Cells
Authors: Zilberberg Jenny , Zhang Wenting , Siegel David S. , Lee Woo Y. 
Published: March 2017

Multiple myeloma (MM) is an incurable B-cell malignancy with a typical survival of 5 to 7 years, and is characterized by: (1) the accumulation of IgG (κ or λ) producing monoclonal plasma cells in bone marrow (BM) and (2) the progression of metastatic osteolytic lesions in bones. We have developed a new approach for the extended culture (&gt; 3 weeks) of difficult-to-preserve primary patient multiple myeloma cells (PMMCs) present in bone marrow aspirates, using an osteoblast (OSB)-derived 3D tissue scaffold constructed in a perfused microfluidic environment [1]. In contrast, the ex vivo viability of PMMCs cannot be preserved using conventional culture techniques beyond a few days.

This biomimetic model was used to show, for the first time, that: (1) the adhesion of PMMCs to OSB, mediated by osteoblastic N-cadherin, and the long-term viability of OSBs were critical factors in maintaining the ex vivo viability and proliferative capacity of PMMCs; (2) perfusion flow enhances the survival of OSBs, and thus increases the long-term viability of PMMCs; and noteworthy, (3) PMMCs can acquire drug-resistance due to the adhesive interactions with OSBs, a phenomenon called cell adhesion-mediated drug-resistance (CAM-DR) [2]. These findings support that the in vitro model is capable of recapitulating critical MM tumor microenvironment associated with the survival and drug-resistance of PMMCs.

Upon further development, our ex vivo model may provide a new means of selecting the best therapy for an individual patient based on the ex vivo response of his or her PMMCs to drug treatment options as well as novel immunotherapeutic treatments such as chimeric antigen receptor (CAR) T-cell therapy. This precision medicine approach is expected to provide a transformative means of: (1) reducing ineffective or unnecessary therapies; (2) minimizing excess toxicity and costs; and (3) inhibiting the development of tumor cells' cross-resistance to additional drugs, as a critical part of the long-term care of MM patients. Also, we anticipate that our approach can be used for: (1) preclinical evaluation of new therapeutics, (2) studying the development of drug-resistant PMMC subpopulations, (3) identifying novel therapeutic targets, and (4) developing ex vivo models of breast and prostate cancers that metastasize to BM via similar mechanisms.

Currently, we are in the early stage of prospectively correlating the ex vivo chemosensitivity and resistance of PMMCs with short-term clinical response, as a means of validating the predictive capability of our ex vivo MM culture platform. We also plan to incorporate the 3D-reconstructed network of primary human osteocytes [3] to study interactions of osteocytes with PMMCs and other BMMCs including immune cells.

References:

1. W. Zhang, et al., “Patient-Specific 3D Microfluidic Tissue Model for Multiple Myeloma”, Tissue Engineering C: Methods, 20, 663-670 (2014).

2. W. Zhang, et al., “Ex Vivo Maintenance of Primary Human Multiple Myeloma Cells through the Optimization of the Osteoblastic Niche,” PLOS ONE, DOI: 10,1371/journal.pone.0125995 (2015).

3. Q. Sun, et al., “Ex Vivo 3D Osteocyte Network Construction with Primary Murine Bone Cells,” Bone Research, 3, 15026; doi:10.1038/boneres.2015.26.

Citation Format: Jenny Zilberberg, Wenting Zhang, David S. Siegel, Woo Y. Lee. Biomimetic Culture Platform for Ex Vivo Preservation of Patient-Derived Multiple Myeloma Cells. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B08.