Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer

Abstract

Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors—an evolutionary phenomenon termed “competitive release.” We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor–positive (ER+) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer.

Tumor Evolution as a Therapeutic Target

“…In chemotherapy-treated breast cancer xenografts, metronomic therapy allowed better control of tumor growth than full-dose therapy (122). In this model, intermittent doses (i.e., drug holidays) failed to control tumor growth (122).…”

“…121) allows the control of tumor growth. This is achieved by keeping a balance between drug-sensitive tumor cells, which proliferate better in the absence of drug, and resistant cells, which prove fitter only in the presence of the drug itself, as exemplified in ovarian and breast cancer xenograft models (121)(122)(123).…”

“…In chemotherapy-treated breast cancer xenografts, metronomic therapy allowed better control of tumor growth than full-dose therapy (122). In this model, intermittent doses (i.e., drug holidays) failed to control tumor growth (122). Indeed, low-dose maintenance regimens have long been evaluated in clinical practice (125); however, evidence showing the control of tumor evolution through metronomic approaches in patients is lacking.…”

A quantitative FastFUCCI assay defines cell cycle dynamics at a single-cell level

“…This suggests that paclitaxel sensitivity depends not only on the strength of the mitotic checkpoint but also on the extent of checkpoint adaptation (Weaver and Cleveland, 2005). An understanding of how these mechanisms enact in vivo in relation to drug pharmacokinetics would inform future development of the recently proposed adaptive strategy for paclitaxel (Enriquez-Navas et al, 2016).…”

Cancer therapy: an evolved approach

“…Recently, he tested the idea in mice with two kinds of breast cancer 8 . When he and his colleagues gave the mice the standard, maximum tolerated dose of the chemotherapy drug paclitaxel, the tumours roared back as soon as the treatment was stopped.…”