Multiple myeloma (MM), an incurable B cell malignancy, is the second most frequent blood disease in the United States. This disease is characterized by a clonal proliferation of malignant plasma cells in the bone marrow (BM), the presence of high levels of monoclonal serum antibody, and the development of bone lesions. Despite the introduction of a number of novel treatments MM patients still are confronted with an average survival time of 3-4 years. As opposed to other hematological malignancies, MM strongly interacts with the BM microenvironment. These interactions are responsible for the specific homing of MM cells to the BM, their proliferation and survival, the resistance of MM cells to drug treatment, and the development of bone disease. Unfortunately, because of the challenges associated with reproducing this complex tumor niche, primary MM tumor cells have been difficult to propagate ex vivo, hampering not only the study of this cancer but the development of technologies that could facilitate personalized treatment strategies in the clinic. To address this void, we propose to develop a physiological and robust technology for better preserving the BM/MM interactions by customizing a 3D bone tissue-like scaffold microfluidic system originally designed at Stevens Institute of Technology to optimize biomaterials for orthopedic implant-related wound-healing. This system will be used as the initial working frame in the current proposal to achieve following specific aims: I) Develop an off-the- shelf technology that enables reconstruction of BM microenvironmental factors regulating survival and proliferation of MM tumor cells present in BM biospecimens. II) Evaluate the utility of the BM biospecimen 3D culturing platform to assess drug treatment strategies for MM. From a clinical perspective, the proposed off-the-shelf microfluidic technology should: 1) maximize sample use by requiring very small amounts of patient BM cells (<1X106 cells) and serum (<2 mL/culture/week) and 2) accelerate the evaluation of new therapeutics for the treatment of MM. We anticipate that our ability to perform real-time monitoring of BM/MM cell developments and interactions and the introduction of perfusion conditions which cannot be evaluated using a static culture system will make our model a valuable tool to identify new mechanisms associated with the MM niche and tumor progression. These advantages offer substantial improvement over the conventional approach and can advance the field of personalized MM therapy. Furthermore, we foresee our methodology being translated to other tumors that are also tightly interconnected to their bone/BM microenvironment.
Multiple myeloma (MM) is the second most frequent blood disease in the United States. Despite the introduction of a number of novel treatments MM patients still are confronted with an average survival time of 3-4 years. In view of the fact that MM is characterized by several relapses and drug resistance, having the capability of selecting the best course of treatment in advance can significantly improve the outcome of MM patients. To this end, the following proposal will center on the development of an off-the-shelf platform that will enable personalized drug evaluation for patients suffering from this disease.
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|Zhang, W; Gu, Y; Hao, Y et al. (2015) Well plate-based perfusion culture device for tissue and tumor microenvironment replication. Lab Chip 15:2854-2863|