Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer
Mark J McKeage1, Bruce C Baguley
1Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Grafton, Auckland, New Zealand. m.mckeage@auckland.ac.nz
Abstract:
The unique characteristics of tumor vasculature represent an attractive target that may be exploited by vascular-targeting anticancer agents. A promising strategy involves the selective disruption of established tumor blood vessels by tumor-vascular disrupting agents (tumor-VDAs), which exhibit antivascular activity, resulting in inhibition of tumor blood flow and extensive necrosis within the tumor core. The tumor-VDA class can be subdivided into flavonoid compounds, which are related to flavone acetic acid, and tubulin-binding compounds. ASA404, of the flavonoid class, is the most advanced tumor-VDA in clinical development and has been evaluated preclinically and in several phase 1 and phase 2 studies. Preclinical studies have demonstrated the selective apoptosis of tumor endothelial cells and the inhibition of tumor blood flow. Synergistic activity was observed with ASA404 and with several chemotherapeutic agents, particularly taxanes. In clinical trials, compared with chemotherapy alone, ASA404 was tolerated well and produced improved activity in patients with nonsmall cell lung cancer when combined with paclitaxel and carboplatin. Phase 3 clinical trials are ongoing. Selectively targeting established tumor vasculature with tumor-VDAs represents a promising and innovative approach to improving the efficacy of standard anticancer therapies.
Insights
Vascular-targeting anticancer agents, like ASA404, disrupt tumor blood vessels, causing necrosis. Combining ASA404 with chemotherapy shows promise for non-small cell lung cancer treatment.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Tumor vasculature presents a unique target for anticancer therapies.
- Vascular-disrupting agents (VDAs) selectively target and disrupt tumor blood vessels.
- Tumor-VDAs can inhibit tumor blood flow, leading to central tumor necrosis.
Purpose of the Study:
- To evaluate the efficacy of ASA404, a flavonoid-class tumor-VDA, in preclinical and clinical settings.
- To investigate the synergistic effects of ASA404 with conventional chemotherapeutic agents.
- To assess the safety and activity of ASA404 in patients with non-small cell lung cancer.
Main Methods:
- Preclinical studies assessing apoptosis of tumor endothelial cells and tumor blood flow inhibition.
- Clinical trials (Phase 1-3) evaluating ASA404 in combination with chemotherapy.
- Pharmacological analysis of synergistic activity with taxanes and other chemotherapeutics.
Main Results:
- ASA404 demonstrated selective apoptosis of tumor endothelial cells and inhibited tumor blood flow in preclinical models.
- ASA404 showed synergistic activity with chemotherapeutic agents, notably taxanes.
- In clinical trials for non-small cell lung cancer, ASA404 combined with paclitaxel and carboplatin was well-tolerated and improved outcomes compared to chemotherapy alone.
Conclusions:
- Targeting tumor vasculature with tumor-VDAs is a promising strategy to enhance standard anticancer therapies.
- ASA404 represents an advanced tumor-VDA with demonstrated efficacy and safety in combination regimens.
- Ongoing Phase 3 trials will further define the role of ASA404 in cancer treatment.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
01:24Regulation of Angiogenesis and Blood Supply
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
01:10Mechanism of Angiogenesis
01:27Tumor Immunotherapy
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...