Most tumors release various signaling molecules to support their incessant growth, invasion, and metastasis. Some of these molecules, called tumor angiogenesis factors (TAFs), can stimulate the formation of new blood vessels, which is crucial for tumor growth. It has been shown that blocking the function of TAFs by chemical or biological molecules can shrink or render tumors inactive, suggesting the potential of anti-angiogenic agents for effective treatment of cancer. The first anti-angiogenic drug (AAD) that successfully inhibits the formation of new blood vessels and thus suppresses tumor growth was approved for clinical use by the U.S. Food and Drug Administration (US-FDA) over two decades ago. At the time of writing, numerous AADs have received clinical approval for the treatment of various types of cancer in human patients. However, AADs in general have limited clinical benefits as anti-cancer drugs even after two decades of clinical use.

A new review appeared in Chinese Medical Journal on July 25, 2024, discusses new ways to use AADs in cancer treatment to improve their clinical efficacy and recommends some methods to achieve this.”In some tumor models, tumor suppression of over 80–90% can be achieved with a single anti-angiogenic agent. The impressive effects of anti-angiogenic monotherapy make it an attractive potential therapeutic approachexplains the author.

Currently, most clinically available AADs work by blocking the binding of an important angiogenic factor called vascular endothelial growth factor (VEGF) to its receptor (endothelial growth factor or VEGFR). While these anti-VEGF drugs show promise in treating some cancersSthey have relatively low effectiveness in other types of cancer. The author explains this further: “Clinically, limited therapeutic benefits have been observed following anti-VEGF-based monotherapy in most cancers, with the exception of clear cell renal cell carcinoma, where bevacizumab monotherapy significantly improves progression-free survival and overall survival.”

In this review, the authors point out several knowledge gaps that may hinder the clinical application of anti-VEGF drugs. Therefore, they call for a better understanding of the differences between human and animal models used in testing anti-VEGF drugs to improve the translation of results from the laboratory to human trials. The researchers also recommend a more comprehensive study of the interaction between AADs and other existing cancer therapies, such as chemotherapy and immunotherapy, to avoid harmful interference and develop new ways to incorporate anti-VEGF drugs into existing cancer therapies.

Since the tumor angiogenic pathways are closely linked, the researchers also point out that specific combinations of AADs may be more beneficial for cancer treatment compared to their monotherapies. The author further highlights: “Since VEGF expression levels are always higher in tumors than in adjacent healthy tissues, targeting the VEGF-VEGFR signaling pathway is an obvious approach to suppress tumor angiogenesis. Non-VEGF angiogenic factors and cytokines contribute to resistance to anti-VEGF drugs during treatment. Therefore, drugs that block non-VEGF angiogenic signaling pathways should be used in combination with anti-VEGF drugs.”

In addition, the researchers warn against the use of combinations of AADs with certain drugs that block non-angiogenic pathways, such as tyrosine kinase inhibitors (TKIs), which prevent the growth and proliferation of tumor cells. The author further explains this: “Clinical experience with anti-angiogenic TKIs that simultaneously block multiple signaling pathways, including the VEGF pathway, shows that these multi-target AADs may not necessarily be more effective than single-target anti-VEGF drugs in cancer therapy.”

Finally, the researchers recommend that factors such as tumor mutations, type of tumor microenvironment and patient profile should be considered when deciding on the optimal strategy for cancer treatment with AADs.”It is possible that genetic mutations in cancer cells and the nature of the tumor microenvironment together determine the optimal AAD combination. Likewise, an in-depth analysis of the cellular and molecular components of the tumor microenvironment will likely provide important clues for the selection of potentially effective AADs and potentially responsive cancer patients.” is the author’s conclusion.