Last month in my blogs I discussed a few completely experimental CRC drug strategies in early phase clinical trials. Drug discovery isn’t all about venturing into the complete unknown however. Identifying ways to significantly improve current therapeutic strategies that have already been proven to help colorectal cancer (CRC) patients is also a key goal. Improvement can come in a number of different ways: e.g. a higher percentage of patients who will respond, a longer time of response before resistance develops, and even patients who will respond to new anti-EGFR therapies (defined below) after they have become resistant to current anti-EGFR therapies. If achieved, these would all be very important advances for patients!

Where We Are Now: Current Anti-EGFR Therapies 

I wanted to begin by discussing the science behind the currently approved anti-EGFR therapies for CRC: cetuximab (Erbitux™) and panitumumab (Vectibix™). Both drugs have proven clinical activity and are FDA-approved for use against KRAS-wild type metastatic CRC.

Antibody Targeted Therapies

Cetuximab and panitumumab are examples of a type of modern cancer therapy called “targeted therapies.” They only react with cells that have the Epidermal Growth Factor Receptor (EGFR). Since many CRC tumors rely on EGFR signaling to grow, it is possible to disrupt the EGFR signals with an anti-EGFR therapy. These therapies target EGFR (hence the name targeted therapies), and do not normally produce the same non-specific side effects that traditional chemotherapy can cause, such as nausea, low blood counts and malaise (whew!). However, EGFR inhibitors do cause a skin rash side effect in many patients because skin cells also have a lot of EGFR. They are also “therapeutic antibodies.” This type of drug is extremely selective for binding to its target (in this case EGFR) which also is an important reason behind their lack of traditional chemo side effects.
EGFR causes cells to grow; anti-EGFR therapies may halt them

The Gas Pedal and More

As you can guess from the name “Epidermal Growth Factor Receptor,” it is a receptor that when activated (pushing the gas pedal) – this causes cells to grow. As a part of a normal living body this is both good and essential. In cancer, this process can be hijacked and used not only to help the tumor grow but also to help the cancer invade other tissues, abnormally grow blood vessels to feed itself and block cellular death which is normally triggered when cells aren’t behaving themselves. All these put together = uncontrolled cancer.

How Do Anti-EGFR Therapeutic Antibodies Work?

The details are VERY complicated but here are two major ways that they combat CRC.
  • Blocking the gas pedal. Cetuximab and panitumumab bind to EGFR and act primarily by physically blocking the growth factor from binding to it. Since many CRC tumors are especially dependent on EGFR signaling to grow, blocking it can stop many tumors from growing and in some cases, even cause them to shrink.
  • Engaging the immune system. Cetuximab and panitumumab interact with the immune system in different ways and levels but without going into those details, they are both in their own ways immunotherapies. The immune system uses antibodies to recognize and bind to dangerous things in the body to flag them for destruction by immune cells. When an anti-EGFR antibody binds to cancer cells expressing EGFR, it tries to act as a flag to get the immune system’s attention. Immune cells are then signaled to the rescue and kill the cancer cell which has been “flagged as being dangerous.”

The Issues

Cetuximab and panitumumab are two very clinically useful therapies. There are however a number of reasons why scientists are working on next generation anti-EGFR therapies, including:
  • Resistance. Unfortunately, resistance eventually develops. There is an urgent medical need for new treatments for patients who develop resistance!
  • Immune system engagement. Can the immunotherapy aspects of their anti-cancer mechanism be increased? There certainly appears to be room for improvement!
Now that we’ve discussed two of the major ways that anti-EGFR therapies work and areas for potential improvement, stay tuned for PART 2 of this series tomorrow where we will try to answer the question:

What are some next generation anti-EGFR therapies currently in trials and why do scientists hope they may be a significant improvement over current therapies?

Tom-runningpicDr. Tom Marsilje is a >20 year oncology research scientist with “currently incurable” stage IV colon cancer and also a Colon Club 2016 Colondar 2.0 model. As mentioned in his introductory post, he is a Ph.D. scientist and not an M.D. He exclusively gives his opinions on the “science” of experimental therapies – nothing written should be misinterpreted as implying medical advice. He is currently undergoing cetuximab therapy. Disclosure: Fight Colorectal Cancer has received funding from companies in the form of unrestricted educational grants, including targeted therapy manufacturers Bristol Myers-Squibb and Lilly – the producers of Erbitux and Amgen – the producer of Vectibix. We maintain ultimate authority over website content and the content written in this article.