Getting the right traction for anti-fibrotic drug evaluation

[Speaker] Alastair G. Stewart:1
[Co-author] Asres Berhan:1, Fernando J Guzman:2, Peter V Lee:2, Trudi Harris:1, Qianyu Chen:1
1:Department of Pharmacology and Therapeutics, University of Melbourne, Australia, 2:Biomedical Engineering, University of Melbourne, Australia

There has been considerable reflection within Pharma, Biotech and Academic circles regarding the relative high failure rate because of lack of efficacy of agents progressing to phase II clinical evaluation (Krishnan et al 2016). The "failure to fail" in earlier animal and in vitro preclinical efficacy testing is generating a high economic burden, and there is an opportunity cost, meaning delays in realising novel agents for unmet needs in chronic disease areas such as fibroses. We are currently exploring the concept of mechanopharmacology in relation to the improvement of preclinical efficacy testing for anti-fibrotic agents. A mechanopharmacological approach recognises the interplay between the mechanics of the cells and the extracellular environment and posits that these be aligned to the parameters of the target tissue/microenvironments in which the drug is intended to act. We will review data suggesting that the actions of one of the major fibrogens, transforming growth factor-beta are greatly down-modulated when fibroblasts and other mesenchymal cells types are cultured within physiological or even pathologically stiff substrates in 3D compared with profiles shown in 2D on stiff plastic substrate. Other features of cell responses including glucocorticoid responses are markedly affected. Some processes such as proliferation are greatly slowed. Thus, it is hoped that careful choice of substrate mechanics and composition may reduce the perturbations in cell physiology and engender a more relevant bioassay with improved prediction of efficacy.

Krishnan, R., Park, J-A., Seow, C.Y., Lee, P.V.S., Stewart, A.G. (2016). Cellular biomechanics in drug screening and evaluation: Mechanopharmacology. Trends in Pharmacological Sciences 37:87-100.
Schuliga, M. J., See, I., Ong, S. C., Soon, L., Camoretti-Mercado, B., Harris, T.Stewart, A. G.. (2009). Fibrillar collagen clamps lung mesenchymal cells in a nonproliferative and noncontractile phenotype. Am J Respir Cell Mol Biol 41(6): 731-741.
Schuliga, M., Ong, S. C., Soon, L., Zal, F., Harris, T, Stewart, A. G. (2010). Airway smooth muscle remodels pericellular collagen fibrils: implications for proliferation. Am J Physiol Lung Cell Mol Physiol 298: L584-L592.

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