Strong Medicine for Cancer
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Cancer researchers (left to right) John Trent and Paula Bates, along with Donald Miller, discovered new compounds called GROs that promise to target and destroy cancer while not harming normal cells. The first human trial of a GRO, AGRO100, began this past fall in Louisville.
Call it luck, serendipity, accident.
Whatever it's called, it's still one of science's best friends.
U of L cancer researchers Paula Bates, Donald Miller and John Trent can attest to that. The team has discovered what promises to be a powerful new weapon in the war on cancer.
As part of their basic cancer studies, Bates, Miller and Trent were looking for short DNA strands that would bind to particular gene sequences. In the process they noticed that the control sequence, which was supposed to have no effect, was quite effective at stopping the growth of prostate cancer cells.
That was in 1997. Now, in 2003, the team at U of L's James Graham Brown Cancer Center has received approval to test its discovery on human subjects. The new cancer treatment, referred to as AGRO100, was approved by the Food and Drug Administration for Phase I clinical trials and administered to the first person in August. It is the first human trial of one of a group of new compounds known as guanine-rich oligonucleotides (GROs), discovered by Bates, Miller and Trent.
"One of the reasons that we are so excited about the potential of these GROs is that they work by a new mechanism that is completely different from other agents currently used to treat cancer," Bates explains. "These compounds are very effective in blocking the growth of cancer cells but have little effect on the growth of normal cells."
Bates says the therapeutic potential of GROs is great.
"It seems to work against many cancers," she says. "We've been looking particularly at prostate, lung, breast cancer and leukemia, but it's worked in almost every type of cancer we've tested in cell cultures."
The commercial potential of the therapy also is promising.
GRO compounds are some of the technologies being developed by Aptamera, a Louisville biotechnology company founded by Bates, Trent and Miller. In 2002 Aptamera was one of the first entrepreneurial concerns to receive funding from Minerva Ventures, a venture capital fund started to nurture and invest in U of L entrepreneurs. U of L's board of trustees approved Minerva Ventures in 2001. By charter, Minerva Ventures can invest only in entities that are affiliated with U of L faculty, staff, students or alumni or in other activities of the university.
GROs' ability to specifically target cancer cells could represent a major advance in cancer therapy, the researchers say.
According to Bates, most chemotherapy agents currently in clinical use are non specific—that is, they kill normal cells in addition to cancerous ones.
"They are especially toxic to fast growing cells such as hair follicles and cells in the gut, which leads to unpleasant side effects including hair loss and nausea," she explains.
"The unique thing about this GRO is that it's cancer selective," Trent says. "It selects cancer cells over normal cells, which should reduce side effects."
GROs are unusually stable short synthetic pieces of DNA that bind tightly to a specific protein found on the surface of cancer cells, interfering with tumor growth. Unlike traditional chemotherapy agents, the GRO leaves normal cells alone and seeks only the specific shape of a protein called nucleolin, which is present in high concentrations on the surface of many types of cancer cells.
What the group has shown in the lab and hopes to demonstrate clinically is that AGRO100 binds to the nucleolin on the cell surface, which causes it to be internalized into the cancer cell where it inhibits division and leads to the cell's death.
"If we can determine that the drug is safe, effectively stunts tumor growth and causes fewer unpleasant side effects for the patient, we will have won a significant battle in the war on cancer," says Damian Laber, a U of L medical oncologist and the trial's principal investigator.
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Donald Miller, along with John Trent and Paula Bates, discovered new compounds called GROs that promise to target and destroy cancer while not harming normal cells. The first human trial of a GRO, AGRO100, began this past fall in Louisville.
The trial also marks a significant milestone for the university.
"This trial represents many of the great things happening at the James Graham Brown Cancer Center and U of L," says Miller, director of the center. "The swift movement of this compound from the research lab to the clinic and to the bedside is exactly the type of research outcome for which we strive.
"That we're able to do all of this in Louisville, thereby helping to support the local economy, is an added bonus."
The scientists praise the high-tech research capabilities of the Brown Cancer Center.
"We're using molecular modeling and NMR (nuclear magnetic resonance) imaging," Trent explains. "You need to understand more than the structure of something—but how it works, too— before you can stop it."
With the clinical introduction of a new therapy successfully under way, one might assume that it is a perfect time for the AGRO100 research team to rest a bit while initial clinical data is gathered.
According to Bates, however, the opposite is true.
"We are continuing to research AGRO100 and nucleolin, the protein it targets," she says. "By understanding the structures of AGRO100 and nucleolin we hope to be able to design new drugs that work in a similar way but that may be even more active. By studying how cancer cells behave differently than normal cells, we also hope to identify new molecular targets for cancer."
The University of Louisville Research Foundation and Miller hold a financial interest in Aptamera. Multiple steps to ensure patient protection and research integrity have been taken consistent with the university's policy for oversight of institutional financial interests in research.
