PROTEIN TRANSDUCTION: - Moores Cancer Center

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SPECIAL DELIVERY: Supersize Cargoes Pack Big Molecular V Punch irtually all drugs that carry out their healing mission inside of cells are comprised of small molecules. Not because small molecules make the best drugs, but because the cell only allows small molecules to penetrate the pores of its protective cell membrane. Now a team of Cancer Center researchers led by Steven F. Dowdy, Ph.D., is rewriting the laws of pharmacology with the development of a method to slip large, informationrich molecules such as enzymes and proteins past the cell’s membrane. The team’s technique for inserting molecules hundreds of times larger than previously thought possible is called protein transduction. It is the foundation of an entirely new field of study that in the last four years has exploded, with more than 1,000 laboratories around the globe now conducting research based upon Dowdy’s method. He and colleagues wrote two landmark papers in 1999 proving the principle that you could ferry large molecules through the cellular membrane and have Steven Dowdy (center) reviews lab images with graduate students (l-r) Eric Snyder, Courtney Havens and Bryan Meade. Above right: A mouse model of human ovarian cancer provides a dramatic illustration of protein transduction. Fifteen minutes after injection of a peptide (green), most cells in the abdominal cavity, where ovarian cancer cells have invaded, have taken up the peptide. them intact and functioning inside the cell. This is done by chemically snipping out a particular segment of a protein. The segment, called a protein transduction domain (PTD), is positively charged. The surface of the cell, any cell, is negatively charged. When the PTD comes in contact with the cell membrane, the two interact in a powerful fashion, tethering securely the PTD and its large-molecule cargo. “Then,” said Dowdy, a 43-year-old molecular oncologist, “the magic happens — that hulking cargo crosses the cell membrane. We don’t yet understand exactly how that happens.” But why is this generating so much excitement among scientists Is it simply interesting molecular acrobatics Far from it, according to Dowdy, who is also an investigator of the Howard Hughes Medical Institute’s group Cancer Center News 4
“ at UCSD. The larger molecules contain much more information — instructions that could be the basis for new drugs that would be more specific in their function, meaning they would work at smaller doses and have fewer side effects. “I like to use the analogy of a house with a mail slot,” says Dowdy. “The small molecule is the equivalent of a single-page letter. It can go in easily, but contains limited information. In contrast, with protein transduction we can put a computer through the same mail slot, have it reassembled on the other side, and get vastly more information inside the house, or cell, than ever before.” Based on his work to date, and the work now of many others, it appears that virtually every chemical structure can utilize this approach — nucleic acids, proteins, peptides, synthetic molecules, carbohydrates and more. “So now, in theory, scientists could redesign the existing smallmolecule drug libraries to these larger size molecules and add much more specific information,” he said. “This could represent an entirely new approach to treating disease; not only cancer, but others ranging from heart disease to headaches and the common cold.” Dowdy acknowledges that the field has not yet matured enough to know exactly how well this will work in practice. Nevertheless, the field is moving forward rapidly and the preclinical work in animals looks very promising. His own laboratory is focusing on using protein transduction for cancer. He and his colleagues have Protein transduction is like putting a computer through a mail slot. We can get vastly more information inside the cell than ever before. — Steven Dowdy, Ph.D. ” been working to introduce tumor suppressor proteins, such as the p53 protein, into mice whose cells have lost this function. They are working with two mouse models of cancer. One type develops peritoneal malignancies, such as ovarian or pancreatic cancer, and the other develops lymphoma. “About 50 percent of the mice we’ve treated, all with aggressive and terminal disease, have achieved long-term survival,” Dowdy said of the work that has not yet been published. “However, doing this in a mouse is a long way from doing it in a human. Still, we’ve shown that we can reconstitute tumor suppressor function and stop the cancerous process in models that closely mimic human disease.” If his results continue to hold up over time, the next step would be to move this work into clinical trials, which Dowdy says is still several years away. Dowdy’s laboratory is also looking to develop new molecules that could be tailored to the job at hand. By attaching multiple cargo domains to the PTD, like cars to a train, he hopes to build highly selective, composite molecules. An example of the potential utility of this approach is found in doxyrubicin, a widely used anticancer drug. “Doxyrubicin is a great drug, but it is susceptible to a protein called p-glycoprotein, which acts like a pump in the cancer cell to push the drug out. This problem is often worse in late-stage and recurrent disease,” said Dowdy. “With our transducible approach, we could, theoretically, add modules that would enable us to selectively bypass the p-glycoprotein and deliver the drug directly to the nucleus in tumor cells and not the normal cells.” Dowdy also said it would be possible to add an imaging compound to a drug warhead and “simultaneously image the death of the tumor, which would give us an idea of how well the drug is working.” By adding these layers of selectivity, the theory goes, one can get further and further discriminations to hit the bull’s eye of the tumor while sparing the surrounding normal cells. “This is the ultimate goal,” he said. “It may be optimistic at this point, but I believe some form of this modular approach will be able to move forward and will give us the kind of selectivity and versatility that small molecules simply are not capable of providing.” —Nancy Stringer, Director, Cancer Center Communications 5 Cancer Center News
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PROTEIN TRANSDUCTION: - Moores Cancer Center

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