Abstract
The discovery of small molecules targeted to specific oncogenic pathways has revolutionized anti-cancer therapy. However, such therapy often fails due to the evolution of acquired resistance. One long-standing question in clinical cancer research is the identification of optimum therapeutic administration strategies so that the risk of resistance is minimized. In this paper, we investigate optimal drug dosing schedules to prevent, or at least delay, the emergence of resistance. We design and analyze a stochastic mathematical model describing the evolutionary dynamics of a tumor cell population during therapy. We consider drug resistance emerging due to a single (epi)genetic alteration and calculate the probability of resistance arising during specific dosing strategies. We then optimize treatment protocols such that the risk of resistance is minimal while considering drug toxicity and side effects as constraints. Our methodology can be used to identify optimum drug administration schedules to avoid resistance conferred by one (epi)genetic alteration for any cancer and treatment type.
Highlights
Alteration of the normal regulation of cell-cycle progression, division and death lies at the heart of the processes driving tumorigenesis
The field of anti-cancer therapy has witnessed a revolution by the discovery of targeted therapy, which refers to compounds targeting specific pathways causing abnormal growth of cancer cells
Our model describes the evolutionary dynamics of a tumor cell population during therapy
Summary
Alteration of the normal regulation of cell-cycle progression, division and death lies at the heart of the processes driving tumorigenesis. The term ‘targeted therapy’ refers to drugs with a focused mechanism that act on well-defined protein targets or biological pathways that, when altered by therapy, impair the abnormal proliferation of cancer cells Examples of this type of therapy include hormonal-based therapies in breast and prostate cancer; small-molecule inhibitors of the EGFR pathway in lung, breast, and colorectal cancers – such as erlotinib (Tarceva), gefitinib (Iressa), and cetuximab (Erbitux); inhibitors of the JAK2, FLT3 and BCR-ABL tyrosine kinases in leukemias – such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna); blockers of invasion and metastasis; anti-angiogenesis agents like bevacizumab (Avastin); proapoptotic drugs; and proteasome inhibitors such as bortezomib (Velcade) [1,2]. The absence of prolonged clinical responses in many cases, stresses the importance of continued basic studies into the mechanisms of targeted drugs and their failure in the clinic
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