Targeting hypoxia can, in turn, target cancer-initiating cells (C-ICs) in colorectal cancer a study team in Toronto has found. Additionally, the team has discovered a biomarker for hypoxia to identify tumours that would most benefit from this innovative treatment method.
C-ICs occur in many tumour types, and are known to be self-renewing. They also become resistant to chemotherapy and radiotherapy, and increase rapidly when exposed to hypoxia. Patients respond poorly to treatment if their tumours are hypoxic (oxygen deficient), and these tumours are more likely to grow and spread aggressively. Despite this, targeting hypoxia is not a standard treatment option.
Dr. Catherine O’Brien (Princess Margaret Cancer Centre, Toronto) led the present study, published in Clinical Cancer Research (March 2018) and funded in part by TFRI. The paper demonstrated that a four-day course of 5-Fluorouracil (5-FU) could drive colorectal cancer cells to enter a hypoxic, cancer-initiating cell (C-IC) state. During this phase the cancer cells were extremely sensitive to the hypoxia-activated prodrug evofosfamide (Evo). Sequential treatment with either 5-FU or chemoradiotherapy (CRT) followed by Evo specifically targeted the colorectal C-ICs.
The non-invasive biomarker (FAZA-PET) they found for hypoxia can predict if a colorectal cancer tumour would respond to this selective targeting. Using non-invasive FAZA-PET/CT imaging, it was found that tumours with higher baseline intratumoral hypoxia responded best to this innovative form of therapy.
This form of novel combination therapy holds tremendous potential to improve patient outcomes. Colorectal cancer is the second most common cancer diagnosed in Canada, and is the second-leading cause of cancer death for men and the third for women.
Study: Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer
Authors: 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, UrMetser, David A. Jaffray, Myles J. Smith, Catherine A. O’Brien.
Funding: This work was supported in part by grants from The Terry Fox Research Institute.