A New Genetic Target for Preventing Tumor Growth

Shawn Lupold
Shawn Lupold

Twenty years ago, scientists considered RNA (ribonucleic acid) to be mainly a genetic middleman. DNA was the big attraction — the Oxford English Dictionary of genetics, the ultimate reference book in the human library, says Shawn Lupold, the Phyllis and Brian L. Harvey Scholar. The transfer of information in the cell goes from DNA, which is in the cell's nucleus, to RNA. Like a town gossip, RNA then gets very busy, taking the information to machinery that makes proteins, and then on to the newly synthesized proteins, which do the work of the cell. But RNA has other roles, too, scientists have discovered, far beyond acting as a messenger, says Lupold. His research largely focuses on RNA, how it works in prostate cancer, and its potential usefulness in diagnosing or even treating the disease.

Several years ago, scientists discovered that cells naturally copy bits of RNA, which then can turn off, or inhibit, other bits of RNA; this is known as "RNA interference," and the RNA — so good at spreading messages — can block them, too, short-circuiting the transfer of information from DNA to protein. "In other words, this is a newly discovered off-switch for cellular pathways," says Lupold. "Not surprisingly, cancer cells take advantage of this pathway for their own growth and survival by turning off growth inhibitory pathways." In a new study done in Lupold's laboratory, Judit Ribas, Ph.D., wanted to know if androgens (the same male hormones that drive the growth of prostate cancer) control these inhibitory RNAs, known as microRNAs, in prostate cancer. "We found that one microRNA, called miR-21, was directly activated by the androgen signaling pathway," Lupold continues. "When miR-21 is expressed at higher-than-normal levels, it turns off unknown growth-inhibitory pathways and makes prostate cancer cells and tumors grow more rapidly. Importantly, we found that just having an elevated level of miR-21 was suffi cient to generate hormone-refractory prostate cancer," advanced cancer that no longer requires androgens to grow. This work, published in September in Cancer Research, was funded by the Patrick C. Walsh Prostate Cancer Research Fund and the Department of Defense. Lupold and colleagues are studying miR-21 to see if it is an early marker for aggressive prostate cancers. "We're also interested in developing miR-21 inhibitors for the treatment of advanced prostate cancers."

Just having a higher level of
miR-21 could create advanced
cancer that no longer needs
hormones to grow.

In another RNA-related project, Lupold and colleagues are investigating the use of certain RNAs as a way to make cancer cells more susceptible to radiation. Xiaohua Ni, Ph.D., a fellow in Lupold's laboratory, is using synthetic "small interfering RNAs," known as siRNAs, to inhibit target messenger RNAs inside the cell, using the same interference pathway favored by microRNAs. Ni is working with Theodore L. DeWeese, M.D, Chairman of Radiation Oncology and Molecular Science. "Cancer cells become highly sensitized to radiation therapy when the cells' DNA repair machinery is inhibited," notes Lupold. "The idea is that with these siRNAs, we can selectively inhibit DNA repair genes and allow physicians to use lower levels of radiation while achieving the same or greater therapeutic effect. If we can selectively target these siRNAs to the prostate, we can reduce the risk of radiation damage to normal tissues, while effectively killing the prostate cancer cells."

To help these siRNAs target specifi cally on prostate cells, the investigators are turning to RNA in yet another form, called RNA aptamers — unique molecules that bind to a target, much like an antibody. RNA, like DNA, is like a twisting railroad track, made up of four building blocks called A, G, C, and U. The sequence of these blocks transmits the genetic code, and also determines how the RNA folds into a three-dimensional shape. Using technology called SELEX, Lupold and colleagues can identify RNA aptamers that bind to particular molecules, including proteins found in cancer. They have screened thousands of different RNA aptamers, and found two that bind to a cell surface protein on prostate cancer cells called PSMA (Prostate Specific Membrane Antigen). "These RNA aptamers can be synthesized and chemically connected to nanoparticles, drugs, and even siRNAs," says Lupold. "They not only attach themselves to prostate cancer cells, but they can enter and deliver the therapeutic package inside the cell." Several labs have used the Lupold lab's aptamers to generate new experimental agents for the treatment and imaging of prostate cancer. "We are currently using the aptamers to selectively deliver our radiationsensitizing siRNAs to prostate cancer cells," says Lupold. "In our collaboration with Radiation Oncology, we hope to translate these aptamer-siRNA therapeutics for clinical trials in the next few years." In the large multidisciplinary effort known as TEMT (for Temperature Enhanced Metastatic Therapy; click here for details), Lupold and colleagues are using the aptamers to target iron-oxide nanoparticles to prostate tumors. This project, led by Robert Getzenberg and DeWeese, uses magnetic frequencies to heat these nanoparticles in order to make tumors more sensitive to radiation and chemotherapy. In these and other RNA-based projects, Lupold says, "we hope to learn more about how prostate cancer becomes aggressive, how we can identify the aggressive form, and how we can better treat it."

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