Biochemistry 101? That sounds complicated and boring. I know, but this isn't. Targeted cancer therapy is actually extremely interesting and becoming increasingly popular for treating certain types of cancer.
You may remember the TIME magazine cover story in 2001 about gleevec as a targeted cancer therapy to treat chronic myeloid leukemia. The development of gleevec represented a major breakthrough in the treatment of leukemia.
What is Targeted Therapy?
In essence, targeted therapy is what it sounds like - therapy specifically tailored to attack the tumor. These therapies are substances that block the progression of cancer cells by targeting specific molecules involved in tumor progression and growth.
Wait what? How do they work? Aren't all cancer therapies aimed to block tumor growth?
Yes, they are but targeted cancer therapies are engineered to specifically attack cancer cells at a molecular level while sparing healthy cells. These drugs target proteins involved in cell signaling pathways and induce programmed cell death known as apoptosis either directly or indirectly by activating the immune system to subsequently destroy cancer cells.
Pretty cool, huh?
Ok...so how are they developed?
Great question. The process is very complicated so here is a simplified version. First, the target is identified. Then, the therapy is developed as either a small-molecule drug or as a monoclonal antibody.
Small Molecule Drugs So basically, scientists screen the effects of thousands of compounds on specific targets. The compounds that appear to bind to the targets the best go through a series of modifications and tests to determine the most effective and specific drug.
Small molecule drugs are small enough to enter cells and bind to receptors inside of cells. They are often administered in pill form.
Many small molecule drugs, such as Gleevec and Velcade, are specialized tyrosine kinase inhibitors. Tyrosine kinases are, in essense, enzymes that add phosphates to other molecules and subsequently signal a cascade of events to maintain cell growth. Mammalian cells have several types of tyrosine kinases, and the cascade of cell processes may be turned on and off. However, in some cancers, certain tyrosine kinases do not turn off. Targeted cancer therapy drugs specifically target these enzymes and prevent the cascade from happening.
But really what does that mean?
That means that they stop a chain of events from happening. By blocking specific enzymes, these drugs actually stop the cells from growing. What's great about these drugs is that they target the specific enzymes relevant to the cancer cells.
Okay what about monoclonal antibodies, what's that all about?
Monoclonal antibodies are larger than small molecule drugs and bind to targets outside of cancer cells. They are formed by injecting animals with target proteins which subsequently produce antibodies to those proteins. The antibody that binds to the targeted protein is isolated and then "humanized" so that the human body does not recognize it as foreign. Humanizing the antibodies involves genetic engineering and replacing the animal portions with human portions. Monoclonal antibodies are often given IV.
What was the first targeted cancer therapy?
Trastuzumab marketed as Herceptin was the first targeted cancer therapy. It is an estrogen receptor blocker that was started by Marc Greene in a laboratory in London in 1985.
Okay okay so is that it?
Actually no. There are several types of targeted cancer therapies. Some targeted cancer therapies are aimed at inhibiting angiogenesis (the formation of blood vessels) while others induce apoptosis (programmed cell death). Others target signal transduction (a cascade of cellular processes which help with cell growth or maintenance).
This seems all very complicated.
It is. But the bottomline is that there are several different types of cancer therapies that are engineered to attack specific proteins responsible for cancer.
Wait, so how does this relate to the mouth?
Good question. Some of these drugs have oral side effects!
These drugs inhibit enzymes that regulate cell growth, metabolism and progression. mTOR inhibitors, such as everolimus (afinitor), are associated with mouth sores. These sores, or ulcers, are often seen on the ventral surface of the tongue (bottom side of the tongue) and the floor of mouth as well as the labial and buccal mucosa (the lining inside the mouth that corresponds to the cheeks). The mouth sores associated with these drugs present as apthous-like sores in contrast to ulcerations associated with radiotherapy and chemotherapy. In other words, they look like cankersores.
Vascular endothelial growth factors/anti-angiogenic medications
Sunitinib (Sutent) is a drug used often to treat kidney cancer and imatinib-resistant GI stromal tumor. It targets several signaling pathways.
Bevacizumab (avastin) is known as an anti-angiogenic medication used to treat several types of cancer including colorectal cancer and some brain cancers. It inhibits blood vessel growth (angiogenesis).
How do they affect the mouth?
Sunitinib administration may be associated with mouth sores. Additionally, bevacizumab and sunitinib, although not common, are associated with a condition known as osteonecrosis of the jaw which is characterized by delayed or abnormal wound healing.