Angiotensin II Type 1 Receptor Blocker Telmisartan Inhibits the Development of Transient Hypoxia and Improves Tumour Response to Radiation
This week we profile a recent publication in Cancer Letters from Dr. Brennan Wadsworth
(pictured, right) in the laboratory of Dr. Kevin Bennewith (left) at BC Cancer.
Can you provide a brief overview of your lab’s current research focus?
Research in the Bennewith lab is designed to improve our understanding of how the environment inside of solid tumours influences treatment response, and how different types of immune cells affect the spread (metastasis) of tumour cells throughout the body. We study how tumour blood flow creates poorly oxygenated (hypoxic) tumour cells, and how hypoxia induces a more treatment resistant and aggressively metastatic tumour cell phenotype. We also study how specialized immune cells (including myeloid-derived suppressor cells, macrophages, regulatory T cells, eosinophils, and B cells) can create localized environments in tissues that are more receptive to metastatic tumour growth. The ultimate goal of our research is to design more effective therapeutic strategies to treat primary tumours and metastatic disease.
What is the significance of the findings in this publication?
This publication demonstrates how a medication normally given to individuals with high blood pressure can be repurposed to stabilize tumour blood flow and improve oxygen delivery to hypoxic tumour cells. Hypoxia can develop in solid tumours by several mechanisms, including unstable blood flow that limits the delivery of oxygen to regions of the tumour. This so-called “transient” hypoxia exposes cells to oxygen tensions that change over time, and is thought to create tumour cells that are particularly resistant to radiation therapy and are more aggressively metastatic. Drugs have been developed to try and normalize tumour blood flow and reduce transient hypoxia, although these drugs only work for short periods of time and have not been overly successful in the clinic. We have found that the angiotensin II receptor blocker telmisartan decreases the deposition of collagen in the tumour by cancer-associated fibroblasts, increases net tumour blood flow to the tumour, and stabilizes microregional fluctuations in tumour blood flow. This blood flow stabilization decreases the development of transient tumour hypoxia and makes the tumour more sensitive to radiation therapy, providing a novel strategy to manipulate the solid tumour microenvironment for therapeutic benefit.
What are the next steps for this research?
We are currently collaborating with scientists and clinicians at BC Cancer and UBC to follow up this research. We are particularly interested in the mechanism of how angiotensin II receptor blockers (ARBs) decrease transient tumour hypoxia, screening other ARBs in tumour cell-derived and patient-derived xenografts, and using ARBs to improve our understanding of how transient hypoxia influences therapeutic outcome.
This work was funded by:
We gratefully acknowledge support for this work through operating grant funding from the Canadian Institutes of Health Research (CIHR). Stipend support was provided by CIHR Canada Graduate Scholarship and Doctoral Research Awards, the Strategic Training in Interdisciplinary Radiation Science for the 21st Century (STARS21) program, a Laurel L Watters Research Fellowship and a Cordula and Gunter Paetzold Fellowship via the University of British Columbia, and the Michael Smith Foundation for Health Research.