Mathematical Modeling of the Role of Survivin on Dedifferentiation and Radioresistance in Cancer

• Published in: Bulletin of mathematical biology 2016-06, Vol.78 (6), p.1162-1188
• Main Authors: Rhodes, Adam, Hillen, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - radiotherapy; Cell Biology; Cell Dedifferentiation - drug effects; Cell Dedifferentiation - physiology; Cell Dedifferentiation - radiation effects; Cell Line, Tumor; Humans; Imidazoles - pharmacology; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - physiology; Life Sciences; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Mathematical and Computational Biology; Mathematical Concepts; Mathematics; Mathematics and Statistics; Mice; Models, Biological; Naphthoquinones - pharmacology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - radiation effects; Original Article; Radiation Tolerance - drug effects; Radiation Tolerance - physiology
• ISSN: 0092-8240; 1522-9602
• DOI: 10.1007/s11538-016-0177-x

We use a mathematical model to investigate cancer resistance to radiation, based on dedifferentiation of non-stem cancer cells into cancer stem cells. Experimental studies by Iwasa 2008, using human non-small cell lung cancer (NSCLC) cell lines in mice, have implicated the inhibitor of apoptosis protein survivin in cancer resistance to radiation. A marked increase in radio-sensitivity was observed, after inhibiting survivin expression with a specific survivin inhibitor YM155 ( sepantronium bromide ). It was suggested that these observations are due to survivin-dependent dedifferentiation of non-stem cancer cells into cancer stem cells. Here, we confirm this hypothesis with a mathematical model, which we fit to Iwasa’s data on NSCLC in mice. We investigate the timing of combination therapies of YM155 administration and radiation. We find an interesting dichotomy. Sometimes it is best to hit a cancer with a large radiation dose right at the beginning of the YM155 treatment, while in other cases, it appears advantageous to wait a few days until most cancer cells are sensitized and then radiate. The optimal strategy depends on the nature of the cancer and the dose of radiation administered.