Limiting the Development of Anti-Cancer Drug Resistance in a Spatial Model of Micrometastases

TL;DR

This study uses a spatial tumor model to identify chemotherapy dosing schedules that can better prevent resistance in micrometastases, potentially improving metastatic cancer treatment.

Contribution

It introduces a hybrid spatial model analyzing how different dosing schedules affect resistance development in metastatic tumors, highlighting effective fractionated protocols.

Findings

Certain fractionated-dose protocols outperform metronomic therapy in eradicating resistant micrometastases.

Protocols are effective across different resistance scenarios and cell line responsiveness.

The study suggests optimized scheduling can limit metastatic progression.

Abstract

While chemoresistance in primary tumors is well-studied, much less is known about the influence of systemic chemotherapy on the development of drug resistance at metastatic sites. In this work, we use a hybrid spatial model of tumor response to a DNA damaging drug to study how the development of chemoresistance in micrometastases depends on the drug dosing schedule. We separately consider cell populations that harbor pre-existing resistance to the drug, and those that acquire resistance during the course of treatment. For each of these independent scenarios, we consider one hypothetical cell line that is responsive to metronomic chemotherapy, and another that with high probability cannot be eradicated by a metronomic protocol. Motivated by experimental work on ovarian cancer xenografts, we consider all possible combinations of a one week treatment protocol, repeated for three weeks, and constrained by the total weekly drug dose. Simulations reveal a small number of fractionated-dose protocols that are at least as effective as metronomic therapy in eradicating micrometastases with acquired resistance (weak or strong), while also being at least as effective on those that harbor weakly pre-existing resistant cells. Given the responsiveness of very different theoretical cell lines to these few fractionated-dose protocols, these may represent more effective ways to schedule chemotherapy with the goal of limiting metastatic tumor progression.