Paul Hergenrother: Finding New Targets by Way of Novel Pathways
While there are thousands of drugs on the market for human diseases, they only hit in the neighborhood of 200 targets, says Paul Hergenrother, professor of chemistry and a member of the Cellular Decision Making in Cancer (CDMC) Theme at the IGB. Many drugs aim at the same target and are either minor improvements or work in a different way. And, while there is some rationale for developing new drugs for old targets, Hergenrother has an entirely different goal.
“To make a large advance in therapy you need to find new targets,” Hergenrother says. And to do that his group “explicitly tries to think about novel pathways and novel ways of targeting proteins inside the cell.”
Hergenrother makes finding new targets sound straightforward, but it is rather like seeking, if not a needle in a haystack, then at least a pincushion’s worth of needles in a haystack — one reason drug companies do not undertake the effort. Tools like the University’s high-throughput facility, which Hergenrother helped create, help make such an undertaking possible. These kinds of projects also require large applications of time and resources. Hergenrother has a lab of more than two dozen, including 16 graduate students, 4 post-docs and 10 undergraduates.
As one of the driving forces in the development of the new CDMC theme, Hergenrother is particularly interested in various cancers, though his work also has potential for drug-resistant bacteria and neuro-degeneration. Because there are countless complex mechanisms by which cancers arise, this line of inquiry presents a particularly exciting challenge for investigators like Hergenrother.
“A growing area of interest in our laboratory is the development of strategies in which we exploit defined molecular defects in cancer to specifically kill these cells,” he says.
One such complex mechanism is apoptosis, programmed cell death. In many cancers apoptosis has been inactivated, leading to unregulated cell proliferation, while in neuro-degenerative diseases, apoptosis has been revved up, attacking healthy cells. In either case, understanding the underlying mechanisms of how cells behave is essential to making large advances against disease.
Hergenrother has two general approaches: one method is to understand the role of certain proteins in a pathway that leads to cancer and to then determine the effect of switching off or on a given protein. His lab then screens for compounds that can control that switch. The other approach is to test compounds on cancer cells and look for compounds that do “interesting” things, like induce death very fast or under hypoxic conditions, similar to conditions in which a cancer cell grows. Then his team works backwards to find the target that the compound is acting on.
In the context of this first approach, Hergenrother’s lab has taken a massive library of compounds housed at the University of Illinois and, using the high-throughput facility, screened many of the compounds to determine their effect on a protein, procaspase-3, which is involved in apoptosis. In cancers like lymphoma, the ability of this protein to kill cells is somehow turned off, despite the fact that the protein is upregulated in the presence of lymphoma. Hergenrother’s lab has both identified a compound, PAC-1, that reactivates the function of procaspase-3 and determined the mechanism by which procaspase-3 was being inhibited.
Of course the journey from the lab to the clinic can be a long one. His lab tested the compound in a test tube, then in cell culture and then in mouse models. In the course of this work they developed more than 50 derivatives of the compound, continually working to make it both safer and more effective. When the results looked promising Hergenrother moved up to a small trial in pet dogs, in collaboration with Tim Fan, professor of veterinary clinical medicine. Dogs are a good model because they develop lymphoma spontaneously and systemically, as do humans. This is different from the standard mouse model of cancer, where lab mice are injected with cancer cells and then treated with drugs.
The canine trial was concerned with determining both a safe dose and the most effective delivery system, whether via IV or injection, or orally. These experiments are complicated by the size of the patients, which can be as large as a 220-pound Mastiff, which required multiple grams of the compound. In the mouse trial, the mice themselves weighed only 40 grams, notes Hergenrother.
In dogs, lymphoma is very fast growing, doubling in size within four or six weeks. Investigators hoped that this trial might buy the dogs a little more time, and the results were encouraging. Of the six dogs in the trial, Hergenrother’s team was able to reverse lymphoma in one dog and stabilize it in three. Although the trials continue and the testing process is far from over, Hergenrother hopes that PAC-1 will one day be helping humans, as well as dogs.