VEGF pathway targeting agents, vessel normalization and tumor drug uptake: from bench to bedside

Area of Science:

• Oncology
• Pharmacology
• Biomedical Engineering

Background:

• Vascular endothelial growth factor (VEGF) pathway targeting agents are used in combination cancer therapies.
• These agents have shown improved efficacy in various carcinomas, including breast, lung, and ovarian cancers.
• VEGF inhibitors induce vessel normalization, which can impact tumor drug uptake.

Purpose of the Study:

• To investigate the impact of VEGF pathway inhibitors on tumor drug delivery and combination therapy efficacy.
• To explore the role of vessel normalization in altering tumor drug uptake.
• To identify the need for novel biomarkers and innovative trial designs for optimizing combination therapies.

Main Methods:

• Review of preclinical and clinical studies on VEGF pathway inhibitors combined with anticancer drugs.
• Analysis of tumor drug delivery changes following bevacizumab treatment.
• Evaluation of efficacy data from combination therapies involving bevacizumab with monoclonal antibodies and chemotherapy.

Main Results:

• Bevacizumab treatment decreased the tumor delivery of radiolabeled antibodies and chemotherapeutic drugs, potentially due to reduced vessel pore size from vessel normalization.
• Combining bevacizumab with cetuximab, panitumumab, or trastuzumab did not improve efficacy in colorectal and breast cancers, respectively.
• Combining bevacizumab with chemotherapy demonstrated increased efficacy in certain cancer types.

Conclusions:

• VEGF pathway inhibitors have a complex effect on tumor drug delivery, with vessel normalization potentially hindering uptake.
• Optimizing combination therapies requires novel biomarkers to identify patients who will benefit, particularly concerning tumor perfusion.
• Further research with innovative trial designs and imaging studies is crucial to understand the interplay between VEGF targeted therapy, vessel normalization, and tumor drug delivery.