Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors

Susan A Kennedy,Brian J Mehigan,Clare T Butler,Maria E Morrissey,John O Larkin,Breandán N Kennedy,Margaret R Dunne,Fiona O’Connell,Amy M Buckley,Paul Mccormick,Jacintha O’Sullivan,Mary-Clare Cathcart

doi:10.1186/s12885-020-07430-y

Abstract

BackgroundColorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication.MethodFollowing drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry.ResultsOur novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers.ConclusionOur results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.

Highlights

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC
Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced Tyrosine Kinase-2 (TIE-2) expression which is involved in the promotion of tumor vascularization
These results suggest 1,4-dihydroxy quininib is acting in an alternate pathway to the Bevacizumab targeting vascular endothelial growth factor (VEGF) pathway and decreases tyrosine kinase (TIE)-2 expression when combined with approved therapies Bevacizumab or FOLFOX

Summary

Introduction

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the antiVEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). As colorectal cancer (CRC) is the third most common cancer, and the second most common cause of cancer-related mortality worldwide, it is a leading public health concern [1,2,3]. While an evaluation of the incidence rates of CRC in the USA shows a decreasing trend between 2000 and 2014 [1] what is most worrying, is that in the last 60 years, CRC has been on the rise in the under 50 population [1]. In the USA in males under 50, CRC is the second leading cause of cancer deaths, while in women under 50, it is the fourth leading cause of cancer deaths [7]

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