Finding the Goldilocks zones of cell signaling pathways in cancer therapy

Abstract

The increase of cancer cell fitness during oncogenesis is accompanied by an increase of several cellular stresses, a phenomenon that may be exacerbated through mitogenic overstimulation. Recently, our group reported an unusual approach to cancer therapy, which relies on mitogenic overstimulation followed by inhibition of stress mitigation pathways. Although mitogenic overstimulation of cancer cells can often be achieved using natural mitogens, which generally are harmless for healthy cells, some types of cancer do not respond well to them. In this case, it might be necessary interventions downstream of mitogenic signaling pathways, a procedure that might also be cytotoxic to healthy cells. Therefore, we hypothesize the existence of a Goldilocks zone, that is, a just right set of such interventions that maximizes treatment efficacy at the same time sparing healthy cells from deleterious effects. To test this hypothesis, we propose to develop a methodology that encompasses: i) a Bayesian model selection procedure that draws candidate models from a reactions database and takes into account the lack of isolation problem that arises during the estimation of signaling pathways models; ii) the designing of classifiers of cell proliferation as a function of signaling pathways dynamics; iii) the incorporation of (i) and (ii) into a combinatorial optimization search for best sets of interventions. To test the proposed methodology, we plan to apply it into synthetic data and on results from experimental assays using cancer and non-tumorigenic cell lines. We also intend to experimentally validate promising predictions obtained with those wet lab assays. Testing this Goldilocks zones hypothesis is a timely endeavor, which could assist the discovery of new mitogenic signaling pathway activators for that novel cancer therapy approach. (AU)