Adaptive therapy achieves long-term control of chemotherapy resistance in high grade ovarian cancer

Abstract

Drug resistance results in poor outcomes for most patients with metastatic cancer. Adaptive Therapy (AT) proposes to address this by exploiting presumed fitness costs incurred by drug-resistant cells when drug is absent, and prescribing dose reductions to allow fitter, sensitive cells to re-grow and re-sensitise the tumour. However, empirical evidence for treatment-induced fitness change is lacking. We show that fitness costs in chemotherapy-resistant ovarian cancer cause selective decline and apoptosis of resistant populations in low-resource conditions. Moreover, carboplatin AT caused fluctuations in sensitive/resistant tumour population size in vitro and significantly extended survival of tumour-bearing mice. In sequential blood-derived cell-free DNA and tumour samples obtained longitudinally from ovarian cancer patients during treatment, we inferred resistant cancer cell population size through therapy and observed it correlated strongly with disease burden. These data have enabled us to launch a multicentre, phase 2 randomised controlled trial (ACTOv) to evaluate AT in ovarian cancer.

Testing Adaptive Therapy Protocols Using Gemcitabine and Capecitabine in a Preclinical Model of Endocrine-Resistant Breast Cancer

“…Our goal was to test if adaptive therapy can improve clinical outcomes, such as time to progression, overall survival, and reduction in toxicity, in breast cancer and, more specifically, to test multidrug adaptive therapies as well as single-drug therapy on endocrineresistant breast cancer. Although a variety of adaptive therapy protocols have been tested in mice [2,4,8,11] and computational simulations [12][13][14], it remains an open question as to which version of adaptive therapy is best and under which conditions one protocol might be better than another [15]. Here, we tested different adaptive therapy protocols and compared them to the time to progression (TTP) of MTD in a preclinical model of breast cancer.…”

Testing Adaptive Therapy Protocols using Gemcitabine and Capecitabine on a Mouse Model of Endocrine-Resistant Breast Cancer

“…Our motivating goal is to test if adaptive therapy can improve clinical outcomes such as time to progression, overall survival and reductions in toxicity in breast cancer, but more specifically to test multidrug adaptive therapies as well as single drug therapy on endocrineresistant breast cancer. Although a variety of adaptive therapy protocols have been tested in mice (2,4,6,10) and computational simulations (11)(12)(13), it remains an open question which version of adaptive therapy is best, and under which conditions one protocol might be better than another (14). Here we test different adaptive therapy protocols, and compare them to the time to progression (TTP) of MTD in a preclinical model of breast cancer.…”