Containing Cancer with Personalized Minimum Effective Dose

Abstract

Resistance to treatment is a challenge in many cancer therapies. This is partly due to the heterogeneous nature of tumors, where drug-sensitive and drug-resistant cells compete for the same resources. This competition is largely shaped by cancer treatment. The rapid reduction of drug-sensitive cell population during therapy with a maximum-tolerated dose relaxes competitive stress on the drug-resistant cell population, promoting relapse. Therefore, maintaining a high level of drug-sensitive cell population with a treatment break or lower dose can impose effective competitive stress on drug-resistant cell populations. Adaptive therapy (AT) exploits the competition between cancer cells. However, given the heterogeneous treatment response of individual patients, determining a personalized optimal treatment that can fine-tune competitive stress remains challenging. Using a deterministic model of cancer cell population competition, this study defines an effective dose window (EDW) as a range of doses that conserve sufficient sensitive cells, while maintaining the tumor volume below a threshold (e.g., initial tumor volume), to maintain a sustained competition against resistant cells. As a proof of concept, we sought to determine the EDW for a small cohort of patients with melanoma (n=8). We first fitted the model to longitudinal tumor response data from each patient. We performed structural and practical identifiability analyses to confirm the reproducibility and uniqueness of the estimated parameters. Then, we considered a subset of the cohort with uniquely identifiable parameters and estimated patient-specific EDW. We demonstrated that if the dose belongs to the EDW, the tumor volume for each patient could be indefinitely contained either using continuous or AT strategy. Using the optimal control theory, we concluded that the lower bound of the EDW approximates the minimum effective dose (MED) for containing cancer. Taken together, using tumor biomarker data, this study provides a proof of concept that there may exist a patient-specific EDW that keeps the tumor below a threshold (e.g., initial volume) by maintaining sustained competition on resistant cells.