Gallaher, J. A. | Search bioRxiv

bioRxiv2018

Connecting the Microenvironmental Niche to Treatment Response in Ovarian Cancer

Ovarian cancer has the highest mortality rate of all gynecologic cancers, which may be attributed to an often late stage diagnosis, when the cancer is already metastatic, and rapid development of treatment resistance. We propose that the metastatic disease could be better characterized by observing interactions within the microenvironmental niche of the primary site that shapes the tumors early phenotypic progression. We present a mechanistic mathematical model of ovarian cancer that considers spatial interactions between tumor cells and several key stromal components. We demonstrate how spatial biomarker imaging data from the primary tumor can be analyzed to define a patient-specific microenvironment in the mathematical model. We then show preliminary results, using this model, that demonstrate how differences in the niche composition of a tumor affects phenotypic evolution and treatment response.

cancer biology↗

bioRxiv2017

Adaptive Therapy For Heterogeneous Cancer: Exploiting Space And Trade-Offs In Drug Scheduling

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells, therefore evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we apply anti-proliferative drug treatments to varying ratios of sensitive and resistant cells. We compare a continuous maximum tolerated dose schedule with an adaptive schedule aimed at tumor control through competition between sensitive and resistant cells. We find that continuous treatment cures mostly sensitive tumors, but with any resistant cells, recurrence is inevitable. We identify two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors.

cancer biology↗