Abstract 5330: Defining the role of TGFB in osteogenic prostate cancer to bone metastases: An integrated biological/mathematical modeling approach
Authors: Cook Leah M. , Araujo Arturo , Basanta David , Lynch Conor C. 
Published: May 2015

Almost 90% of patients that succumb to prostate cancer will have evidence of bone metastases. These metastases are incurable with patients often experiencing intense pain. In bone, prostate cancer cells derive factors necessary for growth and survival by manipulating bone forming osteoblasts and bone resorbing osteoclasts, resulting in areas of excessive osteogenesis and osteolysis, respectively. Our group and others have defined transforming growth factor beta (TGFβ) as being a key factor in the progression of bone metastases. Using semi-quantitative immunohistochemical analysis, we have found in human specimens that TGFβ signaling is much higher in the cancer cells relative to the surrounding bone stroma. Therapeutic inhibition of TGFβ however, presents a dilemma since TGFβ can have differential effects on cell types in the tumor-bone microenvironment. Furthermore, current biological approaches are limited in their ability to assess multicellular parallel interactions over time but this can be overcome via the power of computational modeling. Thus, we have developed an integrated approach where biological results inform a predictive mathematical model, allowing for exploration of complex parallel and multicellular interactions mediated by TGFβ. The model was parameterized with empirical and published data. Simulations of the prostate cancer-bone microenvironment over a 208 day period generated a clinically relevant pathophysiological model with the following outputs: 1) that TGFβ is key for coordinating prostate cancer- induced phases of osteolysis and osteogenesis and 2) that mesenchymal stem cells (MSCs) are crucial for the osteogenic component of the disease. To test these hypotheses, we performed biological studies using a TGFβ antibody-based inhibitor (1D11) that demonstrated: 1) TGFβ in prostate cancer cell conditioned media significantly contributes to MSC and osteoblast precursor recruitment and, 2) using an intratibial model of prostate cancer-induced osteogenesis (PAIII), we identified that TGFβ regulates prostate cancer induced osteolysis and osteogenesis (μCT, histomorphometry). Histological analyses of in vivo specimens will further test the predicted outcomes of the mathematical model. Future studies are focused on evolving the model to incorporate tumor heterogeneity. We believe that integrated computational and biological approaches are key to the development of powerful models that can be used for the delivery of precision medicine to cure prostate to bone metastases.

Citation Format: Leah M. Cook, Arturo Araujo, David Basanta, Conor C. Lynch. Defining the role of TGFB in osteogenic prostate cancer to bone metastases: An integrated biological/mathematical modeling approach. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5330. doi:10.1158/1538-7445.AM2014-5330