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The first international conference on vascular targeting: meeting overview
Philip E Thorpe1, David J Chaplin, David C Blakey
1Department of Pharmacology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. philip.thorpe@utsouthwestern.edu
Abstract:
The First International Conference on Vascular Targeting focused on vascular targeting agents (VTAs) that occlude or destroy the pre-existing blood vessels of solid tumors. The VTAs cause a rapid shutdown in the blood supply to the tumor that kills tumor cells by depriving them of oxygen and nutrients. The VTAs are distinct from antiangiogenic agents, which prevent new blood vessel formation. Two major types of VTAs are being developed for cancer: the ligand-directed VTAs that use antibodies, peptides, and growth factors to deliver toxins, procoagulants, and proapoptotic effectors to tumor endothelium, and the small molecule VTAs that do not specifically localize to tumor endothelium but exploit pathophysiological differences between tumor and normal tissue endothelia to induce acute vascular shutdown in tumors. Both approaches were described at the meeting and highlighted the variety of VTAs in preclinical development, their selectivity for tumor endothelium, their rapid antitumor effects, and the improved activity seen when combined with other anticancer approaches (antiproliferative chemotherapeutic drugs, radiation, radiolabeled antibodies, nitric oxide synthetase inhibitors, and antiangiogenic agents). Early clinical studies were summarized for the small molecule VTAs: the antitubulin drugs, combretastatin A4 phosphate (CA4P) and ZD6126, and the flavonoid, 5,6-dimethylxanthenone-4-acetic acid (DMXAA). The agents lacked the bone marrow and gastrointestinal toxicities associated with antiproliferative chemotherapy. As a marker of biological effect, blood flow reductions in tumors were measured using magnetic resonance imaging or positron emission tomography for all of the agents tested, and single-agent clinical activity was seen. These agents are now being evaluated in combined modality studies to see whether the impressive results obtained in experimental models can be translated into humans.
Insights
Vascular targeting agents (VTAs) rapidly shut down tumor blood supply, killing cancer cells. Early clinical trials show promise for VTAs, with fewer toxicities than traditional chemotherapy.
Area of Science:
- Oncology
- Vascular Biology
- Drug Development
Background:
- Solid tumors rely on existing blood vessels for oxygen and nutrients.
- Vascular targeting agents (VTAs) selectively disrupt tumor vasculature, leading to tumor cell death.
- VTAs differ from antiangiogenic agents, which inhibit new blood vessel formation.
Purpose of the Study:
- To review the development and preclinical/clinical status of vascular targeting agents (VTAs) for cancer therapy.
- To highlight the mechanisms, types, and therapeutic potential of VTAs.
- To discuss the combination of VTAs with other anticancer modalities.
Main Methods:
- Discussion of ligand-directed and small molecule VTAs.
- Review of preclinical data on VTA selectivity and antitumor effects.
- Summary of early clinical studies for small molecule VTAs (CA4P, ZD6126, DMXAA).
- Assessment of biological effects using imaging techniques (MRI, PET).
Main Results:
- VTAs effectively occlude tumor blood vessels, causing rapid tumor cell death.
- Ligand-directed VTAs use targeting moieties to deliver toxins or procoagulants.
- Small molecule VTAs exploit tumor endothelium differences for selective vascular shutdown.
- Early clinical trials demonstrated single-agent activity and reduced toxicities compared to chemotherapy.
- Imaging confirmed reduced tumor blood flow as a marker of VTA efficacy.
Conclusions:
- VTAs represent a promising therapeutic strategy for solid tumors.
- VTAs exhibit rapid antitumor effects with a favorable toxicity profile.
- Combined modality treatments involving VTAs are under investigation to enhance clinical efficacy.