Administration of Hypoxia-Activated Prodrug Evofosfamide after Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Colorectal Cancer

Purpose: Cancer-initiating cells (C-ICs) have been described in multiple cancer types, including colorectal cancer (CRC). 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 targeting hypoxia could represent a novel means to target C-ICs. Experimental Design: Patient-derived CRC xenografts were treated with evofosfamide (Evo), 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 non-invasive method to assess intratumoral hypoxia. Results: Hypoxia was sufficient to drive the formation of CC-ICs and 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 Evo not only inhibits tumor growth of xenografts compared to 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, non-invasive FAZA-PET hypoxia imaging was predictive of a tumor's response to Evo. 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.

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