Abstract 21: Understanding the progression and chemotherapy resistance of Multiple Myeloma in the bone marrow through evolutionary computational models and in vitro experiments

Abstract

Abstract Multiple Myeloma (MM) is a complex and incurable disease, in which malignant plasma cells proliferate in the bone marrow, causing bone lesions and failed hematopoiesis, while tumor-produced immunoglobulin can result in renal failure. Most patients respond well to chemotherapy, yet inevitably relapse as the tumor cells become resistant to all available therapies. The questions we address in this work are: (1) how the marrow microenvironment drives the progression of pre-malignant B cells from an indolent to an aggressive form of disease, and (2) how this progression may select for de novo chemoresistance. These were addressed using mathematical models informed with in vitro data. We created a mathematical model of the marrow incorporating hematopoiesis, spatial geometry of bone and sinusoids, and the paracrine interactions between malignant cells and stroma. In this hybrid 3D agent based model, cells (agents) interact through soluble factors (glucose, oxygen, cytokines, pH buffers, chemotherapy) that are produced, consumed, and diffuse through the interstitial fluid. Each cell type (MM, osteoclasts and osteoblasts, fibroblasts, endothelium) has heritable phenotypes (cytokine production, replication, quiescence, and death) that respond to growth factor levels, ATP production, etc. In vitro studies included hypoxia/re-oxygenation cycles that consisted of exposure of cells to 5 days at 0.2% pO2, followed by re-growth in normoxia. Chronic hypoxia consisted in hypoxia exposure for three weeks before re-oxygenation. Simulations showed that the marrow-tumor system progressed differently depending on the initial phenotypes of the cancer cells. Hypoxia induced by hypercellularity in the myelomatous marrow was identified as a driving force in the establishment of loops between MM and stroma, selecting for higher proliferative response to IL6 and hypoxia-independence. Angiogenesis observed both clinically and in simulations, normalized the oxygen levels, allowing further re-growth of the tumor population. These cycles of growth and angiogenesis result in cycles of hypoxia and re-oxygenation. Higher tumor burdens would finally exhaust the support provided by the stroma and select for individuals that are independent of the microenvironment, paving the way for the leukemic stage of the disease. In vitro data showed that MM cells exposed to cyclic hypoxia are more resistant to Melphalan (under normoxia), indicating that cyclic hypoxia might be a relevant factor in development of de novo chemoresistance in MM. Chronic hypoxia led to a reversal of this phenotype, indicating that chronic and cyclic hypoxia may differentially select for diverging phenotypes. 54% of Caspase-3 activity was induced by 50uM Melphalan in parental 8226/S, whereas 44% was seen in 5-round cyclic-selected cells and 64% in chronic hypoxia treated cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 21. doi:10.1158/1538-7445.AM2011-21