title: Predicting the impact of combined therapies on myeloma cell growth using a hybrid multi-scale agent-based model.
abstract: Multiple myeloma is a malignant still incurable plasma cell disorder. This is due to refractory disease relapse, immune impairment, and development of multi-drug resistance. The growth of malignant plasma cells is dependent on the bone marrow (BM) microenvironment and evasion of the host's anti-tumor immune response. Hence, we hypothesized that targeting tumor-stromal cell interaction and endogenous immune system in BM will potentially improve the response of multiple myeloma (MM). Therefore, we proposed a computational simulation of the myeloma development in the complicated microenvironment which includes immune cell components and bone marrow stromal cells and predicted the effects of combined treatment with multi-drugs on myeloma cell growth. We constructed a hybrid multi-scale agent-based model (HABM) that combines an ODE system and Agent-based model (ABM). The ODEs was used for modeling the dynamic changes of intracellular signal transductions and ABM for modeling the cell-cell interactions between stromal cells, tumor, and immune components in the BM. This model simulated myeloma growth in the bone marrow microenvironment and revealed the important role of immune system in this process. The predicted outcomes were consistent with the experimental observations from previous studies. Moreover, we applied this model to predict the treatment effects of three key therapeutic drugs used for MM, and found that the combination of these three drugs potentially suppress the growth of myeloma cells and reactivate the immune response. In summary, the proposed model may serve as a novel computational platform for simulating the formation of MM and evaluating the treatment response of MM to multiple drugs.
authors.affiliation: Division of Radiologic Sciences and Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA 27157.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Ji
authors.affiliation: Division of Radiologic Sciences and Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA 27157.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Division of Radiologic Sciences and Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA 27157.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Division of Radiologic Sciences and Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA 27157.
authors.forename: Huiming
authors.initials: H
authors.lastname: Peng
authors.affiliation: Division of Radiologic Sciences and Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA 27157.
authors.forename: Weiling
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Division of Radiologic Sciences and Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA 27157.
authors.forename: Brian
authors.initials: B
authors.lastname: Nlong Zhao
authors.affiliation: Division of Radiologic Sciences and Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA 27157.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D018920:Coculture Techniques; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008390:Markov Chains; D008954:Models, Biological; D009010:Monte Carlo Method; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D013269:Stochastic Processes; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D059016:Tumor Microenvironment
keywords: ODE; agent-based model; immune; modeling; multiple myeloma