Abstract 3975: Matrix-depleting anti-hypertensives decompress tumor blood vessels and improve perfusion in patients with glioblastomas receiving anti-angiogenic therapy

Abstract

Introduction: Impaired tumor perfusion is associated with poor drug delivery, hypoxia and metastatic behavior that effectively make cancers difficult to treat [1]. A main driver of impaired perfusion in permeable and impermeable tumor vessels is solid stress caused by proliferating tumor cells and the extracellular matrix that squeeze vessels shut [2]. Here, we demonstrate improved vascular function in glioblastoma patients who receive hypertension treatments with an anti-cancer cell, matrix-depleting effect as part of anti-angiogenic therapy. Methods: We retrospectively assessed data from 40 patients with newly diagnosed glioblastomas (nGBM) and 30 with recurrent glioblastomas (rGBM) receiving cediranib, an oral pan-VEGFR inhibitor, with- (NCT00662506) and without (NCT00305656) chemoradiation, respectively. After cediranib onset, for nGBM, 12/40 patients received matrix-depleting angiotensin II receptor blockers (Valsartan), β1 receptor antagonists (Atenolol) or angiotensin-converting enzyme inhibitors (Lisinopril), while 8/40 patients received non-depleting calcium antagonists (Norvasc, Amlodipine) [3, 4]. For rGBM, 15/30 patients received Atenolol and 7/30 patients Norvasc. Perfusion and vessel caliber MRI were performed at baseline and repeated weekly (nGBM) or monthly (rGBM) [5, 6]. Tumor values were normalized to healthy tissue to account for patient-level systemic effects and variations in hypertension. Results: In the total tumor bed (enhancing + edematous regions), the matrix-depleting alternatives significantly improved the perfused vessel fraction (% of tumor values >½ the value of healthy tissue) from 81% to 93% in nGBM (Wilcoxon: P<0.05) and from 70% to 78% in rGBM (P<0.05). In permeable tumor vessels (enhancing area), the increase in perfusion for nGBM was associated with a 19% higher fraction of small caliber vessels (<½ the size of healthy tissue) compared to baseline (P<0.01) and for rGBM a 20% higher fraction compared to cediranib alone (P<0.01). For matrix-depleting drugs only, the absolute number of small vessels increased relative to that of larger vessels, suggestive of vascular decompression of small caliber vessels by increased open lumen fractions. These effects were not observed with non-depleting calcium antagonists. Conclusion: In line with theoretical [7] and pre-clinical [3] findings, we here present human data demonstrating that adding matrix-depleting anti-hypertensives, safe and inexpensive drugs with decades of use, improve vascular function in glioblastoma patients receiving anti-cancer therapy. Vascular MRI can help refine matrix-depleting drugs by directly assessing mechanisms of action in vivo. References: 1: Science 2005; 307, 58-62 2: PNAS 2012; 109, 15101-8 3: Nat Commun 2013; 4, 2516 4: Blood Press 2006; 15, 198-206 5: PNAS 2013; 110, 19059-64 6: Nat Med 2013; 19, 1178-83 7: PNAS 2013;110:18632-37 Citation Format: Kyrre E. Emblem, Elizabeth R. Gerstner, Gregory Sorensen, Bruce R. Rosen, Patrick Y. Wen, Tracy T. Batchelor, Rakesh K. Jain. Matrix-depleting anti-hypertensives decompress tumor blood vessels and improve perfusion in patients with glioblastomas receiving anti-angiogenic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3975.

Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity

“…For example, angiotensin system inhibition (ASI) with losartan inhibits downstream profibrotic pathways—TGF-β1, connective tissue growth factor, endothelin-1—in CAFs, and thereby reduces solid stress, decompresses vessels, and increases oxygen and drug delivery without increasing malignancy (Chauhan et al 2013). There is evidence of ASI-induced vessel decompression in glioblastoma patients (Emblem et al 2016). Besides decompressing vessels, as TGF-β1 promotes protumor immune suppression (Wrzesinski et al 2007; Pickup et al 2013; Papageorgis and Stylianopoulos 2015), losartan reduces metastasis by blocking monocyte recruitment (Regan et al 2016).…”

Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges

“…A retrospective analysis in glioblastoma found that angiotensin system inhibitors (ASIs), which are agents shown to decompress vessels in preclinical models, also did so in patients. Specifically, small vessels were reperfused (45). This result is supported by finding in a retrospective study that patients who took ASIs to manage hypertension either pretreatment or after bevacizumab had improved overall survival (46).…”

“…Thus, we hypothesize that maximizing decompressed MVD before AAT will improve outcomes. In glioblastoma patients, ASIs increased the amount of perfused vessels by reperfusing small vessels (45). Indeed, retrospective studies of glioblastoma patients indicate that ASIs alone and in combination with bevacizumab and/or chemotherapy increase survival of patients (46).…”

Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy

“…In an orthotopic model of PDAC, inhibition of aberrant TGF-β signaling by losartan restored vessel diameter and permeability ( 60 ). In a retrospective study of glioblastoma patients receiving anticancer therapy, a concomitant treatment with matrix-depleting antihypertensive drugs improved vascular function as assessed by magnetic resonance imaging ( 75 ). The impaired perfusion and hypoxic condition of tumors can be further aggravated by AngII-induced vasoconstriction and increased vascular resistance ( Fig.…”