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

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Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer. / Haynes, Jennifer; McKee, Trevor D; Haller, Andrew; Wang, Yadong; Leung, Cherry; Gendoo, Deena; 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.

In: Clinical Cancer Research, Vol. 24, No. 9, 23.02.2018.

Research output: Contribution to journalArticle

Harvard

Haynes, J, McKee, TD, Haller, A, Wang, Y, Leung, C, Gendoo, D, Lima-Fernandes, E, Kreso, A, Wolman, R, Szentgyorgyi, E, Vines, DC, Haibe-Kains, B, Wouters, BG, Metser, U, Jaffray, DA, Smith, M & O'Brien, CA 2018, 'Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer.', Clinical Cancer Research, vol. 24, no. 9. https://doi.org/10.1158/1078-0432.ccr-17-1715

APA

Haynes, J., McKee, T. D., Haller, A., Wang, Y., Leung, C., Gendoo, D., Lima-Fernandes, E., Kreso, A., Wolman, R., Szentgyorgyi, E., Vines, D. C., Haibe-Kains, B., Wouters, B. G., Metser, U., Jaffray, D. A., Smith, M., & O'Brien, C. A. (2018). Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer. Clinical Cancer Research, 24(9). https://doi.org/10.1158/1078-0432.ccr-17-1715

Vancouver

Author

Haynes, Jennifer ; McKee, Trevor D ; Haller, Andrew ; Wang, Yadong ; Leung, Cherry ; Gendoo, Deena ; 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. / Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 9.

Bibtex

@article{35a010bfc47b426eb0cd9bb2f3633462,
title = "Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer.",
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. {\textcopyright}2018 AACR.",
author = "Jennifer Haynes and McKee, {Trevor D} and Andrew Haller and Yadong Wang and Cherry Leung and Deena Gendoo and Evelyne Lima-Fernandes and Antonija Kreso and Robin Wolman and Eva Szentgyorgyi and Vines, {Douglass C} and Benjamin Haibe-Kains and Wouters, {Bradly G} and Ur Metser and Jaffray, {David A} and Myles Smith and O'Brien, {Catherine A}",
year = "2018",
month = feb
day = "23",
doi = "10.1158/1078-0432.ccr-17-1715",
language = "English",
volume = "24",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
number = "9",

}

RIS

TY - JOUR

T1 - Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer.

AU - Haynes, Jennifer

AU - McKee, Trevor D

AU - Haller, Andrew

AU - Wang, Yadong

AU - Leung, Cherry

AU - Gendoo, Deena

AU - Lima-Fernandes, Evelyne

AU - Kreso, Antonija

AU - Wolman, Robin

AU - Szentgyorgyi, Eva

AU - Vines, Douglass C

AU - Haibe-Kains, Benjamin

AU - Wouters, Bradly G

AU - Metser, Ur

AU - Jaffray, David A

AU - Smith, Myles

AU - O'Brien, Catherine A

PY - 2018/2/23

Y1 - 2018/2/23

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.ccr-17-1715

DO - 10.1158/1078-0432.ccr-17-1715

M3 - Article

C2 - 29476017

VL - 24

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -