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How Do Targeted Therapies Work? - pg. 2

How Do Targeted Therapies Work? - page 2

HER2/neu inhibitors

HER2/neu (also known as ErbB-2) stands for "Human Epidermal growth factor Receptor 2" and is a protein that is over-amplified (over-expressed) in about 20-30% of breast cancer. This results in a more aggressive breast cancer and is referred to as HER2 positive. HER2/neu is a member of the ErbB protein family, more commonly known as the epidermal growth factor receptor family.

  • Herceptin (monoclonal antibody) - generic name Trastuzumab
Image courtesy of Genetech


"How Herceptin Works (Proposed Mechanism of Action)

  • Herceptin is a biologic medicine (not chemotherapy) that specifically inhibits the HER2 protein
  • Based on preclinical studies, Herceptin works by attaching to HER2 receptors and blocking signals that make the cancer more aggressive, and also by signaling the body's immune system to destroy the cancerous cells". - Quote courtesy of Genentech

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Angiogenesis inhibitors (learn more in section titled Angiogenesis Inhibitors)

Tumor cells, just like normal cells, need an adequate blood supply in order to perform vital cellular functions. Actively dividing tumors secrete special proteins that signal the surrounding area to sprout new blood vessels.

This new blood vessel formation is called angiogenesis. The main proangiogenic factor is called VEGF, which stands for vascular endothelial growth factor. VEGF is a ligand that binds to a VEGF receptor on the surface blood vessels, stimulating the growth and formation of new blood vessels. Secretion of VEGF by tumors, stimulates new blood vessel growth and allows them (tumors) to feed and sustain their own growth.

The concept behind angiogenesis inhibition, then, is to stop this process and thereby fight tumor progression. An example is Avastin.

  • Avastin (monoclonal antibody) - generic name Bevacizumab
  1. Cartoon image of Avastin is labeled #1.
  2. Tumor cells release VEGF to stimulate blood vessel growth.
  3. Avastin binds to the growth factor VEGF and prevents it from interacting with its receptors.
  4. VEGF receptors sit on the endothelial cells that line blood vessels. Avastin/VEGF blocks their activation.

Activation of these receptors normally leads to endothelial-cell growth and the formation of new blood vessels to the tumor. Preventing this growth also inhibits metastasis and may improve sensitivity to cytotoxic drugs.

Image and explanation, courtesy of Ohio State University    
Proteasome inhibitors

The proteasome is a structure inside the cell that breaks down proteins that have been labeled to undergo degradation and recycling. This process is important because it removes possibly damaged or defective proteins. But even more important, it is a required process for normal regulation of cellular growth, division, angiogenesis, and death.

By binding part of the proteasome, a drug can inhibit the breakdown of some of these proteins that have been marked for destruction. This "wreaks havoc" in the cell, and can result in growth arrest or death of the cell. An example of a protease inhibitor is Velcade.

  • Velcade (Small Molecule) - generic name Bortezomib


Immunotherapy (learn more in section titled Immunotherapy)

The classes of targeted therapies described above all bind to and block specific targets, disrupting the chain of events needed for tumor cell proliferation. In contrast, targeted immunotherapy agents bind to their targets, not to interfere with growth signals, but rather to trigger immune signals.

By binding to specific protein particles (antigens) that are found on the surface of certain types of cancer cells, targeted immunotherapy agents can lead to a series of anti-tumor immune reactions in the body, ultimately causing the tumor cell to die.

Targeted immunotherapy drugs are essentially a collection of monoclonal antibodies, each with different targets. Antibodies are proteins that seek out and bind to specific antigens; every antibody has a particular antigen with which it "fits".

Antibodies are named for the antigen to which they bind, e.g. the anti-CD20 antibody binds to the antigen CD20. An example of an immunotherapy drug is Rituxan.

  • Rituxan (a monoclonal antibody) - generic name Rituximab
  1. Rituxan is an antibody developed to bind to the CD20 protein.
  2. CD20 is present on all B cells, including chronic lymphocytic leukemia cells. The drug coats the cancer cells with antibody. This attracts natural-killer cells.
  3. Natural-killer cells normally destroy antibody-coated cells. The drug may also trigger changes inside cancer cells that lead to programmed cell death (apoptosis) and make the cells more sensitive to chemotherapy.
Image courtesy of Ohio State University  





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