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Targeting HPV-Transformed Cells

December 19, 2013

Electron micrograph of a negatively stained human papilloma virus (HPV)

Human papillomavirus (HPV)

An NIDCR-supported research team at the University of Iowa’s Carver College of Medicine has identified aptamers that can bind to tonsil cells transformed by human papillomavirus 16 (HPV-16), which is the cause of most HPV-related oral cancers. (See NIH/National Cancer Institute video on how HPV transforms cells.) Such aptamers could someday be developed into targeted therapies that seek out and attach to virus-induced proteins on the cell surface and then deliver a cancer drug that can turn off cancer growth or kill the oral cancer cells. Aloysius J. Klingelhutz, Ph.D., and coauthors said that they are the first to report finding aptamers that specifically attach to and internalize into HPV-transformed cells.

Because the conventional treatment for oral cancer can be disfiguring and can greatly diminish quality of life, researchers around the world are trying to design a drug that could target the cancer cells only and kill them, while sparing nearby healthy tissues. An aptamer is one of the options for targeted therapies. It can bind specifically to molecular targets, such as the changes on the cell surface made by HPV, and interfere with the function of its protein target, or it can be combined with a substance that does the interfering.

In the 1980s and 1990s, the first targeted drugs against diseases were protein-based antibody therapies. However, a therapeutic aptamer offers several advantages over antibody therapy. For example, because aptamers are a single chain of nucleic acids (the components of DNA) rather than made from protein, the immune system is far less likely to notice it and cause unwanted side effects, such as a life-threatening allergic reaction. A second advantage is a much smaller size. Aptamers have a far easier time flowing through the bloodstream and slipping inside the diseased tissues they were designed to target. Another important difference is that aptamers can be produced on a large-scale far more cheaply than antibodies.

Dr. Klingelhutz’s team found the aptamer they call C5 by screening a library of C5 schematicabout 10 trillion candidates. All of the candidates were first screened by challenging them with normal tonsil cells. The aptamers that bound to normal cells were eliminated as contenders because the idea was to find an aptamer specific for HPV-transformed cells, not one that attached to normal cells. Next, the researchers challenged the remaining aptamer candidates with the task of binding to receptors and internalizing, and they rinsed away the candidates that didn’t internalize. Round after round, they performed the same step to winnow down the candidates to the best internalizing aptamers. In the end, after 12 such rounds, they identified C5 as the best aptamer because it was 8 times more likely than the negative control aptamer to internalize into an HPV-transformed tonsil cell. In addition, C5 was 3 times better at internalizing into HPV-transformed tonsil cells than into normal tonsil cells.

The researchers don’t know yet whether the C5 aptamer could distinguish between healthy and HPV-transformed tonsil cells in a patient with oral cancer, and they acknowledge that higher specificity might be needed. Future studies could attempt to find aptamers with even greater ability to attach to and internalize into HPV-transformed cells.

Because obtaining adequate funding for research is more of a challenge now than ever before, Dr. Klingelhutz said that, “We decided to publish our aptamer sequences with the hope that someone else might be able to use the information in their research.” Dr. Klingelhutz said that if he obtains funding, he would like to develop a compound that could turn off the growth of HPV-related oral cancer cells by combining a cell-specific aptamer, such as C5, with a substance known as small interfering RNA (siRNA). The aptamer would help the siRNA get inside the cancer cells, and the siRNA would override the HPV signals that turned the cells into cancer.

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This page last updated: March 13, 2014