Abstract PO-033: The angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient tumour hypoxia and improves response to ionizing radiation therapy

Abstract

Abstract Poorly oxygenated (hypoxic) cells are key components of the solid tumour microenvironment that drive tumour heterogeneity. Hypoxia regulates a variety of processes that promote tumour cell survival and metastasis, and hypoxic tumour cells are resistant to therapy. Patients with tumours that contain hypoxic cells have worse outcome after radiotherapy, chemotherapy, and even surgery, underscoring the therapeutic relevance of hypoxia in driving more aggressive tumour phenotypes. Hypoxic tumour cells result from deficiencies in the delivery of oxygen relative to the high oxygen demand of tumour cells. “Chronic” hypoxia develops due to the limited diffusion distance of oxygen through tumour tissue, while “transient” hypoxia occurs due to fluctuations in microregional tumour perfusion and oxygen delivery over time. Transiently hypoxic cells are more resistant to radiation therapy and are more metastatic than chronically hypoxic cells although, despite decades of work in this area, there are no effective long-term strategies to specifically target transiently hypoxic cells in solid tumours. Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are widely prescribed anti-hypertensive agents that can also exhibit anti-fibrotic activity. Recent evidence indicates that the ARB losartan can inhibit collagen I (Col1) deposition in tumours by cancer-associated fibroblasts (CAFs), reduce blood vessel constriction, and increase net tumour blood flow, although the influence of losartan or other ARBs on transient hypoxia and tumour radiation response is unknown. We hypothesized that ARB-mediated inhibition of Col1 deposition from CAFs increases tumour blood flow by stabilizing microregional fluctuations in tumour perfusion and that ARBs will reduce transient tumour hypoxia. We tested the ARBs losartan and telmisartan in human tumour xenografts using positron emission tomography and intravenously injected fluorescent perfusion dyes to quantify tumour perfusion, and a combination of exogenous hypoxia markers and the hemorheological agent pentoxifylline to assess transient tumour hypoxia. We found that CAF-containing tumours had reduced Col1 levels in response to telmisartan, but not losartan, consistent with the improved pharmacokinetics and AT1R binding affinity of telmisartan. Telmisartan increased net tumour blood flow and stabilized microregional fluctuations in tumour perfusion. Importantly, telmisartan decreased overall hypoxia in the tumours by specifically targeting transient tumour hypoxia, which translated into a significant improvement in radiation response. These data indicate that telmisartan reduces a therapeutically-relevant population of transiently hypoxic tumour cells. Understanding how the solid tumour microenvironment influences cancer therapy is central to improving treatment outcome. Our work underscores the importance of transient tumour hypoxia and supports future clinical studies to evaluate telmisartan as a neoadjuvant for radiation therapy. Citation Format: Brennan J. Wadsworth, Rachel A. Cederberg, Che-Min Lee, Natalie S. Firmino, S. Elizabeth Franks, Jinhe Pan, Nadine Colpo, Kuo-Shyan Lin, Francois Benard, Kevin L. Bennewith. The angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient tumour hypoxia and improves response to ionizing radiation therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-033.