It's always nice to get a little something extra when you weren't expecting it. Like when you find that crumpled up twenty dollar bill in a pair of jeans you haven't worn in a while.
But what about in the highest of stakes? Like finding out that an existing cancer therapy has therapeutic effects on a different kind of cancer that it wasn't intended for? Researchers in Boston recently made just such a surprise finding.
Erbitux, usually used to treat cancers of the colon, head and neck, was recently discovered to double the tumor response rate as well as double patient survival time for patients with triple-negative breast cancer when it was used along with a type of chemotherapy called cisplatin. This is a great example of the incredible advances being made in a field of new drugs referred to as “targeted therapy.”
Targeted therapy is a class of medications that fall under the umbrella of the fast-growing field of “personalized medicine.” Ever since the human genome was decoded in 2003, the vast amounts of genetic information it has produced has allowed academia and private industry to create and develop medication and therapy based on how our cells grow and function with proteins, cellular messengers and DNA signaling molecules.
New models of genetic testing can reveal information about how each patient's body specifically responds to certain drugs, and physicians can take this information and use it to decide on a customized course of action. So essentially, the days of a “one treatment fits all” approach -- which was based on using the evidence of what works for a large number of people in a study -- are becoming a thing of the past. The future is moving toward looking at each individual's specific genes and DNA to determine how their body personally and precisely responds to certain therapies and tailoring treatment to that person.
The current news about Erbitux is a great example that illustrates how personalized medicine (and specifically targeted therapies for cancer) work. Previously, cancer medications, like many chemotherapies, acted on the part of the cell that caused the cell to grow and divide. Many traditional chemotherapies go to work on the part of a cell's DNA that allows it to grow and divide. Disrupting cellular growth and division is an effective cancer treatment because cancer is the abnormal growing and dividing of cells. Unfortunately, the effects of chemotherapy work on ALL dividing cells, including the ones that are healthy and growing and being replaced in our digestive tract and our hair follicles, This is the cause the debilitating side effects of chemo such as nausea, vomiting and hair loss.
Targeted therapy is a sniper rifle compared to chemotherapy's baseball bat. There are two classes of therapies that fall under the banner of targeted therapy: small molecules and monoclonal antibodies (which Erbitux is a member of).
Now strap on your learning helmets, because you're about to get a quick education in cell biology! In each cell, there are countless different proteins on the surface, each with a specific task of signaling to the DNA on the inside of the cell what's happening on the outside of the cell. Different hormones and proteins that our bodies produce will interact with a specific protein on the cell surface, which will then start a domino effect of signaling different proteins inside the cell to activate, with the final step being a signal to the cell's DNA to activate a gene for a specific purpose. Once the gene is activated, the cell will go to work performing its task, whether that task is to divide, produce a specific protein or hormone, or even to commit apoptosis --suicide.
Antibodies are small proteins that our bodies make. These antibodies recognize and attach themselves to bacteria or foreign objects in our body. Our immune system then recognizes the antibody and destroys it, along with whatever the antibody is attached to.
Monoclonal antibodies are developed in a laboratory to act just like human antibodies. Like an incredibly complex jigsaw puzzle, the monoclonal antibody has one piece out of millions that it fits with perfectly. Monoclonal antibodies take advantage of these cell signaling systems by either blocking the intended cell surface protein, or tricking it into activating the cell when the human-produced hormone is missing or absent. In the case of cancer therapies, many times these cell surface proteins trigger pathways that allow cancer cells to continue growing and dividing.
The best way to illustrate this action would be with examples. Erbitux, for example, seeks out and attaches to the cancer cell's receptor hormone for “epidermal growth factor” and then blocks that receptor's action. The cell can no longer respond to epidermal growth factor in the body, and this prevents it from growing and dividing. Here's where the "personalized medicine" aspect comes in. When a patient is diagnosed with a colon cancer, or head and neck cancer, they will have a diagnostic assay performed on a sample of the tumor. Through immunologic techniques, we can see if that particular tumor grows and responds to epidermal growth factor. If it does, then Erbitux can probably be used to suppress the growth of that tumor.
Other monoclonal antibodies work the same way but on different cell surface hormone receptors. Avastin is a successful monoclonal antibody that attaches to the cell surface receptor for a hormone called vascular endothelial growth factor-A (VEGF-A). By attaching to the receptor Avastin prevents the cancer cell from sending out signals that bring blood vessels to the new cancer cells. With the blood cut off, the result is slowed or stopped growth (tumors need a blood supply too, right?).
is probably one of the most well-known and important monoclonal antibodies. It revolutionized breast cancer treatment when it was discovered that in many breast cancers, the HER2 cell surface protein was over-expressed, causing uncontrolled growth of the cancer cells. Herceptin is able to precisely bind to the HER2 surface protein and shut it down so the cancer cells either stop dividing entirely, or it slows down growth enough to let other chemotherapies eliminate the cancer.
Small molecules work in a similar fashion but are not specifically defined as antibodies. (Antibodies have a consistent, specific structure that defines them; small molecules can be anything under a certain molecular size.) Like monoclonal antibodies, small molecules are molecular compounds designed to interact and bind to a specific cell surface receptor and inhibit that receptor's action on the cell's DNA. In some cases, the molecules are small enough that they can absorb right through the cell's membrane and have direct effect on the proteins inside of the cell.
Gleevec is an example of a targeted therapy designed and executed for a specific genetic target that was created from a mutation which caused Chronic Myelogenous Leukemia (CML). In 95% of the cases of CML, patients have a genetic mutation called a translocation, in which parts of two different chromosomes break off and switch places. In CML, part of chromosome number 9 and part of chromosome number 22 break off, and switch places. This mutation is known as the Philadelphia Chromosome, and its presence leads to CML by creating a new, mutated gene called bcr-abl.
The bcr-abl gene causes leukemia because the abl portion of it makes a surface protein called a tyrosine kinase to become constantly active. The constant activity of tyrosine kinase leads to rapid, unregulated cell division and growth. Gleevec, however, can bind to a specific site on this new cancer-causing surface protein and essentially shut it down, or at least reduce its activity to the point where CML patients can maintain the disease in a chronic condition.
The science behind personalized medicine and targeted therapies is certainly complex, but it's an incredible testament to the wealth of information and the potential future therapies that patients have at their fingertips because of the decoding of the human genome. Exquisitely specific and effective therapies currently exist (and more are being developed) that reduce cancers that were at one point a certain death sentence to now chronic, manageable conditions.
