journal contribution
posted on 2023-03-31, 19:49 authored by Jennifer Haynes, Trevor D. McKee, Andrew Haller, Yadong Wang, Cherry Leung, Deena M.A. Gendoo, Evelyne Lima-Fernandes, Antonija Kreso, Robin Wolman, Eva Szentgyorgyi, Douglass C. Vines, Benjamin Haibe-Kains, Bradly G. Wouters, Ur Metser, David A. Jaffray, Myles Smith, Catherine A. O'Brien Supplementary Figure S1. Hypoxia increases stem gene expression and stabilizes HIF proteins. Supplementary Figure S2. Chemotherapy enriches for colorectal C-IC markers and increases expression of Wnt and HIF targets. Supplementary Figure S3. Growth of colorectal cancer PDXs shown in Figure 4. Supplementary Figure S4. Hypoxic fraction in a panel of colorectal cancer PDX models. Supplementary Figure S5. Growth of colorectal cancer PDXs shown in Figure 5. Supplementary Figure S6. Hypoxia gene sets are prognostic for clinical outcome of colon cancer patients.
Funding
UHN
STTARR
Colon Cancer Canada
Canadian Institutes of Health Research
Terry Fox Research Institute
Ministry of Economic Development, Employment and Infrastructure
Ministry of Innovation of the Government of Ontario
Gattuso-Slaight Personalized CancerMedicine
FP7
History
ARTICLE 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.
