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

• Published in: Clinical cancer research Vol. 24; no. 9; pp. 2116 - 2127
• Main Authors: Haynes, Jennifer, McKee, Trevor D, Haller, Andrew, Wang, Yadong, Leung, Cherry, Gendoo, Deena M A, Lima-Fernandes, Evelyne, Kreso, Antonija, Wolman, Robin, Szentgyorgyi, Eva, Vines, Douglass C, Haibe-Kains, Benjamin, Wouters, Bradly G, Metser, Ur, Jaffray, David A, Smith, Myles, O'Brien, Catherine A
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.05.2018
• Subjects: 5-Fluorouracil; Adjuvant therapy; Biomarkers; Cancer; Cancer therapies; Chemoradiotherapy; Colorectal cancer; Colorectal carcinoma; Dilution; Experimental design; Hypoxia; In vivo methods and tests; Positron emission; Radiation; Therapeutic applications; Therapeutic targets; Therapy; Tomography; Tumors; Xenografts; Xenotransplantation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-17-1715

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. 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 limiting dilution assays. FAZA-PET imaging was utilized as a noninvasive method to assess intratumoral hypoxia. 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. 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. .