Abstract
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. Clin Cancer Res; 24(9); 2116-27. ©2018 AACR.
Highlights
Hypoxia is a common feature of many solid tumors and is often associated with tumor aggressiveness and therapeutic resistance [1,2,3,4]
Hypoxia was sufficient to drive the formation of cancer–initiating cell (CCIC) and colorectal cancer cells surviving conventional therapy were more hypoxic and cancer-initiating cells (C-IC)-like
Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by evofosfamide inhibits tumor growth of xenografts compared with 5-FU or CRT alone, and significantly decreases the cancer-initiating cell (CC-IC) fraction
Summary
Hypoxia is a common feature of many solid tumors and is often associated with tumor aggressiveness and therapeutic resistance [1,2,3,4]. Tumor hypoxia was linked to increased self-renewal capacity, the canonical feature defining cancer-initiating cells Functional assessment of C-ICs in glioblastoma and breast cancers have shown that exposure to hypoxia results in increased C-IC numbers as measured by in vivo limiting dilution assays, the gold standard assay for self-renewal [11,12,13,14]. These studies indicate that hypoxia is sufficient to drive acquisition of self-renewal capacity in a number of solid tumor-initiating cell subsets
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