title: Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer.
abstract: The ability to rapidly assess the efficacy of therapeutic strategies for incurable bone metastatic prostate cancer is an urgent need. Pre-clinical in vivo models are limited in their ability to define the temporal effects of therapies on simultaneous multicellular interactions in the cancer-bone microenvironment. Integrating biological and computational modeling approaches can overcome this limitation. Here, we generated a biologically driven discrete hybrid cellular automaton (HCA) model of bone metastatic prostate cancer to identify the optimal therapeutic window for putative targeted therapies. As proof of principle, we focused on TGFβ because of its known pleiotropic cellular effects. HCA simulations predict an optimal effect for TGFβ inhibition in a pre-metastatic setting with quantitative outputs indicating a significant impact on prostate cancer cell viability, osteoclast formation and osteoblast differentiation. In silico predictions were validated in vivo with models of bone metastatic prostate cancer (PAIII and C4-2B). Analysis of human bone metastatic prostate cancer specimens reveals heterogeneous cancer cell use of TGFβ. Patient specific information was seeded into the HCA model to predict the effect of TGFβ inhibitor treatment on disease evolution. Collectively, we demonstrate how an integrated computational/biological approach can rapidly optimize the efficacy of potential targeted therapies on bone metastatic prostate cancer.
authors.affiliation: Tumor Biology Dept, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Leah M
authors.initials: LM
authors.lastname: Cook
authors.affiliation: Integrated Mathematical Oncology Dept, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Araujo
authors.affiliation: Genitourinary Oncology Dept, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Julio M
authors.initials: JM
authors.lastname: Pow-Sang
authors.affiliation: Dept. Cancer Imaging and Metabolism, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Mikalai M
authors.initials: MM
authors.lastname: Budzevich
authors.affiliation: Integrated Mathematical Oncology Dept, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: David
authors.initials: D
authors.lastname: Basanta
authors.affiliation: Tumor Biology Dept, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Conor C
authors.initials: CC
authors.lastname: Lynch
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary* / Q000628:therapy*; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation; D002470:Cell Survival; D003198:Computer Simulation; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology; D010014:Osteolysis; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1