The VEGFR Inhibitor Cediranib Improves the Efficacy of Fractionated Radiotherapy in a Colorectal Cancer Xenograft Model

Abstract

Background/Purpose: Radiotherapy (RT) increases local tumor control in locally advanced rectal cancer, but complete histological response is seen in only a minority of cases. Antiangiogenic therapy has been proposed to improve RT efficacy by “normalizing” the tumor microvasculature. Here, we examined whether cediranib, a pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, improves microvascular function and tumor control in combination with RT in a mouse colorectal cancer (CRC) model. Methods: CRC xenografts (HT29) were grown subcutaneously in mice. Animals were treated for 5 consecutive days with vehicle, RT (1.8 Gy daily), cediranib (6 mg/kg po), or combined therapy (cediranib 2 h prior to radiation). Tumor volume was measured with calipers. Vascular changes were analyzed by dynamic contrast-enhanced MRI, oxygenation and interstitial fluid pressure probes and histology. To investigate vascular changes more in detail, a second set of mice were fitted with titanium dorsal skinfold window chambers, wherein a HT29 tumor cell suspension was injected. In vivo fluorescence microscopy was performed before and after treatment (same treatment protocol). Results: In vivo microscopy analyses showed that VEGFR inhibition with cediranib led to a “normalization” of the vessel wall, with decreased microvessel permeability (p < 0.0001) and tortuosity (p < 0.01), and a trend to decreased vessel diameters. This seemed to lead to lower tumor hypoxia rates in the cediranib and combination groups compared to the control and RT groups. This led to an increased tumor control in the combination group compared to controls or monotherapy (p < 0.0001). Conclusions: The combination of RT with cediranib enhances tumor control in a CRC xenograft mouse model. Microvascular analyses suggest that cediranib leads to vascular normalization and improved oxygenation.

Evaluation of metastatic niches in distant organs after surgical removal of tumor-bearing lymph nodes

“…Previous studies have shown that local radiotherapy causes a stronger expression of angiogenic factors than anti-angiogenic factors and disturbs the configuration imbalance of VEGFs in the vascular bed of the metastatic site, which then results in outbreak growth of dormant metastatic tumors [ 24 , 25 ]. Adjuvant applications of the exogenous VEFGR inhibitor cediranib after radiotherapy restored tumor inhibition, and studies have shown that using angiogenesis inhibitors to target the VEGF pathway or knocking out the VEGF gene in mouse models with pancreatic cancer or glioblastoma has anti-cancer therapeutic effects by reducing the tumor volume and prolonging survival, but the two actions change tumor phenotypes and enhance tumor invasion and metastasis [ 26 – 28 ]. The discontinuation of VEGF inhibitors still enhances the tumor invasion, suggesting that this treatment increases the persistence of tumor invasion.…”

Barriers to Radiation-Induced In Situ Tumor Vaccination

“…Preclinical studies in colorectal cancer xenografts have demonstrated that inhibition of the VEGF receptor (VEGFR) with concomitant fractionated RT resulted in normalization of vasculature and improved tumor control compared to RT or VEGFR-inhibition alone (129). Hyperfractionated RT is currently being combined with bevacizumab in glioblastoma patients and with sorafenib (a protein kinase inhibitor targeting VEGFR) in patients with pancreatic cancer (NCT00884741, NCT00375310).…”

Radiotherapy Both Promotes and Inhibits Myeloid-Derived Suppressor Cell Function: Novel Strategies for Preventing the Tumor-Protective Effects of Radiotherapy

“…However, RT also inhibits antitumor immunity by facilitating the development of immune suppressive cells, such as T regulatory cells (Tregs) (31), tolerogenic and immune suppressive dendritic cells (DC) (32), tumor-associated macrophages (TAMS) (33), tumor-associated neutrophils (TANs) (34), and MDSC (24), via a series of soluble molecules such as TGFβ (35), adenosine (36), VEGFA (37), CSF1 (24), and CCL2 (38). It is beyond the scope of this article to discuss all of these mechanisms, so the below discussion focuses on MDSC, which are present in virtually all cancer patients and are universally considered a major obstacle to cancer immunotherapies.…”