A Traffic Cop For Stopping Cancer Cells?
January 15, 2013

Study Finds Blocking Pathway Allows Easier Elimination Of Cancer Tumors

Connie K. Ho for redOrbit.com — Your Universe Online

Researchers from the Fox Chase Cancer Center recently discovered a novel method of improving cancer drugs, where they could block a specific pathway in the cell and provide an easier way for drugs to eliminate tumors.

According to the American Cancer Society, cancer occurs when there is uncontrolled growth and expansion of abnormal cells. It is caused by external factors (such as chemicals, infectious organisms, radiation, and tobacco) along with internal factors (inherited conditions, immune conditions, hormones, and mutations due to metabolism). The findings of the study on pathway blockage were recently featured in the January issue of Cancer Discovery.

"Ideally, this research will eventually enable scientists to find drugs that disrupt this pathway and boost the impact of current therapies," remarked Dr. Igor Astsaturov, an attending physician who serves at the Department of Medical Oncology at the Fox Chase Cancer Center, in a prepared statement. "That's the long-term plan."

The scientists believe that this new way seems to be able to increase the ability of drugs, such as the commonly prescribed cetuximab (Erbitux) that has been utilized in colorectal, head, and neck cancer treatments in eliminating tumors. Normally, these drugs stop the activity of the epidermal growth factor receptor (EGFR). EGFR is found on the cell´s surface and picks up signals from the environment, alerting the cancer cells on dividing and growing. EGFR inhibitors work to kill cancer cells.

"The whole mantra of modern day oncology is to suppress these inputs,” continued Astsaturov in the statement.

However, the EGFR inhibitors are not always successful and some malignant cells can resist treatment when they find ways of averting the drug. As such, many investigators are still searching for ways to eliminate these surviving cancer cells which could help remove the tumors completely. This group of scientists first made a breakthrough in 2010 when they found a pathway in the cell that could be shut down, causing a suppression of EGFR activity. That particular pathway is made up of a series of enzymes that can produce new molecules of cholesterol when working together. In particular, cancer cells need to produce cholesterol for new cells and so the pathway is important in this process of cholesterol production.

When the scientists observed cancer cells in the study, they were able to inactivate an important gene in the cholesterol synthesis pathway. This led to the discovery that the cells were more susceptible to a treatment that included cetuximab. Furthermore, the mice that did not have this specific pathway also became more vulnerable to the cetuximab treatment.

"Most tumors are only moderately sensitive to inhibitors of EGFR, but when these tumors lack an essential gene in the cholesterol pathway, they become exquisitely sensitive to the anti-EGFR drugs," noted Astsaturov in the statement. "The cancers literally melt away in mice."

During the study, the mice developed patchy, scaly skin when the researches took out one of the cholesterol genes from the mouse genome. A biopsy of the patchy skin revealed that there was no activity of the EGFR protein. The results of the study demonstrated that stopping cholesterol synthesis could also limit EGFR. With the blockage of the cholesterol biosynthesis pathway, the production of the cholesterol molecule is halted and cells begin to accumulate intermediate products of the cholesterol. As a result of this stoppage, the cancer cells cannot easily transport important elements, like EGFR, which has to move between the inside of the cell and its surface to work correctly.

"If you disrupt this traffic, the cancer cells don't survive," explained Astsaturov in the statement.

Based on the findings, the team of investigators believes that they can one day create drugs or possibly explore available drugs that can shut down this cholesterol synthesis pathway; they are planning to continue to study how the pathway works and how each protein functions.

"These proteins represent targets for additional drugs, which could be combined with EGFR inhibitors," concluded Astsaturov in the statement.

This study is done at a particularly crucial time, as cancer is considered the second most common cause death in the U.S. by the American Cancer Society. The number of deaths related to cancer is exceeded only by heart disease. In 2012, approximately 577,190 Americans were predicted to die of cancer.