Protein “Switches” Designed to Transform Cancer Cells into Chemotherapy Factories

Scientists have devised a protein “switch” that instructs cancer cells to manufacture their own anticancer chemotherapy.

In lab tests, the researchers, from Johns Hopkins University (Baltimore, MD, USA), demonstrated that these switches, working from inside the cells, can activate a powerful cell-killing drug when the device identifies a marker linked to cancer. The goal, the scientists said, is to deploy a new type of weapon that causes cancer cells to self-destruct while sparing healthy tissue.

This new cancer-fighting strategy and promising early lab test results were reported in September 2011 in the online early edition of Proceedings of the [US] National Academy of Sciences. Although the switches have not yet been evaluated on human patients, and much more testing must be done, the researchers reported that they have taken an exciting first step toward adding an innovative weapon to the difficult task of treating cancer.

One key problem in fighting cancer is that broadly applied chemotherapy usually also harms healthy cells. In the protein switch strategy, however, a physician would instead administer a “prodrug,” meaning an inactive form of a cancer-fighting drug. Only when a cancer marker is present would the cellular switch turn this harmless prodrug into a potent form of chemotherapy.

“The switch in effect turns the cancer cell into a factory for producing the anticancer drug inside the cancer cell,” said Dr. Marc Ostermeier, a Johns Hopkins chemical and biomolecular engineering professor in the Whiting School of Engineering, who supervised development of the switch. “The healthy cells will also receive the prodrug and ideally it will remain in its nontoxic form. Our hope is that this strategy will kill more cancer cells while decreasing the unfortunate side effects on healthy cells.”

To establish that these switches can work, the research team effectively assessed them on human colon cancer and breast cancer cells in Dr. Ostermeier’s lab and in the laboratory of Dr. James R. Eshleman, a professor of pathology and oncology in the Johns Hopkins School of Medicine. “This is a radically different tool to attack cancers,” said Dr. Eshleman, a coauthor of the PNAS journal article, “but many experiments need to be done before we will be able to use it in patients.

The next step is animal testing, expected to begin within one year, according to Dr. Ostermeier. His team made the cancer-fighting switch by fusing together two different proteins. One protein detects a marker that cancer cells produce. The other protein, from yeast, can turn an inactive prodrug into a cancer-cell killer. “When the first part of the switch detects cancer, it tells its partner to activate the chemotherapy drug, destroying the cell,” Dr. Ostermeier stated.

In order for this switch to work, it must first get inside the cancer cells. Dr. Ostermeier reported that this could be done through a technique in which the switch gene is delivered inside the cell. The switch gene serves as the blueprint from which the cell’s own machinery constructs the protein switch. Another strategy, he said, would be to develop methods to deliver the switch protein itself to cells. Once the switches are in place, the patient would receive the inactive chemotherapy drug, which would turn into a cancer attacker inside the cells where the switch has been turned on.

Although many researchers are developing methods to deliver anticancer drugs specifically to cancer cells, Dr. Ostermeier noted that the protein switch approach avoids problems encountered in those methods. “The protein switch concept changes the game by providing a mechanism to target production of the anticancer drugs inside cancer cells instead of targeting delivery of the anticancer drug to cancer cells,” he said.

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