Discontinuous Schedule of Bevacizumab in Colorectal Cancer Induces Accelerated Tumor Growth and Phenotypic Changes

Abstract

Antiangiogenics administration in colorectal cancer patients seemed promising therapeutic approach. Inspite of early encouraging results, it however gave only modest clinical benefits. When AAG was administered with discontinuous schedule, the disease showed acceleration in certain cases. Though resistance to AAG has been extensively studied, it is not documented for discontinuous schedules. To simulate clinical situations, we subjected a patient-derived CRC subcutaneous xenograft in mice to three different protocols: 1) AAG (bevacizumab) treatment for 30 days (group A) (group B was the control), 2) bevacizumab treatment for 50 days (group C) and bevacizumab for 30 days and 20 without treatment (group D), and 3) bevacizumab treatment for 70 days (group E) and 70 days treatment with a drug-break period between day 30 and 50 (group F). The tumor growth was monitored, and at sacrifice, the vascularity of tumors was measured and the proangiogenic factors quantified. Tumor phenotype was studied by quantifying cancer stem cells. Interrupting bevacizumab during treatment accelerated tumor growth and revascularization. A significant increase of proangiogenic factors was observed when therapy was stopped. On withdrawal of bevacizumab, as also after the drug-break period, the plasmatic VEGF increased significantly. Similarly, a notable increase of CSCs after the withdrawal and drug-break period of bevacizumab was observed (P<.01). The present study indicates that bevacizumab treatment needs to be maintained because discontinuous schedules tend to trigger tumor regrowth, and increase tumor resistance and CSC heterogeneity.

Revascularization after angiogenesis inhibition favors new sprouting over abandoned vessel reuse

“…In the eye, choroidal neovascularization in AMD and retinal neovascularization in proliferative diabetic retinopathy are caused by angiogenesis; however, even advanced clinical imaging methods have insufficient resolution to examine revascularization dynamics at the single-vessel level [3, 12]. Tumor vessels are similarly angiogenic, and although pre-clinical and clinical studies report tumor revascularization following stoppage of anti-VEGF treatment [9, 19, 20, 31], the detailed mechanisms by which revascularization may occur are less well studied. In a prior study by Mancuso and colleagues, revascularization of experimental tumors after a short duration (7 days) of anti-VEGF therapy was reported to occur by reuse of the empty basement membrane sleeve (ebms) remnants of regressed vessels [32].…”

A Tumor-in-Host DEB-Based Approach for Modeling Cachexia and Bevacizumab Resistance

“…To further assess the predictive performances of the hypoxiatriggered resistance model on new experiments, data related to patient-derived colorectal cancer xenograft mice treated with bevacizumab at long-term intermittent and continuous schedules were taken from the literature (45). In this experiment, bevacizumab was administered (5 mg/kg) twice a week for a treatment period of 30 days, 50 days, 30 days followed by 20 days without treatment, 70 days or 70 days treatment with a break period between days 30 and 50.…”

“…The hypoxia-triggered resistance model and its parameter values derived on the DU-145 cell line were used to predict the colorectal cancer tumor response to bevacizumab treatments, whereas the tumor-related parameters were estimated by using the experimental tumor weight data reported in ref. 45 (host body weights were not available). As documented by the agreement between model simulations and observations (Fig.…”

Recent Advances in Monoclonal Antibody Therapy for Colorectal Cancers

“…The antitumor effects of regorafenib were evaluated in seven PD CRC xenografts [67]. Third, bevacizumab, a humanized antibody to VEGF, showed a significant delay in CRC tumor growth relative to that of the non-treated animals [68]. Fourth, intraperitoneal injection of DC101, an anti-VEGFR mouse monoclonal antibody, inhibited tumor growth and induced apoptosis in CRC in a KM12L4 xenograft model.…”