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Scientists Find New Way to Boost Cancer Drugs

Blocking cellular pathway makes it easier for drugs to destroy tumors (Jan. 14)

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 the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

The new findings were 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,” said Igor Astsaturov, MD, PhD. “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, Bristol-Myers Squibb), which is used to treat colorectal and head-and-neck cancers. These drugs work by blocking the activity of the epidermal growth factor receptor (EGFR), which is located on cell surfaces and senses cues from the environment, telling cancer cells to grow and divide, according to Astsaturov. “The whole mantra of modern-day oncology is to suppress these inputs,” he said.

Although EGFR inhibitors succeed in killing cancer cells, some malignant cells still find ways to evade the drug and become resistant to treatment. Consequently, researchers are looking for ways to kill these surviving cancer cells and thus annihilate tumors completely. In 2010, Astsaturov and his colleagues identified a pathway in cells 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 laboratory, the researchers inactivated a key gene in the cholesterol synthesis pathway and found that 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 remarked. “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 found 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, which 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,” Astsaturov said.

Eventually, researchers can design drugs or look for existing ones that block this cholesterol synthesis pathway, according to Astsaturov. For now, however, 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 destroy tumors in humans that evade current therapies. “These proteins represent targets for additional drugs, which could be combined with EGFR inhibitors,” he says.

Source: Fox Chase Cancer Center; January 14, 2013.

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