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DR. DALE NAGLE - University of Mississippi, Oxford
The Research: Getting Specific--Screening Algae and Cyanobacteria for More Targeted Cancer Drugs
Like his mentor, William Gerwick ,
Dale Nagle is a natural products chemist that focuses on identifying compounds from
algae and cyanobacteria with therapeutic potential, particularly in treating cancer.
He has conducted fieldwork around the world and screened countless extracts. Whereas
anti-cancer research has traditionally focused on compounds toxic to cancer cells,
Nagle currently focuses on the development and use of novel screening assays to
identify products that incapacitate genes that tumor cells rely on for growth and
survival. The goal of this approach is to discover new drugs that target cancer cells
more specifically compared to treatments now in use or in development. Existing drugs
are typically toxic to cancer cells but also to varying degrees other types of cells,
leading to harmful side effects.
 - VIDEO CLIP 1: "Research Interests of the Nagle Lab"
 Suffocating Tumors Instead of Poisoning Them
For decades, much of natural products research, both terrestrial and marine, has focused on the discovery
of agents that kill tumor cells, rather than attacking the tumor as a unit. Because other types of cells
are also affected, many cancer drug therapies have harmful, even deadly side effects. Hair loss associated
with chemotherapy is a result of this problem because cytotoxic compounds are often deadly to hair cells as well.
Rather than focusing on toxicity, one of the novel assays Nagle and his colleagues have developed tests
for products that attack a tumor's critical ability to adapt to low oxygen concentrations. As tumors grow,
their oxygen demands typically outstrip the supply of oxygen available to them from surrounding blood
vessels. Nonetheless, the tumor cells adapt to this lower oxygen availability such that they can continue
to thrive. Nagle's team has designed a reporter system that targets hypoxia inducible factor (HIF1), one
of the genes responsible for this adaptive capability in tumors. Reporter systems are genetic sequences
that match the sequences of target genes but that also include coding information for products that give
off light, such as luciferase, an enzyme responsible for a firefly's light. If the gene or genes in question
are turned "on", meaning they are producing proteins, the reporter system is also expressed, leading to the
production of, in this example, luciferase, which can be easily observed as an indicator a gene is turned on.
The goal for potential treatments is to find products that suppress, or turn off, the gene. So, Nagle's group
places tumor cells in low-oxygen conditions then applies sample extracts to identify those that contain compounds t
hat turn off the hypoxia inducible factor, which should kill them. The work has been done primarily with breast
cancers. Using this technique, the team has screened thousands of extracts and purified compounds, both from samples
they have collected themselves, and also from the National Cancer Institute's repository of marine organisms.
More recently, with funding from the Department of Defense Biomedical Research Unit, the Nagle team has been
using the same basic screening technique in pursuit of potential prostate cancer treatments. They have, with
interesting results, been comparing the response of prostate cancer cells in the assay to results with breast
cancer cells. The same natural products have in some cases elicited different responses from breast and prostate
tumors, with one at times showing more sensitivity to specific compounds than the other. "I think we're seeing
some evidence that multiple targets are probably necessary to really get a full picture of what's going on,"
says Nagle, in light of the fact that cancer treatment research has often been focused on a single target.
- VIDEO CLIP 2: "Reporter Systems in Gene Activity Monitoring"
- VIDEO CLIP 3: "Extract Screening, the HIF1 Gene, and Work With Different Tumor Cell Lines"
Trying to Hit PPAR
Another innovative route Nagle and his team are exploring to identify possible new cancer treatments has its
roots in a popular treatment for adult onset diabetes. Thiazolidinediones are a class of drugs that bind with
molecules known as peroxisome proliferator-activated receptors (PPAR). This binding causes up-regulation of,
or increased production of proteins coded by, certain genes that reduce resistance to insulin. Years ago
researchers discovered that in some cases a by-product of this PPAR up-regulation led to breast tumor cell death.
Nagle is screening both marine and terrestrial natural products, in search of new classes of PPAR-targeting
compounds that might serve as prototypes for drugs that could activate PPARs to cause certain types of tumors
to regress or their cells to undergo programmed cell death.
The Life Aquatic
Nagle's past collection fieldwork locations have included Japan's Okinawa, several Canadian sites, Florida,
Jamaica, various parts of Micronesia, including Guam, Saipan, Yap, Truk (also known as Chuuk), and Palau,
and even Pohnpei. More recently, he and his colleagues have begun sampling aquatic plants from swamps and
wetlands both because these organisms' natural products have seldom been studied, and because Oxford, Miss.
is many hours from an ocean. This aquatic work has already led to promising leads, says Nagle, including
the discovery of the most potent hypoxia inducible factor inhibiting compound yet known. The compound is
already being tested in animal models to explore its commercial potential.
- VIDEO CLIP 4: "All Over The Map: Oregon,
Guam...and Inland Mississippi?"
Fending Off the Men in Gray Suits and Dodging Snakes
"We've had some pretty memorable experiences," says Nagle. One of his most memorable underwater experience was
working in Micronesia's famous Truk Lagoon, the famous resting place of countless World War II airplane, ship
and other wrecks. Sadly for Nagle (and the reefs), the area where he and his colleagues were collecting samples
was a popular sight among locals for dynamite fishing, a practice that inevitably ended up producing quick and
easy meals for sharks. As a result, the sharks began to associate boats with free food. The sharks were so common
that Nagle and his sampling partner had to work back to back with one collecting samples and the other punching
approaching sharks in the nose to fend them off and hopefully get across the message that it was not feeding time.
"They were very curious," says Nagle, "a little bit too much so."
With his new aquatic species work, new threats have emerged, namely snakes such as the potentially deadly snake
known as a cottonmouth or water moccasin. Nonetheless, Nagle counts sunburn his greatest threat. "I feel as along
as I don't step on them, the snakes usually don't bother me.
- VIDEO CLIP 5: "Adventure in Field Collection:
You Watch for Sharks and I'll Grab the Sponge"
Summer Love
Nagle first became interested in natural products while a pharmacy student at Oregon State University. One summer
"as a way to make a little money and to do something outside of taking classes" he spent a summer working in Bill
Gerwick's laboratory. He became so fond of the field that summer that once he completed his pharmacy training he
decided to stay at Oregon State to get a Ph.D. under Gerwick working with anti-tumor and other bioactive compounds
from algae and cyanobacteria. From there Nagle moved all the way to the University of Guam's marine laboratory,
where he worked with Valerie Paul and his research took on a more biological focus. With Paul, he studied the
possibility that certain cyanobacteria can produce noxious compounds that ward off fish that might otherwise graze
on them. This could allow species to bloom whose growth might otherwise be kept in check. Nagle also explored how
some marine organisms have developed specialized eating habits based on the chemicals in certain prey. To move
further in the biomedical direction, he went from Guam to a stint at the University of Texas at Southwestern
Medical Center in Dallas and began studying how small molecules can regulate gene function. After that, he moved
to his current professional home at the University of Mississippi.
- VIDEO CLIP 6: "Educational Background"
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