A mathematical investigation of the multiple pathways to recurrent prostate cancer: comparison with experimental data.

Considerable research is aimed at determining the mechanisms by which hormone-refractory prostate cancer develops. In an effort to assist in the understanding of recurrent prostate cancer and the cellular processes that mediate this disease, a mathematical model is presented that describes both the pretreatment growth and the posttherapy relapse of human prostate cancer xenografts. Our goal is to evaluate the interplay between the multiple mechanisms that have been postulated as causes of androgen-independent relapse. Simulations of the model show that molecular events that render the androgen receptor irrelevant to disease progression, such as upregulation of BCL2, can result in relapse after androgen deprivation therapy. However, decreased apoptosis of androgen-independent cells alone overestimates the effects of hormone therapy when compared to experimental data. When decreased apoptosis is combined with continual androgen receptor activation, the posttherapy growth dynamics are in excellent correlation with experimental observations of the growth of LuCaP xenografts. Furthermore, the mathematical model predicts that upregulation of the androgen receptor, together with its increased activation, is alone sufficient to result in the androgen-independent growth of LNCaP xenografts. Recent experimental studies that suggest that the posttherapy increase in and continual activation of the androgen receptor are common and crucial features of recurrent prostate cancer provide validation of the model predictions. This approach provides a framework for using mathematical techniques to study novel therapeutic strategies aimed at controlling this disease.