A new drug, developed after years of work by two Hopkins scientists, specifically targets prostate cancer cells, gets inside them, and sabotages their ability to repair DNA damage, so that they are more likely to be killed by radiation therapy.
Idea One: Stop Cancer Cells from Repairing Themselves
The drug is a combination of two ideas, begun in separate labs by Theodore L. DeWeese, M.D., Professor and Chairman of Radiation Oncology and Molecular Radiation Sciences, and Shawn Lupold, Ph.D., the Phyllis and Brian L. Harvey Scholar. About seven years ago, DeWeese was the first to describe the use of a substance called a “small interfering RNA ,” or siRNA , to hinder a prostate cancer cell’s ability to repair DNA damage. “An siRNA is a tiny molecule made up of ribonucleic acid (RNA ), arranged in a very precise and specific manner,” DeWeese explains. Once they’re made, siRNA s can be put into cells to target another type of RNA in the cell, called messenger RNA ; this is the molecule that serves as the cell’s “how-to guide” for making proteins, including proteins that repair DNA damage from radiation.
Cancer cells are like roaches; they
can hide anywhere, and even though
they don’t scurry away when you
turn on the light, it’s similarly hard to
spot and kill them all.
“It’s fascinating to see how the siRNA and messenger RNA work together; they link up tightly and specifically, like a zipper,” says DeWeese. “Together, they tell the cells to destroy the messenger RNA , and this stops the machinery from repairing DNA damage.” In published work, DeWeese’s group reported that putting these siRNA s into prostate cancer cells made them about twice as sensitive to radiation.
Idea Two: Give Cancer Cells Nowhere to Hide
Cancer cells are like roaches; they can hide anywhere, and even though they don’t scurry away when you turn on the light, it’s similarly hard to spot and kill them all. If only we could shine a spotlight on them, so they had nowhere to hide. Lupold has done this, in a highly sophisticated way, at the molecular level. Several years ago, Lupold began developing and testing molecules called aptamers for cancer cells. Aptamers are also small bits of RNA , but unlike the siRNA s DeWeese makes, Lupold’s molecules act as targeting beacons — tiny spotlights — that seek out cancer cells and stick to targets on their surface. Think of paintball, on a tiny scale. Aptamers don’t treat the cancer, but they target the heck out of it, so that other forms of treatment can aim and fire at these cells only, and minimize damage to normal tissue. Lupold began working on these aptamers when he was a student in the lab of Donald S. Coffey, Ph.D., the Brady’s renowned research director for many years. Lupold, DeWeese notes, “was the first to show that his aptamers would specifically bind to the PSMA (prostate-specific membrane antigen) on the surface of most prostate cancer cells, and do so in manner that would carry the aptamer inside the cancer cells. His aptamers are so good at binding PSMA that multiple investigators around the world have been using them in their own research, as a way to very specifically target and deliver agents to and inside prostate cancer cells and tumors.” A few years ago DeWeese and Lupold joined forces to make and test a new drug that combines an aptamer with siRNA drug. They have done this, with promising results. “The result is prostate-specific,” says Lupold, “making these cells much more sensitive to radiation.” Also lending their expertise to this project are scientists Xiohua Ni, Ph.D., and Yonggang Zhang, M.D. They have shown that the combined drug can be made successfully, that it can target PSMA on prostate cancer cells, that siRNA can be sent like a PSMA seeking missile to the cell and that, once it gets inside, that it can disrupt the DNA damage- control system.
Think of paintball, on a tiny
scale. Aptamers don’t treat the
cancer, but they target the heck
out of it, so that other forms of
treatment can aim and fire at
these cells only, and minimize
damage to normal tissue.
Most recently, in mice, the team has demonstrated that the combined drug makes the prostate cancer cells dramatically more sensitive to radiation, and that it provides substantial, long-term control of human prostate tumors. “Also,” says DeWeese, “treatment of human prostate tissue with the new aptamer-siRNA agents, immediately after radical prostatectomy, results in a notable decrease in DNA repair proteins.” Thus, the drug is working well both in pre-clinical models and in clinical samples.
Where do they go from here? DeWeese and Lupold are excited about their results, and are moving toward a clinical trial of their drug. They are also conducting further tests in animals to see how well the drug targets prostate cancer cells when it is administered intravenously, with the hope that this will prove a new method of sensitizing metastatic prostate cancer cells to both chemotherapy and radiation.