期刊
CLINICAL CANCER RESEARCH
卷 24, 期 9, 页码 2116-2127出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-1715
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资金
- Colon Cancer Canada
- Canadian Institutes of Health Research [FDN14847, 357163]
- Terry Fox Research Institute [TFRI PPG 1036]
- Ministry of Economic Development, Employment and Infrastructure
- Ministry of Innovation of the Government of Ontario [ER14-10-121]
- Gattuso-Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre
- National Research Fund Luxembourg
- Marie Curie Actions of the European Commission (FP7-COFUND)
- Banting Postdoctoral Fellowship
Purpose: Cancer-initiating cells (C-IC) have been described in multiple cancer types, including colorectal cancer. C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities; however, recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then therapeutic targeting of hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived colorectal cancer xenografts were treated with evofosfamide, a hypoxia-activated prodrug (HAP), in combination with 5-fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage in vivo limiting dilution assays. FAZA-PET imaging was utilized as a noninvasive method to assess intratumoral hypoxia. Results: Hypoxia was sufficient to drive the formation of CC-ICs and colorectal cancer cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by evofosfamide not only inhibits tumor growth of xenografts compared with 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, noninvasive FAZA-PET hypoxia imaging was predictive of a tumor's response to evofosfamide. Conclusions: Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach. (C) 2018 AACR.
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