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Blocking cell surface expression of EGFR
By Dross at 2013-01-15 02:59
Blocking cell surface expression of EGFR

Shutting down a specific pathway in cancer cells appears to improve the ability of common drugs to wipe those cells out, according to new research from scientists at Fox Chase Cancer Center, published 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," says Igor Astsaturov, MD, PhD, Attending Physician in the Department of Medical Oncology at Fox Chase. "That's the long-term plan."

The new approach appears to enhance the tumor-killing ability of a commonly prescribed class of drugs that includes cetuximab (Erbitux), used to treat colorectal and head and neck cancers. These drugs work by blocking the activity of the epidermal growth factor receptor (EGFR), which sits on the cell surface and senses cues from the environment, telling cancer cells to grow and divide, says Astsaturov. "The whole mantra of modern day oncology is to suppress these inputs." Although EGFR inhibitors succeed in killing cancer cells, some malignant cells still find ways to evade the drug, and become resistant to treatment. Consequently, many researchers are actively looking for ways to kill these surviving cancer cells, annihilating tumors completely.

In 2010, Astsaturov and his colleagues identified a pathway in the cell that, when blocked, completely suppressed EGFR activity. Interestingly, the pathway consists of a series of enzymes that, when working in concert, synthesize new molecules of cholesterol, an essential component of the cell wall. This pathway is particularly important to cancer cells, which are constantly dividing and therefore need to produce more cholesterol for the new cells. Working with cancer cells in the lab, the researchers inactivated a key gene in the cholesterol synthesis pathway, and found the cells became more vulnerable to treatment with cetuximab. The same was true in mice that lacked this particular pathway, says Astsaturov. "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," he says. "The cancers literally melt away in mice." The researchers then removed one of the cholesterol genes from the mouse genome, and saw that mice developed patchy, scaly skin. When they biopsied this affected skin, they saw no activity of the EGFR protein, reaffirming that shutting down cholesterol synthesis interrupts EGFR. They also observed the same pattern in normal cell lines. When the cholesterol biosynthesis pathway is blocked, explains Astsaturov, the normal chain of events that creates a cholesterol molecule is interrupted, and cells accumulate intermediate products of cholesterol that block the normal movement of substances around the cell. This cellular traffic jam makes it difficult for the cell to transport important components, such as EGFR, which has to move between the inside of the cell and its surface to function properly. "If you disrupt this traffic, the cancer cells don't survive."

Eventually, says Astsaturov, researchers can design drugs or look for existing ones that block this cholesterol synthesis pathway. For now, his lab is trying to uncover more details of how the pathway works, the role of each protein that is involved and whether if, by blocking a protein, they can wipe out tumors in humans that evade current therapies. "These proteins represent targets for additional drugs, which could be combined with EGFR inhibitors," he says.



1 comment | 1683 reads

by gdpawel on Sun, 2013-01-27 12:31
The epidermal growth factor receptor (EGFR) is a widely expressed Ag that is successfully targeted in tumor patients by monoclonal antibodies (mAbs or moAbs) or tyrosine kinase inhibitors (TKIs).

There are lots of peculiar molecules that help cancer cells survive and grow. Block one pathway and another pathway steps in to take its place. Lots of money is being spent, lots of smart people are working real hard, but they are paddling upstream with a busted oar and not getting far. The bottom line is that the cancer cell is very complex and if a drug blocks one pathway of its growth, it can find a new route.

The complexity, redundancy and promiscuity of signal pathways has the capacity to salvage cancer cells from the lethal effects of EGFR inhibitors. Molecular pathways inside cells have an incredible amount of cross-talk. So blocking one molecule precisely is like keeping one person from talking and expecting that the rumor won't spread just as fast. They are doing genomic analyses which are not capable of reproducing this complexity, so they do clinical trials (trial-and-error).

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When chemotherapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what's observed with duel inhibitor combinations. The beauty of phenotype analysis is that it allows exploration of drugs and combinations that most clinicians wouldn't think of. It's these counterintuitive explorations that are leading to meaningful advances.

The EGFR Signaling Pathway

[url]http://cancerfocus.org/forum/showthread.php?t=3543

As an editor of the Journal of Medicinal Foods, Dr. Robert A. Nagourney has published and edited many articles. He has written that the most sophisticated Western medical centers, purveyors of allopathic medicine, spent decades denigrating natural products as quackery. Nutritional supplements, antioxidants and natural extracts were viewed as the purview of hippies and nuts. Yet, a brief examination of the most active compounds in cancer therapy today quickly establishes how wrong-headed this mindset was.

As Western scientists have developed a greater understanding of cellular circuitry and cancer metabolism, they have been dragged, kicking and screaming, to the admission that nature is indeed the best organic chemist.

Reports of the Chinese herb combination PHY906 are but the latest example of this reality. Careful analysis reveals PHY906 — a combination of four herbs — contains 64 compounds including flavonoids, saponins and monoterpenes.

The terpenes are among the most important and ubiquitous bioactive compounds found in nature, with effects on cholesterol metabolism, Ras gene signaling, and mitochondrial function. PHY906 is one more example of the adage that “there is nothing new under the sun.”

The National Foundation for Cancer Research announced that scientists at Yale University have proven what Chinese medicine practitioners have known for centuries – herb combinations can help heal cancer patients. More specifically, scientists have shown through phase I and II clinical trials that the herbal formula PHY906 reduces gastrointestinal side effects caused by chemotherapy treatments for colon and rectal cancer patients.

This 1,800-year-old formula is comprised of Chinese peonies, Chinese liquorice, fruit of the Chinese date tree and flowers of the Chinese skullcap plant. The combination works by restoring the fast growing intestinal cells that are the collateral damage of the chemotherapy. It allows the anti-cancer drugs to do the job with less compromise to healthy cells. Easing gastrointestinal symptoms help patients maintain hydration and nutrient intake; sustain a proper weight; and reduce inflammation and pain.

As Eastern and Western medical practices continue to intertwine, patients will realize the best outcomes. By incorporating natural supplements, diet and lifestyle changes, cancer patients can benefit from better health while minimizing the harmful side effects of increased medication.

[url]http://www.ncbi.nlm.nih.gov/pubmed/20720216

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