This article was published in the Spring 2010 issue of The Baylor Line and written by Todd Copeland.
Baylor’s Dr. Kevin G. Pinney and Dr. Mary Lynn Trawick are striving to develop a new weapon against cancer.
THE FIGHT AGAINST CANCER is being waged on many fronts, with scientists and doctors working in labs and hospitals around the globe. Many people are familiar with the work being done at such institutions as the University of Texas M.D. Anderson Cancer Center in Houston and the Dana-Farber Cancer Institute in Boston. But one of the more intriguing battle grounds—though relatively small in scale—can be found on the third floor of the Baylor Sciences Building on the campus of Baylor University.
There, in a group of labs busy with activity even on a late Fri-day afternoon at the end of the spring semester, Dr. Kevin G. Pinney, professor of chemistry, and Dr. Mary Lynn Trawick, associate professor of biochemistry, are guiding research on a number of possible weapons against cancer. But there’s one line of research that has become a particular focus—the toxicity of a new chemical compound based on a benzosuberene molecular template.
You could call this compound the Great Inhibitor. Created by Pinney’s research group, it’s a nightmare for cancer cells because it greatly inhibits a key protein’s ability to form micro-tubules, which are essential to cell structure and development. When the compound and human cancer cells have met in Trawick’s lab, the compound has effectively turned out the lights on the cells. Party over.
The promising aspects of this research recently attracted the interest of the Cancer Prevention and Research Initiative of Texas (CPRIT), which in January awarded Pinney and Trawick a $200,000 grant. In summarizing the work supported by its grant, CPRIT noted that it is “extremely rare to identify new cancer treatment agents that demonstrate” such toxic strength.
“We’re really excited to get this grant,” Pinney said. “The competition was really tough.”
But before this compound can be anointed as a future hero in cancer treatment, Pinney and Trawick first have to determine the exact mechanism behind the compound’s destructive power. Right now, all they really know is that it wreaks havoc on a cancer cell’s ability to multiply. They have a good idea how it goes about doing so, and the CPRIT grant is certainly giving them the opportunity to deter-mine whether or not they are right.
However, Trawick is quick to observe that the project could result in nothing of direct use as a cancer treatment. It could pan out, or it could flame out. Even if the Baylor professors can determine the compound’s “mode of action” in affecting cancer cells, a process for safely delivering the compound to the site of a tumor would have to be developed and the long process of FDA approval completed before a new line of cancer treatment could come into existence.
With that in mind, Pinney acknowledges that his and Trawick’s research on the benzosuberene-based molecule could be thought of as the equivalent of a “Hail Mary” pass thrown at the end of a close football game. If the play is successful, jubilation will follow. But the ball could also fall straight to the ground.
It’s a risky enterprise, Pinney concedes, but it’s exciting science nevertheless. “We’re definitely hoping this Hail Mary is like the one Doug Flutie threw,” he said, referring to the famous pass that enabled Boston College to beat Miami in 1984. “We want to win.”
A dynamic partnership
One person who has his fingers crossed for the project’s success is Jimmy Mansour, chair of CPRIT. “The research project of these two scientists is exactly what we at CPRIT are looking to fund,” Man-sour said at a presentation ceremony at Baylor on April 12. “These types of investments will bring us close to the outcome we all so desperately want—a cure for cancer.”
CPRIT was created in 2007 when voters approved an amendment to the Texas constitution authorizing $3 billion to be spent over ten years to fight cancer. Pinney and Trawick’s research was one of sixty-six projects to receive funding in CPRIT’s initial group of grants, which totaled $61 million.
That Pinney and Trawick’s research made the cut is remarkable, given that CPRIT received 880 applications for this round of grants. Their project, like twelve others receiving funding, was categorized as “High Impact/High Risk.” Explaining the label, Mansour said that such projects “could be game-changing in the fight against cancer,” and he specifically described the Baylor-based research as “out of the box, interesting science.”
When asked what made her and Pinney’s research so high in risk and potential impact, Trawick said the “High Impact/High Risk” designation is due to the compound’s extreme toxicity; which has both advantages and disadvantages. “Trying to make the compound selectively targeted to cancer cells is a big challenge,” she said. “It’s so toxic that it could prove to be damaging to anything it touches, not just cancer cells. On the other hand, to treat some of the more difficult types of cancer, you need something very powerful.”
Trawick said the compound at the center of the CPRIT-funded research is the “leading compound” among a number of others that she and Pinney have worked on in the past and continue to study. They have received more than forty research grants, from sources both internal and external to Baylor, over the years. And in late May, the duo learned that they had received a grant from the National Institutes of Health (NIH).
Although this new compound has its foundation in this preceding work, Trawick said it represents something of a leap of faith rather than just the next step in their studies. “This project is taking our research into a new direction because of the nature of the com-pound and our lack of understanding about the compound’s mechanism of action,” Trawick said. “We’re stepping out into the dark.”
The first step on this journey occurred in Pinney’s large, third-floor lab, where ten or so students—ranging from post–dots to undergraduates—can be found at work on just about any given day. (Trawick’s lab is conveniently located just down the hall.)
The welcoming paragraph on the Pinney Group’s website states, “Research focuses on understanding the salient features of small molecule molecular recognition of selected bioreceptors including proteins and enzymes. Specific applications are in the discovery and development of vascular disrupting agents for the treatment of solid tumors and ophthalmologic disorders, as well as new compounds to treat both Chagas’ Disease and brain disorders, such as clinical depression and obsessive compulsive disorder.”
If such sentences make your eyes glaze over or your head spin, don’t worry. A simpler explanation of Pinney’s chemical creations exists. Think “knock out.”
Essentially, his team makes compounds (also interchangeably called molecules) designed to find and bind to certain parts of a cell, such as proteins or enzymes. This foothold then gives the compounds the opportunity to significantly impair the cell’s structural integrity and its ability to divide. An extension of this work centers on compounds that selectively disrupt the blood supply to cancer cells. No blood means no tumor growth.
Right now, there are no such vascular disrupting agents (VDAs) available to treat cancer. Their effectiveness has yet to be proven. But Trawick and Pinney, along with researchers in other labs and companies around the world, are busy trying to develop the compound that will be able to do the job.
Like other such scientific work, it’s a slow process with moments of success balanced against a steady hum of failure. Trial and error is the common lot of scientists, and Pinney and Trawick know the drill by heart. They’ve been working steadily for years, determined and optimistic that a breakthrough is coming.
The two scientists’ partnership empowers the research. After Pinney’s group creates a compound, Trawick’s research group tests its toxicity, using cells from human cancer cell lines that are cultured in the Molecular Biosciences Center down the hall. The biochemist’s results can be quickly relayed back to the chemist, making their collaboration efficient and effective. Modifications can be made, and the next round of research commences. It’s a scientific duet.
“One important aspect of collaborating between chemistry, bio-chemistry, and biology is that you can have immediate feedback from each other, from someone outside your discipline, and that really helps the science,” Trawick said.
“It’s a great collaboration because I’m a synthetic organic chemist. My training’s in making molecules,” Pinney said. “And Mary Lynn’s a biochemist and does cell biology. So we can create a new compound, and she can then help us determine its mechanism of action.”
Target: tubulin
Right now, the exact mechanism of Pinney’s new benzosuberene-based molecule remains a riddle wrapped in mystery inside an enigma. But Pinney and Trawick have a theory about how it works, and they are counting on their research to clear up the matter.
Like the others that preceded it, this compound was created in the Pinney Research Group’s lab, where on a day in mid-May grad students and a post-doc were handling fluid-filled beakers beneath ventilation hoods and working with instrumentation at other work stations. Led Zeppelin’s Physical Graffiti was playing on a stereo. Who says scientists aren’t cool?
Pinney and his fellow researchers developed the molecule through a process of tinkering. “This new molecule is an analogue of some other molecules we’ve made before,” Pinney said. “And we had a biological target in mind, which was the same target as many of those previous molecules.”
That target was one of the “bioreceptors” mentioned on the Pinney Research Group’s website—a globular protein called tubulin that plays a key role in the life of a cell. “We knew what kind of chemical structures tended to bind with tubulin,” Pinney said. “And we knew that our previous compounds of this type had proven to be dam-aging to cancer cells when Mary Lynn’s group looked at them. But there were some improvements we could make.”
Pinney said that creating a molecule is like putting together a puzzle whose pieces can be assembled in a variety of ways. Knowing which pieces work together well, he and the members of his research group tinker away until they devise a final structure that seems promising. “We start with small pieces of the molecule that we can purchase, and then, as organic chemists, we sometimes create new pieces to work-with,” Pinney said. “After it’s assembled, then the molecule can be tested. In this case, we improved on our previous efforts in terms of the molecule’s toxicity. Did we just get lucky? Maybe a little. Serendipity certainly plays a big role in science.”
When the new compound traveled over to the Trawick Group’s biochemistry lab, they put it through the same paces as previously tested molecules. Exposing human cancer cells to the compound, Trawick’s team discovered that Pinney’s new creation was remark-ably “nasty” to the cells, as Trawick said with a smile.
So how does this nastiness work, exactly? Trawicic and Pinney know that tubulin is at the heart of the matter. This protein does two important things, Trawick said. First, it forms microtubules in cells, and microtubules are important because they help create the three-dimensional structure of cells, known as the cytoskeleton. Second, microtubules are essential for the processes of mitosis and cytokinesis through which a cell divides into two cells.
By affecting tubulin’s ability to form microtubules, then, a compound can effectively alter a cell’s structure and freeze the cell’s multiplication into other cells. When achieved within a cancer cell, both of these effects would be tremendously beneficial to patients and their doctors in fighting a killer.
“There’s the potential that this compound is a vascular disrupting agent,” Trawick said_ t does bind to the protein tubulin, and it tends to disrupt the formation of microtubules. That then disrupts the blood supply to the tumor because when microtubules collapse in cells that line blood vessels, you get a collapse of the tumor vasculature.”
Such “tumor-starving” compounds have been hailed as potentially being a major step forward in the quest for a cancer-eradicating agent. However, Trawick cautioned, they still need to figure out exactly how Pinney’s creation works since not all tubulin-binding agents are VDAs.
“This compound’s mechanism of action is something we have to confirm,” she said. “In general, targeting the tubulin-microtubule network is something that is promising in terms of fighting cancer.”
Pinney is equally enthusiastic about the prospects of figuring out his compound’s powers. “We know it interacts as an inhibitor of tubulin assembly, but we think that’s only part of its mechanism,” he said. `A nice component of this grant is that it includes a sub-contract with the University of Texas Southwestern Medical Center in Dallas to do some tumor-imaging work using advanced techniques to determine the compound’s effectiveness in attacking cancer cells.”
Scientific know-how
The recent grant from CPRIT marks just the latest chapter in the long story of Pinney’s interest in chemistry’s application in medicine, as well as his collaboration with Trawick.
“Even back in high school, I was very interested in cancer,” Pinney said. “As a Christian, I felt God calling me in that area, but I didn’t really see myself as a physician. When I went to the University of Illinois as a graduate student, I worked with a professor who really excited me about coupling quality synthetic chemistry with addressing big issues in medicine, using chemistry as a tool to probe medical questions or to develop a treatment.”
Pinney’s undergraduate years were spent at Ohio Wesleyan University, where he earned a BA in 1984, and at the University of Illinois, where he earned a BS in 1985. After receiving a PhD from Illinois in 1990, he was an NIH postdoctoral fellow at the University of South Carolina from 1990 to 1993.
Pinney arrived on the Baylor campus in 1993 and has been balancing a teaching load with progressive research ever since. He said that Baylor has been a very supportive environment. “One of the things that was crucial for us was Baylor being willing to file patents back in the mid-1990s, when we didn’t have a corporate sponsor,” he said. “Baylor initially incurred costs in filing those patents in the early days of our program.”
There has been a natural progression in Pinney’s work and his research partnerships. “I was fortunate in the mid-1990s to develop a collaboration with George R. (Bob) Pettit at Arizona State University, who’s a natural products chemist,” he said. “And then comes a connection with OXiGENE, which had licensed some products from Pettit’s group that they were developing as vascular disrupting agents. Bob put in a good word for me, as did one of my colleagues who was working with OXiGENE on a separate project at that time.”
A biopharmaceutical company based in San Francisco, California, OXiGENE came to Baylor in the late 1990s to hear a presentation by Pinney about his anti-cancer research. In 1999, Pinney and Baylor University entered into an umbrella agreement with OXiGENE for research. “The fact that Baylor had filed patents on my work was key to OXiGENE becoming involved with us, because in 1999 they were able to license those patents from Baylor, and then they had something they could build on as a company,” Pinney said.
Pinney and Trawick began collaborating in 2001. “Kevin was kind enough to ask if we were interested in doing the primary assay for compounds that bind to the protein tubulin,” Trawick said. “I was really interested in proteins, and Kevin was interested in my group’s help in examining the ability of synthetic compounds to inhibit tubulin from producing microtubules.”
Trawick’s interest in proteins can be traced back to her years as a research fellow at the NIH, from 1978 to 1983, just prior to joining Baylor’s faculty. “I came to Baylor in 1983 from the National Institutes of Health, where I worked on enzymes and cell biology,” she said. “I was interested in blood-clotting proteins then, and then I began focusing on tubulin when I had the opportunity to work with Kevin.”
After earning a BS from the University of Michigan in 1970, Trawick graduated from Case Western Reserve University with a PhD in peptide chemistry in 1974. During her time at Baylor, she has also been a visiting scientist at the NIH in three separate years, and she has co-authored with Pinney and others in their groups a number of peer-reviewed journal articles on the results of their research. So if you’re interested in “Application of the McMurry Coupling Reaction in the Synthesis of Tri- and Tetra-arylethylene Analogues as Potential Cancer Chemotherapeutic Agents,” just check out their article in the October 2009 issue of Bioorganic and Medicinal Chemistry.
Pinney’s and Trawick’s research groups operate separately from each another, but there are plenty of things binding them together, from the research projects on which they are collaborating and even, sometimes, in the graduate postdoctoral students who work in their groups. Right now, for instance, Trawick and Pinney are co-mentoring a grad student who has interdisciplinary interests.
“We have our separate laboratories, separate equipment,” Pinney said. “And we really do very different things, with my group focusing on chemistry and Mary Lynn’s group being primarily focused on biochemistry and cell biology. But there is a great sense of team-work, and it’s really been a great collaboration.”
Team effort
A large portion of Pinney’s professional life concerns scientific research. But another equally large portion is dedicated to passing along a love of science to the next generation.
Pinney is a past recipient of the Cornelia Marschall Smith Professor of the Year Award, which recognizes excellence in teaching, research, and service. And he also is involved in the High School Summer Science Research Program, in which a group of accomplished high school students from around the country come to Baylor for six weeks during the summer to learn from professors and graduate students.
For Pinney and Trawick, teaching students is a daily process, whether it’s in the classroom or the lab. “The chemistry and biochemistry department has always been particularly strong in undergraduate research, because essentially you can’t teach the experimental sciences unless you’re doing hands-on research,” Trawick said. “It’s part of the curriculum. Our students go to classes to learn the material, but they don’t necessarily do science there. It’s in the research lab where they get a firsthand exposure to what science is. They learn all the aspects of designing and conducting experiments. So it’s a wonderful opportunity for them.”
Pinney agreed, saying, “I see research as one of the purest forms of teaching, because you’re asking students to have a fundamental understanding of a subject and then push it into the unknown.”
As a teacher, Pinney guides his students toward higher levels of knowledge and experience. But as the head of the Pinney Research Group, he relies on the twenty or so undergrads, grad students, and post-docs who work in his group to guide him toward the next big breakthrough in his research.
“Our students really are the heart of the team,” he said. “They do the trial-and-error work that is an unavoidable part of science. They work late nights and weekends. They deserve a lot of the credit because they fight the daily battles and come up with ideas to move projects forward.”
For the roughly thirty students who work side by side with Pinney and Trawick in their respective research groups, the opportunity to participate in real science that could have a large impact on the world is exciting.
Two of Trawick’s assistants are Amanda Charlton-Sevcik, a doctoral student, and Tracy Strecker, a post-doctoral research associate who earned a PhD from the University of Nebraska Medical Center. Strecker is often the “hands-on” guy when the experiments with the human cancer cells are conducted. “I’m gaining a lot of experience here that will set me up for a career as a researcher in this field, possibly with a pharmaceutical company,” he said.
Clinton George is a doctoral student who works in the Pinney Research Group. A graduate of the University of Texas at Austin, he’s finishing his third year at Baylor and notes that the long hours in the lab are time well spent.
“I’m getting a well-rounded background in chemistry and have had a major stake in developing a more robust, more economical way of developing these new compounds,” he said. “The main thing I enjoy about it is getting to collaborate with a lot of different people who have different backgrounds and getting their perspective on different aspects of creating new material. It’s a team effort.”
From Pinney’s perspective, his students’ role in his research has increased over time, and their contributions have been invaluable.
“As I get older, the best thing I can do is to surround myself with people who are smarter than I am,’ he said. “I rely a lot on my students, whether they’re undergraduates, graduate students, or post-doctoral research associates, to come up with new ideas and to fuel the enthusiasm beyond just the mundane aspects of our work. For students, it’s great. They get exposed to a particular focus of applying research on a particular disease. It also helps them figure out what they want to do professionally”
Battle plan
The CPRIT grant is designed to fund two years of research, which Pinney describes as “a very short timeframe.”
Both Pinney and Trawick have an awareness of the race against time involved in successfully investigating the cancer cell-fighting mechanism of this new compound. Their research groups are going full tilt, through the summer and over weekends.
But they also sense the larger race against time that is the search for a cure for cancer. “The good news today is that for many types of cancer, a diagnosis is not the same as it was ten years ago. The combination of early detection and more specific, better treatment is really saving lives,” Pinney said. “But there remain some kinds of cancer that are extremely deadly. As a scientific community, we need to do a better job with those.”
Both of the Baylor scientists hope the benzosuberene-based compound will become part of the solution, and that optimism helps drive them forward. But they are also realistic. They know that even if they are able to determine exactly how the tubulin-inhibiting compound works, its development into an actual drug faces considerable obstacles.
“We know that it is an extremely toxic compound to cancer cells, but that toxicity also poses a threat to healthy cells,” Trawick said. “One possible application, as a cancer treatment, is to find a way to deliver this compound in a non-toxic manner and have it released into the tumor. We’re trying to selectively target the micro-environment of the tumor.”
If it turns out that the compound operates chiefly as a vascular disrupting agent, it will join several others under development, Pinney said.
The key now is whether they can tailor this compound so it can be selective. “There are probably ten to fifteen compounds around the world that are being researched and developed as VDAs, and several companies are working on bringing them out as drugs,” Pinney said. “But none are available as drugs right now. None have been approved. But VDAs represent a very promising horizon.”
The promise of a cure is a powerful motivator. So don’t be surprised if you’re walking by the Baylor Sciences Building late one night and you see a set of third-floor windows lit up. The lights are seemingly always on up there, illuminating the work of Pinney, Trawick, and their students in the quest to develop the next big weapon against cancer.
Todd Copeland is editor of the Baylor Line.
