What Are Targeted Antiangiogenic Therapies?



How do cancer cells stimulate angiogenesis?

In healthy tissue, angiogenesis is an essential process for growth and development, as well as wound healing and growing new healthy tissue. 

Angiogenesis is also the way tumors grow their own blood vessels to supply themselves with oxygen and nutrients — like an invading army taking control of your country’s highway and electrical systems to further their goal of conquest.

Angiogenesis is a complex system regulated by proangiogenic and antiangiogenic factors. Angiogenesis involves migration, growth and differentiation of endothelial cells (cells lining the inside walls of blood vessels). 

Tumor cells secrete enzymes that stimulate proangiogenic factors. Tumor cells can also stimulate the neighboring normal cells to produce proangiogenic signals and aid the tumor angiogenesis.

What are targeted antiangiogenic therapies?

Targeted antiangiogenic therapies inhibit the formation of new blood vessels in tumors by blocking the factors that promote angiogenesis. Targeted antiangiogenic therapies come in two forms:

  • Small molecule drugs: Microscopic molecules that can work on the cell surface or get right inside the cell to interfere with the cellular processes.
  • Monoclonal antibodies: Lab-produced cancer-specific antibodies that are too large to get inside a cell, but work by attaching to protein receptors on the cell surface, thus signaling the body’s immune system to kill them.

Following are the targeted therapies with angiogenesis inhibitors:


Vascular endothelial growth factor (VEGF) family consists of six types of glycoproteins (VEGF A, B, C, D, E and placental growth factor) which cells secrete to stimulate angiogenesis. The VEGF molecules bind to VEGF receptors in endothelial cells and stimulate them to form new blood vessels. There are three types of VEGF receptors, VEGFR1, 2 and 3.

VEGF-targeted therapies have been developed as monotherapy or for administration along with chemotherapy. Many monoclonal antibodies and small molecule drugs that target this pathway are in clinical trials. Cancers can, however, develop resistance to medications.

The FDA-approved therapies that target VEGF are:

  • Bevacizumab (Avastin)
  • Bevacizumab-awwb (Mvasi)

Both are monoclonal antibodies approved for the treatment of:

Angiopoietins/Tie receptors

Angiopoietins are growth factors secreted by cells to promote angiogenesis from pre-existing blood vessels. Four angiopoietins have been identified (Ang1 to Ang4), and Ang1 and Ang2 are required for the formation of mature blood vessels. Angiopoietins bind to protein molecules known as Tie receptors on the endothelial cells and activate them.

Currently there are no FDA-approved angiopoietin/Tie receptor targeted therapies, though many are in clinical trials.

FGFR inhibitors

Fibroblast growth factor (FGF) and FGF receptors play an important role in neo-angiogenesis, proliferation and stem cell survival. Fibroblasts are connective tissue cells which make up the extracellular matrix, which provides structural support to keep the cells in their natural positions.

FGFR inhibitors are in early phases of clinical trials.

Notch inhibitors

The Notch signaling pathway plays a major role in embryonic vascular development and sprouting and branching of new blood vessels in angiogenesis. Targeted therapies to inhibit the Notch signaling pathways are in early phases of clinical trials.

Integrin targeted agents

Integrins are protein receptors on cell surfaces which attach the cell to the extracellular matrix. Integrins enable two-way interactions between the cell’s cytoskeleton and the extracellular matrix. Cytoskeleton is a network of microfilaments and microtubules which help the cell maintain its shape and organize the cellular components.

Integrins are necessary for vascular proliferation, adhesion, immune response, and wound repair. Many tumors are found to have excessive presence of integrins. Integrin targeted therapies are in clinical trials.

Vascular targeting agents

While antiangiogenic therapies prevent formation of new blood vessels, vascular targeting agents damage existing blood vessels in solid tumors and deprive them of blood supply.

Vascular targeting agents are designed to locally interrupt the cytoskeleton and cell-cell interactions in the endothelial cells in solid tumors. This leads to plasma leak, viscous blood flow and clot formation which block the supply of oxygen and nutrients to the tumor.

Currently there are seven small molecule vascular targeting agents in phase II clinical trials and several in preclinical development.


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