By Dana Wallace
More than one million people are diagnosed with cancer in the United States each year, according to the American Cancer Society. That sobering statistic is one of the main motivators prompting researchers from the Baylor College of Arts & Sciences to spend countless hours in their laboratories, searching for ways to prevent and cure the disease.
Baylor’s ability to effectively study cancer received a huge boost when new faculty members were hired as part of the University’s 10-year strategic plan Baylor 2012, which was launched in 2002.
“The Baylor 2012 initiative was really the catalyst that transformed our department in the last decade,” said Dr. Patrick Farmer, chair and professor of chemistry and biochemistry. “Since 2008, we have recruited a great set of world-class scientists, several of whom have contributed to drugs in the development pipeline. These young researchers are the future of science at Baylor.”
Arts & Sciences faculty have helped Baylor bring in more than $5 million in grants and other funding during the past six years to study cancer, and the University’s current strategic plan, Pro Futuris, provides a foundation for even more growth in the future.
The cancer research being done at Baylor is exciting, with more than a half dozen faculty members and the students they supervise in the lab working to discover solutions to varied problems. The profiles that follow will not only introduce you to the more than half dozen faculty who are working to combat cancer, but will also spotlight the varied problems these faculty members and their students are working to solve.
App-le of His Eye
Research by Baylor scientists has led to the creation of a new diagnostic tool that can detect an aggressive form of eye cancer. After Dr. Bryan Shaw’s young son was diagnosed with retinoblastoma, a pediatric eye cancer, Shaw was driven to act.
“When you see your child receiving radiation to his left eye just a few weeks after losing his right eye –– all before his first birthday –– you get deeply, heavily motivated,” said Shaw, assistant professor of chemistry and biochemistry.
One of the main indications of retinoblastoma is leukocoria or “white eye,” which can be seen in photographs during the earliest stages of the disease. Shaw and his wife first noticed their son Noah’s white eye in family photographs, which inspired Shaw to try to make digital photography a tool in the early detection of the cancer.
Shaw partnered with Dr. Greg Hamerly, associate professor of computer science and director of Baylor’s computer science graduate program, to develop the CRADLE app –– which stands for ComputeR Assisted Detector of LEukocoria. They hope the new app will assist with diagnosis of cancer and other eye diseases that exhibit white eye.
Pediatricians and oncologists are experimenting with the app as a tool to perform the red reflex test, the primary screening test for retinoblastoma. Normally, the red reflex test is performed with an ophthalmoscope, one of the handheld lights on the wall of every doctor’s office, but Shaw said studies have shown the test can have false-negative rates of up to 90 percent in detecting retinoblastoma.
“Our son passed all of his red reflex tests, and he had retinoblastoma the entire time,” Shaw said.
CRADLE is being tested against the ophthalmoscope at the Dana-Farber Cancer Institute at Harvard University, Boston Children’s Hospital and St. Jude Children’s Research Hospital. Clinical studies are being led by a pediatric oncologist Shaw met at Harvard when his son was there for a checkup. His passion is to improve pediatric cancer diagnoses in environments with limited resources.
The partnership has been a perfect match. It was imperative to Shaw for the new app to be available for free, particularly to help parents and children in underdeveloped countries where the death rate from retinoblastoma is highest.
“Kids might not get to see a pediatrician in their first year of life, but they’ll get their picture taken,” Shaw said.
CRADLE launched in October 2014 for the iPhone and in July 2015 for Android devices. Shaw said it’s already had 41,000 downloads, is on every continent and led to two cancer diagnoses in Germany. Another child was diagnosed with a non-cancerous eye condition.
Last year, Baylor alumna Sarah Lessman (BA ’04, MS ’05) realized the power of the app.
“Over the Thanksgiving weekend I took a picture of my boys and noticed a white glow in my 2-year-old, Landon’s, left eye. I remember reading an article somewhere about Bryan’s son (and) I knew something wasn’t right,” said Lessman, who then used CRADLE to discover the glow had been appearing in photos of her son since March 2015.
That glow was an early indication of the disease her son’s doctors would soon diagnose.
“Dr. Shaw and the research he is doing probably saved my son’s eye,” Lessman said.
Her son had a positive well child check last summer, but thanks to Shaw’s work and Lessman’s memory, doctors diagnosed her son with Coats’ disease, which is caused by abnormal growth of blood vessels behind the retina. The disease leads to partial or full blindness and will require Landon to have surgeries for the rest of his life to try to save his eye.
He’s focused on synthetic and medicinal chemistry, while she’s focused on biochemistry and cell biology. Together, they make a formidable team using their decades of research experience to fight cancer.
Dr. Kevin Pinney, professor of chemistry and biochemistry, and Dr. Mary Lynn Trawick, associate professor of chemistry biochemistry, began collaborating years before the Baylor Sciences Building opened in 2004.
“It takes many individuals with diverse research talents and skills to truly move initial discovery forward,” Pinney said, emphasizing the value of working with a strong team.
Pinney and Trawick use funding from three main sources –– the Cancer Prevention and Research Institute of Texas (CPRIT), OXiGENE Inc., a clinical stage biopharmaceutical company, and a $1.46 million grant from the National Institutes of Health and the National Cancer Institute –– to keep their laboratories in constant motion.
Their research is focused primarily in two areas of discovery, the first being small molecule anticancer drugs. Pinney and Trawick are looking at a number of areas of research to help create these drugs, such as ways to stop cell division. Another involves using drugs known as vascular disrupting agents to disrupt blood flow to tumors, starving them of oxygen and nutrients and leading to their death.
The second area of their collaboration is focused on certain types of advanced cancer, with the goal of developing anti-metastatic drugs that have the potential for stopping a variety of cancers from spreading. Their research targets the cysteine protease cathepsin L (CTSL), an enzyme secreted by cancer cells. By inhibiting CTSL, cell invasion and cancer migration can be significantly reduced.
Stopping the Great Escape
During his time as an undergraduate student at Baylor, Dr. Joseph Taube, assistant professor of biology, got his start as a researcher performing experiments with Drs. Pinney and Trawick in their labs. Since joining the biology faculty at Baylor, Taube has been busy conducting research into cancer cells that metastasize (or spread) to other sites in the body.
In order to metastasize, a tumor cell that originated in one organ must change its character and adapt to a new organ, essentially reprogramming itself.
“Metastasis is the major cause of death in most cancer patients,” Taube said.
Taube’s work is concentrated inside tumor cells beginning their escape to other parts of the body. He models tumor cell metastasis in the lab, forcing cancer cells to undergo a process called epithelial-mesenchymal transition (EMT). Work done by other researchers has shown that EMT is a way that cells can go from being “happy in the primary tumor” to wanting to escape and survive on their own. Because EMT requires numerous cellular changes, Taube is working to find the genes responsible for implementing those changes.
In research he did while serving as a postdoctoral fellow at Houston’s MD Anderson Cancer Center, Taube found a gene called a microRNA that must be turned off for a cell escape to occur. In fact, putting microRNA-203 back into cells reversed the EMT and blocked the movement of the cells in mice.
At Baylor, Taube is investigating a category of genes that modify the chromosomal environment around other genes to turn them off or on.
He describes the process as much like winding and unwinding a spool of thread. The “threads” are long strands of DNA, comprised of thousands of genes, which must be organized around spools made from proteins. Those genes that are wound tightly on the spools are turned off. Taube is focused on the regulatory genes that can chemically modify the spool proteins, thus unwinding the thread and triggering genes at those locations to turn on. When EMT genes are turned on in this manner, they drive the tumor cells to escape and metastasize.
Taube’s work has particular relevance for patients with what’s known as triple negative breast cancer (TNBC). In instances of TNBC, the three most common types of receptors that cause most breast cancers to spread –– estrogen, progesterone and the hormone epidermal growth factor receptor 2 (HER-2) –– are absent, meaning that patients have tested negative for them.
Unlike other types of breast cancer, TNBC patients don’t respond to targeted drug treatments because the receptors aren’t there. Patients can only be treated with chemotherapy, radiation and surgery.
Taube’s research at MD Anderson showed that some patients with triple negative breast cancer share a particular molecular pattern with a strong EMT signature, meaning that drugs that target the EMT pathway could provide these patients more options for treatment.
In fact, one drug first tested by Taube and his colleagues at MD Anderson is already being tested in mice that have had tumors directly removed from human patients and implanted inside the mice. He hopes that this promising drug will move into a clinical trial in the next few years.
A new Baylor partnership of veteran researchers is taking advantage of state grant money to explore new frontiers in the fight against cancer.
Dr. Daniel Romo, The Schotts Professor of Chemistry, joined the Baylor faculty in fall 2015. He partners with Dr. John Wood, The Robert A. Welch Distinguished Professor of Chemistry and CPRIT Scholar in Cancer Research, in the formation of the CPRIT Synthesis and Drug-Lead Discovery Laboratory. More than 25 years after the two crossed paths at Harvard University while doing postdoctoral work, they are excited to join forces again.
Romo and Wood’s collaborative lab builds on work from their individual research groups and is funded in part by a $4.2 million CPRIT grant awarded to Wood.
“Our research efforts are similar, but our strengths are different enough to make them complementary,” Wood said.
The lab’s focus is on the anticancer potential of natural products –– small molecules isolated from natural sources such as bacteria, plants and marine sponges.
“Natural products have historically been the greatest starting point for drug discovery, accounting for 50 percent of the currently approved drugs, and 70 percent when you consider antibiotics and anticancer agents,” Romo said.
With natural products’ history of providing insight into how cells operate and impact disease, they serve to help Romo and Wood look deeper into cell biology to better understand what is taking place at the molecular level. Cell biology itself is focused on understanding the structure and function of cells, which are considered the basic units of life.
Natural products have also served often as promising drug leads, or candidates, including those that could treat cancer. Romo said that the development of most drugs is typically a 10-year process, with only one out of 10,000 molecules synthesized as a so-called drug lead actually becoming a drug.
Once a natural product is identified, with its structure defined and how it works determined, derivatives can be prepared to determine how quickly it might be metabolized for use in the body (metabolic stability), the extent to which it can be used and absorbed by the body (bioavailability), and to determine its effectiveness and safety. Once this is achieved, a compound can be considered a potential clinical candidate, Wood said. In preparing a complex molecule, small changes are made in a stepwise fashion from the simple starting materials.
Wood and Romo believe that their work in the laboratory is not only to develop new anticancer drugs, but to train future researchers.
“Although our research, through the molecules we prepare, has the potential of impacting medicine by providing new drugs or lead compounds in the development of new drugs, the primary impact comes from the students who are developing the skills needed to prepare complex molecules,” Wood said.
He added that in most instances, Baylor graduates will move on to positions in the pharmaceutical industry and play a key role in both developing and preparing new drugs.
“Of the 200 top-selling brand-name drugs used to treat a variety of disease, nearly all have been initially conceived of and eventually prepared by someone who holds a PhD and is trained as a synthetic organic chemist,” Wood said, noting that the collaborative effort of the new CPRIT lab at Baylor has the potential for extraordinary impact on not only cancer, but on medicine in general.
Mapping Molecules, Finding Clues
Like a treasure hunter in search of a sign, Dr. Touradj Solouki’s anticancer research at Baylor is uncovering mysteries along the way.
Solouki, professor of chemistry and biochemistry, hopes that saliva and human breath contain biological markers or clues that can provide pre-cancer or early stage diagnosis, ultimately giving patients a non-invasive diagnosis and a better chance of receiving treatment.
“We have a long way ahead of us before cancer can be eradicated,” he said.
Using a measuring instrument called an ultrahigh resolution mass spectrometer, Solouki compares the molecular components from the breath of someone who’s healthy with those of a cancer patient. The molecules are sent through hundreds of feet of tubing and are sorted. A coating inside the tube causes the molecules to segregate, allowing researchers to discard what’s not needed and prepare the remainder to be studied.
Solouki said his research team at Baylor has made significant strides in developing instruments and methods for analyzing the samples.
But what happens when a cancer patient is unable to benefit from early detection? That’s the focus of research being done by one of Solouki’s Baylor colleagues, Dr. Elyssia Gallagher, assistant professor of chemistry and biochemistry.
Gallagher’s work concentrates on looking for clues that appear during cancer progression –– namely, how protein interactions change in cancer patients. Proteins do the work of the cell. They perform chemical reactions, transport molecules into and throughout the cell and allow cells to communicate.
“In each cell, DNA (the genetic makeup for all living organisms) is copied to RNA, and then RNA is used to determine the sequence of molecules that make up the protein. The process in which RNA is used to make a protein is called translation,” Gallagher said. “After a protein is translated, additional chemical groups can get added that change the function of the protein.”
Those altered proteins are at the heart of Gallagher’s research. Some proteins contain post-translational modifications (PTMs) that change their structure and function. Her focus is on glycosylation, a PTM that involves the addition of sugars.
Cancer develops when processes in cells go wrong.
“It’s known that in certain types of cancer the glycosylation patterns of proteins change. We’re studying how these changes prevent proteins from communicating normally with other proteins or other cells,” Gallagher said, noting that a better understanding of these changes could help identify new ways to treat cancer.
Gallagher is also looking for new ways to detect PTM changes.
“Not only are we looking at the protein-protein interactions, but we’re also developing new techniques to find the glycosylation patterns that are wrong,” she said, adding that she hopes those new techniques will ultimately lead to an earlier cancer diagnosis.
DNA Replication and Repair
A father now fighting cancer, a mother-in-law who’s a cancer survivor and a grandfather and grandmother who’ve fought the same battle all help to bring focus and passion to Dr. Michael Trakselis’ work.
The research conducted by Trakselis, associate professor of chemistry and biochemistry, centers on DNA replication and repair. DNA carries most of the genetic details for the development, function and reproduction of living organisms, including human life.
More than 250 proteins in human cells go into battle to fix DNA damage of nearly 10,000 events per cell each day. The repair process is continuous, and responds to damage that occurs through both natural and environmental factors such as ultraviolet (UV) light and radiation.
Cells with severe DNA damage or ones that can no longer repair DNA can either die, go dormant or divide uncontrollably, which often leads to cancerous tumors. The ability of a gene to repair itself is vital to ensuring that organisms function as they should.
Trakselis studies DNA replication and repair in archaea, a class of single-cell organisms that mirror what takes place in the human body and can be easily studied in the lab.
The DNA replication system of archaea has less than half of the proteins in humans, yet carries out the same processes with similar precision. This allows Trakselis’ team to delve deeply into the enzyme mechanisms and draw parallels on a more simple scale by making hypotheses in archaea, and then testing the specifics in human cells.
“There is still a wealth of basic scientific knowledge in DNA replication and repair that needs to be determined before we can effectively make specific drugs,” Trakselis said.
People with genetic predispositions to cancer often have specific mutations in DNA repair genes. By studying the effects of these mutations, Trakselis’ team can uncover the unknown roles of these proteins and also learn how alternative mutations in these genes lead to cancer.
The ultimate goal is first to characterize the specific roles of unknown DNA repair genes, then exploit that knowledge for diagnostics, including cancer genome sequencing and targeted chemotherapy approaches.
Trakselis hopes to better understand not only what causes the mutations that can lead to cancer, but also to learn more about their downstream effects so that researchers will ultimately be able to more effectively design drugs that kill cancer cells in their tracks. He has recently discovered two new proteins that appear to play a major role in maintaining DNA stability.
Melanoma, Melanin and Mutations
Dr. Patrick Farmer, the chair of Baylor’s chemistry and biochemistry department, wants to know –– how does the color of someone’s skin make them more susceptible to the cancer known as melanoma?
“This depends on the molecular biology of the melanin, the pigments that determine your hair and skin color, how the pigments are packaged and how they react to light and other things in someone’s environment,” Farmer said. For more than a decade, he’s been studying melanoma, a cancer of the cells that make the black, blonde or red melanin pigments.
Farmer is also researching new copper-based drugs for melanoma that have a selective and dramatic toxicity to melanoma in laboratory studies. Several compounds have been used in clinical trials. One is the drug disulfiram, better known as Antabuse, which is used to make alcoholics sick if they drink.
“Disulfiram’s action against melanoma is very different. It causes the melanoma to accumulate copper, which causes the cells to die,” Farmer said.
His team has developed a hypothesis about how the compounds target melanoma, which ties in with the recent identification of a common mutation in the BRAF kinase pathway, something found in most melanomas. This mutation activates many other cellular processes, leading to the accelerated growth and spread of the cancer.
“Identification of the BRAF mutation has changed the game for melanoma treatment in the last 10 years,” Farmer said. “There are new drugs that work. The copper connection to this mutation is an idea we hope to contribute to, and one we hope will have clinical application.”
Farmer’s research has also resulted in discoveries that have nothing to do with cancer. One offshoot has been to identify topical treatments that lighten skin.
A Bright Future
Baylor scientists are encouraged by the growing number of collaborations on campus between colleagues from varied scientific disciplines and believe that such cooperation will benefit future anticancer research.
“Cancer is a complex disease,” Wood said. “In my opinion, continued progress in mitigating it will not be driven by a single traditional branch of science like biology, chemistry or medicine, but from a complex interplay of fields. By providing a diverse and cooperative research environment, Baylor is making a clear statement that it is serious about becoming a world-class research university.”