Integrated computational modeling of bone metastasis, microenvironment and therapy

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Integrated computational modeling of bone metastasis, microenvironment and therapy

Thursday, 03.03.2016

In the context of the multidisciplinary research project CancerSys - Multiscale modeling for personalized therapy of bone metastasis, financed by FCT and involving the institutions IDMEC, INESC-ID, IT (Instituto Superior Técnico, Universidade de Lisboa), Hospital de Santa Maria and IMM, a dynamic computational model capable of representing the biochemical aspects of bone metastases growth and the effect of the therapies used in this disease.

The model includes the interactions between bone cells in the bone remodeling process, which is strongly influenced by the PTH concentration, as well as modeling the changes in the microenvironment caused by tumor cells, which potentiate a vicious cycle of bone resorption and growth of the metastases. Moreover, it also includes the treatment of bone metastases, through the effect of chemotherapy, bisphosphonates and denosumab. With this model we expect to contribute to the development of clinical decision support systems and to optimize therapeutic regimes for patients with bone metastases.



Rui Moura Coelhoa, João Miranda Lemosb, Irina Alhoc, Duarte Valérioa, Arlindo R Ferreirad, c, Luís Costad, c, Susana Vingaa

a IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal

b INESC-ID, Instituto Superior Técnico, Universidade de Lisboa, Rua Alves Redol, 9, 1000-029 Lisboa, Portugal

c Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal

d Hospital de Santa Maria, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal

Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength.

Journal:
Journal of Theoretical Biology


http://dx.doi.org/10.1016/j.jtbi.2015.11.024