A two-drug combination simulation study for metastatic castrate resistant prostate cancer

Prostate cancer often evolves resistance to androgen deprivation therapy leading to a lethal metastatic castrate-resistant form. Besides androgen independence, subpopulations of the tumor are genetically heterogeneous. With the advent of tumor genome sequencing we asked which has the greater influence on reducing tumor size: genetic background, heterogeneity, or drug potency?

A previously developed theoretical evolutionary dynamics model of stochastic branching processes is applied to compute the probability of tumor eradication with two targeted drugs. Publicly available data sets were surveyed to parameterize the model.

Our calculations reveal that the greatest influence on successful treatment is the genetic background including the number of mutations overcoming resistance. Another important criteria is the tumor size at which it is still possible to achieve tumor eradication, for example, 2-4 cm large tumors have at best a 10% probability to be eradicated when 50 mutations can confer resistance to each drug.

Overall, this study finds that genetic background and tumor heterogeneity are more important than drug potency in treating mCRPC. It also points toward identifying metastatic sites early using biochemical assays and/or dPET.

The Prostate. 2018 Jul 19 [Epub ahead of print]

Alex Root, H Alexander Ebhardt

Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.