March is Colorectal Cancer Awareness Month, and the Birmingham community, along with University of Alabama at Birmingham faculty, staff, students and community members, will have the opportunity to attend the second annual Colon on the Green event Friday, March 2, from 11 a.m.-1 p.m. on the Campus Green.
In 2015, UAB, UAB Medicine and the UAB Comprehensive Cancer Center in conjunction with the American Cancer Society initiated the “80 by ʼ18” colorectal cancer effort to actively promote colorectal cancer screening among its employees to reach 80 percent of eligible UAB employees to get screened by 2018.
This fun event is hosted by UAB Employee Wellness to keep the momentum going with its employees, as well as jump-start awareness among students. While employees are encouraged to educate themselves about colorectal screening options, students are urged to get the conversation started and determine their own family history.
“With early detection, colorectal cancer is one of the most preventable and treatable cancers, and this Colon on the Green event is a fun and engaging way to raise awareness,” said Anna Threadcraft, RDN, L.D., director of UAB Employee Wellness.
The Birmingham and UAB communities are invited to enjoy the festivities featuring informational tables, raffles, photo booths, music from Blaze Radio and the 30-foot Inflatable Colon.
For more information, click here or call 205-996-7343.
A third-year Doctor of Philosophy in Nursing (Ph.D.) student from the University of Alabama at Birmingham School of Nursing was selected for the National Cancer Institute Cancer Prevention Fellowship Program. Jacqueline Vo, BSN, R.N., is the first person from UAB to receive the fellowship.
The fellowship is a four-year postdoctoral program for early scientists training in cancer prevention and control. She was chosen out of 112 applicants across a wide arrange of fields. She credits her success to UAB.
“I didn’t realize how many opportunities the UAB School of Nursing had provided me until something like this happened, and then I knew just how many resources it has,” Vo said. “I want all undergraduate nursing students to realize this too. I want them to realize there is a whole other route they can take in the field of research. Opportunities of a lifetime start here, and I want everyone to realize that, if I can do it, they can too.”
Vo is a Robert Wood Johnson Foundation Future of Nursing Scholar and recipient of a two-year, American Cancer Society Doctoral Degree Scholarship in Cancer Nursing. She earned her BSN from the School of Nursing in 2014.
Since the inception of the fellowship in 1987, only a few nurses have been chosen. Vo, a former staff nurse in the Cardiothoracic Intensive Care Unit at UAB Hospital, says the selection committee was impressed that she has clinical experience as a bedside nurse to supplement extensive training as a nurse researcher.
“They loved that I had clinical experience, and that I had interacted with patients,” Vo said. “The interviewers saw that I bring a whole different perspective to research because I have had that patient interaction.”
She will begin the fellowship this August.
Allogeneic blood or marrow transplantation recipients are at a significantly higher risk of cognitive impairment in the years post-transplantation, according to a study published in Journal of Clinical Oncology.
Published by Noha Sharafeldin, M.D., M.Sc., Ph.D., instructor in UAB’s Institute for Cancer Outcomes and Survivorship and Division of Hematology and Oncology, this study helps add a missing piece to a long-unsolved puzzle about post-transplant effects on recipients, specifically that vulnerable subpopulations of similar transplants can benefit from targeted interventions in the years after they receive their lifesaving treatment.
While it has been studied that cognitive impairment after myeloablative allogeneic BMT can occur, it has been unclear if similar impacts to cognitive functioning occurs after reduced-intensity allogeneic or after autologous BMT. This cognitive function deficit impacts areas of a survivor’s life ranging from societal integration to their return to work, as well as a decline in memory, learning, attention and concentration.
“With this research from our longitudinal prospective assessment, we are able to deduce that a significant population of allogeneic BMT survivors will experience cognitive impairment that can and will impact different aspects of their lives moving forward,” Sharafeldin said. “And it’s critical that we as clinicians develop interventions for these patients. This research is the just beginning of our figuring out how we can best care for BMT survivors and enable them to live healthy lives.”
Between 2004 and 2014, 477 patients treated with BMT at City of Hope underwent standardized neuropsychological testing before their transplant, and at the six-month and one-, two- and three-year marks after transplant; testing was conducted on eight cognitive domains, including executive function, verbal fluency and speed, processing speed, working memory, visual and auditory memory, and fine motor dexterity. In addition, 99 healthy patients underwent identical testing as a benchmark for cognitive function.
In analyzing the data, at three years post-transplant, evidence of cognitive impairment was present in 35.7 percent of allogeneic recipients. Furthermore, 38 percent of allogeneic recipients who participated at the three-year mark had not yet returned to work, and impairment was associated with a tenfold increased odds of not returning to work at three years post-transplant. The study was conducted under the lead of Smita Bhatia, M.D., MPH, professor in the UAB Department of Pediatrics and director of the UAB Institute for Cancer Outcomes and Survivorship, and was funded by the Leukemia and Lymphoma Society. In addition to Sharafeldin’s analysis, Yanjun Chen, M.S. and F. Lennie Wong, Ph.D, also conducted the analysis, Alysia Bosworth, B.A., conducted the cognitive testing, and Sunita Patel, Ph.D., served as the lead neuropsychologist; all are affiliated with City of Hope.
“From this data, it’s clear that we have to make strides in supporting allogeneic BMT recipients in their recovery to ensure that we are educating patients and their families on signs of cognitive impairment. This data will help us identify patients at highest risk of cognitive impairment and inform the development of interventions that facilitate a patient’s recovery and return to normal life,” Sharafeldin said.
Sharafeldin recently received a Leukemia and Lymphoma Society career development award that will support her future research at UAB on intervention strategies to improve cognitive function in transplant recipients.
Long after cancer treatment ends, many continue to deal with one particular symptom that refuses to go away: fatigue. In a new study, researchers at the University of Alabama at Birmingham and Harvard Medical School have found that the power of placebos, even when fully disclosed to patients, might be harnessed to reduce fatigue in cancer survivors.
For cancer survivors, few treatments are available to alleviate fatigue after treatment, and the most effective pharmacological interventions come with side-effect warnings that include panic, psychosis and heart failure. In a study published in Nature Scientific Reports, investigators found that cancer survivors who knowingly took placebo pills reported a 29 percent, clinically meaningful, improvement in fatigue severity, and a 39 percent improvement in the extent to which fatigue disrupts quality of life.
The placebo pills are made of cellulose, so there is no “active ingredient,” pharmacologically speaking. Upon enrollment, researchers told participants the pills are simply placebos, or inert pills, and each participant had a clear understanding of the placebo effect up-front. Investigators found that patients’ opinions of the placebo effect did not matter in the outcome of the study.
“Some people who thought the placebo wouldn’t do anything had a good response; others who believed it would help didn’t have a response,” said Teri Hoenemeyer, Ph.D., lead author and director of Education and Supportive Services at the UAB Comprehensive Cancer Center. “Fooling or deceiving patients may be unnecessary for placebo effects to produce benefits, with automatic neurological processes being a possible mechanism for the effects. This has revolutionary implications for how we might exploit the power of placebo effects in clinical practice.”
The study involved 74 survivors of different types of cancer who reported moderate to severe fatigue. They were randomized either to the open-label placebo condition or to treatment as usual. Patients prescribed the open-label pills were told they were receiving placebos and asked to take two of the pills, twice per day, for three weeks.
After the three weeks, patients being treated as usual were offered the opportunity to take the placebo pills for three weeks, while those who originally took the placebo pills discontinued them. After another three weeks, those knowingly taking placebo pills significantly reduced their fatigue. The group taken off the placebos maintained their reduction in fatigue, as well.
“Cancer survivors report that fatigue is their most distressing symptom, even more distressing than other symptoms like nausea or pain, and clinicians struggle to find ways to help them with it,” Hoenemeyer said. “The effects of the placebo pills on fatigue were so dramatic that we had a number of the study patients ask if they could be given more placebo pills. For ethical reasons, we were unable to do so.”
Ted Kaptchuk, study co-author and director of the Harvard-wide Program in Placebo Studies, has previously shown that open-label placebos can bring relief to patients with irritable bowel syndrome, chronic low-back pain and migraine headache. This is the first study to test the effects of open-label placebos with cancer survivors.
“Participants still had benefits three weeks after they stopped taking the placebo pills, which hasn’t been shown before,” said Kevin Fontaine, Ph.D., co-author and chair of the Department of Health Behavior in the UAB School of Public Health. “The extension of benefits even when the placebo pills are discontinued has been a surprise finding that has many placebo researchers excited.”
The Breast Cancer Research Foundation of Alabamapresented $950,000 — its largest donation to date — to the UAB Comprehensive Cancer Center on Feb. 2. BCRFA has donated more than $7.7 million to UAB since its inception in 1996.
BCRFA makes an annual donation to the Cancer Center with proceeds from its fundraising efforts during the previous year, including BCRFA events, corporate and individual donations, and sales of the breast cancer specialty license plate tags.
“The Breast Cancer Research Foundation of Alabama has been central to providing the critical monies for the development and maintenance of the breast cancer research program, making our program one of the most prominent breast cancer programs in the country,” said Michael Birrer, M.D., Ph.D., the new director of the UAB Comprehensive Cancer Center. “BCRFA is a perfect example of motivating the community to support new and evolving research.”
BCRFA’s pilot funding has provided the seed money for many projects to get off the ground. For example, one research project evaluated a new compound, UAB-30, for its ability to prevent breast cancer. The project has evolved now into a clinical trial and, furthermore, secured additional national funding based on data provided by BCRFA seed money.
Other projects range from examining biomarkers for immunotherapy response to focusing on inhibitors and their impact on chemo drug effectiveness, to a study on the spread of metastatic breast cancer to the brain.
“Patients come to the UAB Comprehensive Cancer Center because they can be seen by clinical breast cancer experts and receive ‘cutting-edge’ therapies based upon the ongoing research program,” Birrer said.
All BCRFA donations remain in Alabama to support research at the UAB Cancer Center and its collaborative partners, providing a lifesaving impact both locally and globally. Community partners for this year’s gift include Tameron Automotive, Belk, The Thompson Family Foundation, Sirote & Permutt, The Alabama Power Foundation, Renasant Bank, Wind Creek Wetumpka, Protective Life Foundation, Thrivent Financial, Spectrum Reach, and iHeart Media, among many others.
Every three minutes, someone is diagnosed with blood cancer, and the UAB Medical Student Oncology Interest Group is trying to help.
On Tuesday, Feb. 6, representatives from the OIG will host a drive for Be The Match to help expand the national bone marrow registry. Representatives and volunteers from Be the Match will be present to help people fill out paperwork and obtain buccal swabs for HLA typing.
According to Be the Match, thousands of patients with blood cancers like leukemia or other diseases like sickle-cell anemia need a marrow transplant to survive. By signing the registry, this does not mean someone is signing up to donate bone marrow. In fact, most people in the registry are never contacted to donate bone marrow.
The drive will be held from 10 a.m. to 1 p.m. outside Volker Hall’s Lecture Room A. For more information, please call 205-552-9371.
Stable, biocompatible microcapsules from the lab of Eugenia Kharlampieva, Ph.D., have gained a new power — the ability to scavenge reactive oxygen species.
This may aid microcapsule survival in the body as the tiny polymer capsules carry a drug or other biomolecules, says Kharlampieva, associate professor of chemistry in the University of Alabama at Birmingham College of Arts and Sciences and scientist in the UAB Comprehensive Cancer Center. The microcapsules may also find use in antioxidant therapy or in industrial applications where scavenging of free radicals is needed.
Reactive oxygen species play a Janus-like role in the body — they can be a weapon against pathogens when produced by the immune system; but excess production of reactive oxygen species during biological stress can damage human cells in diseases like diabetes, atherosclerosis, Alzheimer’s disease, kidney disease and cancer.
Current natural and synthetic antioxidants lack biocompatibility and bioavailability, and they are chemically unstable. This means they have a limited capability to scavenge reactive oxygen species. The new microcapsules do not show these limitations, and they may provide a way to locally modulate oxidative stress.
Kharlampieva and colleagues describe the construction and properties of these new microcapsules in the paper “Manganoporphyrin-polyphenol multilayer capsules as radical and ROS scavengers,” published in Chemistry of Materials, a publication of the American Chemical Society. Graduate student Aaron Alford and research associate Veronika Kozlovskaya, Ph.D., are co-first authors, and Hubert Tse, Ph.D., associate professor of microbiology in the UAB School of Medicine, is co-corresponding author with Kharlampieva.
The UAB researchers have previous experience making and testing biocompatible microcapsules with alternating layers of tannic acid and poly(N-vinylpyrrolidone), or TA/PVPON. The layers are formed around a sacrificial core, such as solid silica, that is dissolved after the layers are complete.
Tannic acid is a natural antioxidant, and the TA/PVPON microcapsules have some reactive oxygen species-scavenging ability. However, they lose that ability and begin to degrade with prolonged exposure to the oxygen radicals.
So, the Kharlampieva team explored adding a metalloporphyrin to the PVPON layer of the TA/PVPON microcapsules.
Specifically, they devised a synthesis to covalently attach a manganoporphyrin to the PVPON. The addition of this pendant catalyst created an MnP-PVPON/TA capsule with the following characteristics: 1) the microcapsules synergistically remove reactive oxygen species, including superoxide and hydrogen peroxide, at dramatically increased rates compared to unmodified TA/PVPON microcapsules; 2) the microcapsule does not degrade with long exposure to reactive oxygen species; and 3) the microcapsules are nontoxic to mouse splenocytes.
Furthermore, the manganoporphyrin was stably contained within the microcapsule without release, and researchers showed that both manganoporphyrin and tannic acid were required for the synergistic scavenging of reactive oxygen species.
The presence of the manganoporphyrin did not interfere with the alternate-layer construction of the microcapsules, and the MnP-PVPON/TA capsules had increased wettability compared to the PVPON/TA capsule, which may aid microcapsule maintenance in the blood. The microcapsules had five or five and a half bilayers placed around a 4-micrometer silica particle.
Biological experiments with the MnP-PVPON/TA capsules are underway.
Besides Alford, Kozlovskaya, Tse and Kharlampieva, co-authors are Bing Xue, Nirzari Gupta and William Higgins, UAB Department of Chemistry; Dana Pham-Hua, UAB Department of Microbiology; and Lilin He and Volker S. Urban, Oak Ridge National Laboratory, Oak Ridge, Tennessee.
Support for this work came from National Science Foundation grant DMR 1608728, National Institutes of Health grant DK099550, American Diabetes Association Career Development Award 7-12-CD-11 and Juvenile Diabetes Research Foundation Award 1-SRA-2015-42-AN.
Hippocrates once said, “Let food be thy medicine …”.
These five words have been the foundation of one doctoral student’s research endeavors.
“Hippocrates didn’t just mean to eat, drink and be merry. He literally meant to let food be your medicine,” said 26-year-old Kendra Royston, a fifth-year PhD student and graduate research assistant in biology. “Researchers are finding that what you eat and what is readily available in nature not only tastes good, but it also helps combat certain diseases. God says that what we need is in the land, so if we have a big laundry list of foods that are available to eat and we know they are beneficial, why aren’t we eating them?”
For the past five years, the Huntsville native has studied how nutrition can impact disease development, particularly with breast cancer. The research has been fascinating and, as a result, led her down a path she didn’t see coming.
Royston fell in love with music at a very young age. She started with piano lessons in elementary school, but soon gained an interest in wind instruments. Her initial desire was to play the saxophone, but her band director noticed her arms were long and suggested the trombone.
The first time she picked up a trombone, she fell in love. She joined the band and played throughout her high school and college years, even earning a full scholarship to Stillman College. Her passion for music also carried over to art and writing.
Most would not have imagined the self-proclaimed band geek “who is a little bit quirky” would have chosen a life of science, but Royston’s interests went beyond the arts.
Her fascination with medicine and science goes back as far as she can remember. Her mom bought her “this huge Gray’s Anatomy” book when she was 8 years old and she would spend hours reading and looking at the images. There was no doubt in her mind she would pursue some kind of science career. What? She didn’t know — until she was introduced to Upward Bound Math-Science.
Upward Bound is a U.S. Department of Education program designed to strengthen the math and science skills of participating students by connecting them to university faculty members who do research in those areas.
Royston’s first research experience was studying entomology in an agriculture lab at Alabama A&M University. The research looked at how certain insects could serve as bioindicators of nutrients in soil.
“I hate bugs, so I quickly discovered that entomology was not what I wanted to do for the rest of my life,” she said.
But that first lab experience opened her eyes to the many opportunities available in research, so she continued to search for “where she belonged.” It took her a few more years, but she finally found it.
While an undergraduate at Stillman College in Tuscaloosa, Royston spent her summers at UAB through a summer enrichment program with the UAB Minority Health & Health Disparities Research Center. Although she had been exposed to research at a young age, she had decided to become an obstetrician/gynecologist and there was no swaying her decision.
“I just wanted to practice medicine,” Royston said. “But those summers at UAB opened my eyes and showed me I could still pursue a career in women’s health without strictly going the medical school route.”
During her third year in the summer enrichment program Royston was introduced to research that looked at dietary compounds and the impact those compounds can have on breast cancer, specifically in triple negative breast cancer, which primarily impacts African American women who are diagnosed at a younger age.
Triple negative breast cancers are not receptive to hormone therapies because the three hormone receptors – progesterone receptor, estrogen receptor and HER2/neu – are not active. Therapies currently on the market target these hormones thereby inhibiting the cancer from growing and proliferating, but because the hormones are not active in women with triple negative breast cancer, the treatments often do not work.
The research efforts Royston was involved in that summer focused on trying to reactivate the hormone receptors using the dietary compound, sulforaphane, which is found in cruciferous vegetables, such as broccoli and asparagus.
But it was more than just the research that drew Royston in; it was the way the research was explained that struck a chord with the young undergraduate.
“I’ve always had a soft spot for helping people, especially women,” she said. “Women are very strong. They are required to do a lot, especially when it comes to mothers and raising children. They are the backbone of every community. It’s important to ensure that women are healthy so they continue to be that backbone for their families.”
“More than 200,000 women are diagnosed with breast cancer each year and 40,000 are dying every year. Something needs to be done, and this research is trying to do something to help these women,” Royston added. “That was the turning point. I realized I could really make a difference by not just catching it when it’s too late, but I could be at the forefront, discovering cutting edge research and developing top-notch treatments that stop it before it becomes a problem. Once it progresses past a certain point, as a medical doctor you can only say ‘I’m sorry’ and that’s not anything I ever want to tell anybody.”
Once the decision was made to pursue a graduate degree, Royston had to figure out where and how. She wanted UAB, but had been waitlisted by one program and still hadn’t heard from the biology department so she decided to return to Huntsville and work on her master’s at Alabama A&M.
Her belongings were packed and she had an apartment already lined up in Huntsville when she got a call from the Graduate Program Director of UAB’s biology department asking if she was still interested in the graduate program.
“It was a holiday, classes started in August and I was already packed and ready to move to Huntsville,” she said. “I really thought it was a joke, so I told him, ‘Sure, as long as it’s paid for.’ He immediately emails me information on the National Science Foundation’s Louis Stokes Alliances for Minority Participation program. So, I changed my plans.”
The Continued Research
While Royston’s undergraduate research looked at making current treatments more effective, her research as a graduate student has taken a slightly different approach. She read about a “miracle” nutrient called withaferin A that had initially gained popularity in the Western world as a steroid. It had been used frequently in wound healing and inhibition of inflammation, but she couldn’t find any research on the compound in relation to cancer and epigenetics.
She began looking at withaferin A in combination with sulforaphane and got some interesting data. The combination of the compounds worked more efficiently at breast cancer cell death. Her first paper described how the compounds inhibited cell growth and how they played a role in the epigenetic process. Royston is now looking at genes that are responsible for cell cycle regulation. She is also studying a tumor suppressor gene that is involved with cell cycle progression and trying to figure out why it is typically underexpressed in cancer.
A more recent addition to her research experience has been as a Susan G. Komen Graduate Trainee in Disparities Research through the School of Nursing. The grant’s focus is on survivorship and education, particularly for young breast cancer survivors. The team offers a support group, hosts community events, performs surveys and teaches cognitive intervention methods.
“The skills I’m building through this grant are invaluable,” Royston said. “When you’re researching a disease it’s very important to understand what the problem is, and to do that, you need to talk to people. Now, I can go back to the drawing board and develop a methodology to address what I’m hearing. Being in the community makes you realize that these are people, not just test subjects or samples. It puts more urgency behind your research when you realize that your research can potentially save someone’s life in the long run.”
Life as a doctoral student is not easy and it keeps Royston on her toes, but music and art still play a huge role in her life. She continues to perform on stage and attend Battle of the Bands competitions when she has time, and the walls of her office are covered with her drawings and various art work. She said her “artsy” self plays well with the more serious researcher and provides a much-needed outlet for stress relief.
“You don’t tend to think of a scientist as artsy, and I’m left-handed, too,” she said. “But I like to think that I come at the problem from a different perspective. I often joke that my abstract mind allows me to come up with different solutions to problems.”
Her current challenge: Figuring out her future.
With an anticipated spring or summer graduation date, Royston is currently searching for a postdoctoral position that will enable her to continue expanding her skillset in public health and community-based research. She hopes to focus on translational research, which is a combination of basic science and actual application.
While breast cancer has been the center of her research to date, Royston has thought about branching out into other types of cancer or even looking at drug development. Regardless of the direction her research takes, she knows she wants to close the gap with health disparities.
“I want to be extremely instrumental with diversifying the face of research,” she said. “I’m very passionate about finding a way to put people in a position where they can impact their community by doing groundbreaking research in areas often forgotten. All research is important because people are impacted one way or another. I want to help eliminate these health disparities, whether it be behind-the-scenes or knee-deep at the bench doing the research or just stepping back and telling others to do it. I just want to make a difference.”
Ragan Cain will never forget the day she received her cancer diagnosis.
In 2010, she was seeking fertility treatment at a Birmingham hospital. Her physician performed a typical physical exam and while checking her neck noticed a nodule on Cain’s thyroid. She was referred to an endocrinologist who biopsied the nodule and diagnosed the nodule as benign. She was examined every year after that with the same diagnosis.
During this routine check in 2017, her physician said the nodule felt a little different.
“That’s when I decided to get proactive about my health,” Cain said.
Cain, an Alabama native and chief administrative officer for Tacala, LLC, made the decision to get a second opinion with UAB Medicine, where she was seen by Brooks Vaughan, M.D., assistant professor in the Division of Endocrinology, Diabetes and Metabolism.
“We went back and forth about what we should do,” Cain said. “The nodule was small, and an original benign biopsy created a strange set of circumstances. After much discussion, Dr. Vaughn and I agreed to have his team at UAB re-biopsy the nodule.
Vaughan’s team performed a fine-needle biopsy Dec. 19, 2017. Results were expected after Christmas, but Cain received the call on Dec. 21.
“I knew when I saw that phone number, something was wrong,” Cain said.
She was diagnosed with papillary thyroid cancer, which is the most common type of thyroid cancer. It makes up nearly 80 percent of all cases of thyroid cancer and is one of the fastest-growing cancer types, with more 20,000 new cases a year. Although a person can get papillary thyroid cancer at any age, most patients will present before the age of 40. It is also the thyroid cancer with the best prognosis, and most patients can be cured if treated appropriately and early enough.
“When you’re 40 years old and eat healthy and do the right things, you think you have pretty good health,” Cain said. “It was a big surprise, as I know it is to everyone who receives a cancer diagnosis. I spent the days following feeling like I was in a fog.”
After receiving her diagnosis, Cain was able to schedule an appointment the following day with Herb Chen, M.D., Fay Fletcher Kerner Endowed Chair in the Department of Surgery.
“Dr. Chen came highly recommended to me, and he just helped to ease my mind,” she said.
Chen removed the nodule Jan. 8, 2018, by performing a total thyroidectomy — the complete removal of the thyroid gland. Chen, a senior adviser in the UAB Comprehensive Cancer Center and president-elect of the American Association of Endocrine Surgeons, says UAB is a highly sought-after destination for thyroid surgeries.
“We are a high-volume surgery center,” Chen said. “Our endocrine surgeons are internationally known and have the experience to treat all types of thyroid and parathyroid disease.”
Two weeks after the procedure, Cain returned for a checkup and received good news. However, she still wonders if some of the fear and anger she put on herself might have been non-existent if she had made the decision to get her nodule further examined sooner. Because of this experience, she is now an advocate for others’ being proactive about their health.
“I was of course afraid when I received the diagnosis,” she said, “and I thought that I was doing the right thing by having my thyroid checked every year; but clearly I didn’t take it seriously enough. I was angry at myself for waiting so long. It was a reminder of what I already knew, but I finally applied it to myself. Dr. Ed Partridge of the UAB Comprehensive Cancer Center is known to have said, ‘Treat your first cancer seriously, and you may not have to deal with more down the road.’ I felt strongly that it was important to receive this treatment at UAB. They have taken this diagnosis seriously and treated me with great care, concern and reassurance.”
In animal experiments, a human-derived glioblastoma significantly regressed when treated with the combination of an experimental enzyme inhibitor and the standard glioblastoma chemotherapy drug, temozolomide.
The regression seen in this combination therapy of temozolomide and the inhibitor SLC-0111 — which targets the enzyme carbonic anhydrase 9, or CA9 — was greater than that seen with either SLC-0111 or temozolomide alone, says research leader Anita Hjelmeland, Ph.D., assistant professor in the Department of Cell, Developmental and Integrative Biology at the University of Alabama at Birmingham.
“Our experiments strongly suggest that a strategy to target a carbonic anhydrase that is increased in glioblastoma, CA9, will improve temozolomide efficacy,” Hjelmeland said. “We believe the drug combination could improve patient outcomes in glioblastomas sensitive to chemotherapy.”
Glioblastoma is the most common primary brain tumor seen in adults. Half of the tumors recur less than seven months after undergoing the standard treatment of surgery, temozolomide and radiation. The median survival after diagnosis of this deadly cancer is 12 to 14 months. Thus, new approaches to therapy are urgently needed.
Solid tumors like glioblastoma create microenvironments within and around themselves. A common condition is hypoxia, a shortage of oxygen as the tumor outgrows its blood supply. Tumor cells shift to making their energy through glycolysis, a method of metabolism that does not require oxygen. Glycolysis, in turn, changes the acid-base balance at the tumor — the extracellular space becomes more acidic and the tumor cell interiors become more alkaline, adapting to this change.
In the face of this hypoxia and acid stress, tumor cells over-produce CA9, a membrane enzyme that converts carbon dioxide and water to bicarbonate and protons. This reaction aids maintenance of the altered acid-base balance in the tumor microenvironment.
Thus, CA9 is a possible therapeutic target, and the inhibitor SLC-0111 shows more than 100-fold specificity against CA9, versus two other forms of human carbonic anhydrases, CA1 or CA2. Furthermore, collaborators on this project have previously shown that SLC-0111 exhibits effectiveness against breast cancer xenografts in animals. SLC-0111 has been tested in Phase I clinical safety trials sponsored by Welichem Biotech Inc. in Canada for patients with advanced solid tumors.
The research team led by Hjelmeland and co-first authors Nathaniel Boyd, Ph.D., and Kiera Walker, both working in Hjelmeland’s UAB lab, studied glioma cells in cell-culture that were derived from an aggressive pediatric primary glioblastoma and from an adult recurrent tumor. The researchers also studied the tumor in mice, using the adult recurrent glioblastoma.Thus, CA9 is a possible therapeutic target, and the inhibitor SLC-0111 shows more than 100-fold specificity against CA9, versus two other forms of human carbonic anhydrases, CA1 or CA2. Furthermore, collaborators on this project have previously shown that SLC-0111 exhibits effectiveness against breast cancer xenografts in animals. SLC-0111 has been tested in Phase I clinical safety trials sponsored by Welichem Biotech Inc. in Canada for patients with advanced solid tumors.
One reason for recurrence of glioblastoma is a therapeutically resistant sub-population of glioma cells known as brain tumor initiating cells. Part of the focus of the Hjelmeland team was to look at the effect of the combination therapy on that subset of glioblastoma cells.
The researchers found that the combined treatment with temozolomide and SLC-0111 in cell culture experiments: 1) reduced glioblastoma cell growth, 2) induced arrest of the cell-division cell cycle by creating breaks in DNA, 3) shifted the tumor metabolism and intracellular acid-base balance by decreasing metabolic intermediates, and 4) inhibited enrichment of brain tumor initiating cells.
In experiments with mice, the combined treatment with temozolomide and SLC-0111: 1) delayed tumor growth of a patient-derived, recurrent glioblastoma xenograft implanted beneath the skin of immunocompromised mice, as compared to temozolomide alone, and 2) improved survival of the mice when the xenograft was implanted in the brain, a placement that more closely models glioblastoma in patients.
“Clinical trials in glioblastoma often initiate with patients that have a tumor recurrence, and we have demonstrated in vivo efficacy for SLC-0111 with temozolomide in a recurrent glioblastoma,” the researchers wrote in their study, published in JCI Insight. “Therefore, our data strongly suggest the translational potential of SLC-0111 for glioblastoma therapy.”
“With funds from the Southeastern Brain Tumor Foundation,” Hjelmeland said, “we continue to determine whether there are subtypes of glioblastomas that are most likely to respond to combinatorial therapy.”
Co-authors with Hjelmeland, Boyd and Walker in the paper, “Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo,” are Joshua Fried and Bo Xu, M.D., Ph.D., Southern Research, Birmingham, Alabama; James R. Hackney, M.D., UAB Department of Pathology; Paul C. McDonald, Ph.D., and Shoukat Dedhar, Ph.D., BC Cancer Research Centre, Vancouver, British Columbia, Canada; Gloria A. Benavides, Ph.D., and Victor Darley-Usmar, Ph.D., UAB Center for Free Radical Biology; Raffaella Spina, Ph.D., and Eli E. Bar, Ph.D., Case Western Reserve University, Cleveland; Alessandra Audia, Ph.D., and Krishna P. Bhat, Ph.D., MD Anderson Cancer Center, Houston; Sarah E. Scott, Catherine J. Libby, Anh Nhat Tran and Mark O. Bevensee, Ph.D., UAB Department of Cell, Developmental and Integrative Biology; Corinne Griguer, Ph.D., and G. Yancey Gillespie, Ph.D., UAB Department of Neurosurgery; Susan Nozell, Ph.D., UAB Department of Radiation Oncology; Burt Nabors, M.D., UAB Department of Neurology; and Emily Gordon, Ph.D., and Sara J. Cooper, Ph.D., HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.“With funds from the Southeastern Brain Tumor Foundation,” Hjelmeland said, “we continue to determine whether there are subtypes of glioblastomas that are most likely to respond to combinatorial therapy.”
This work was supported by National Institutes of Health grant CA200085, NS096531, CA1515122, the UAB Brain Tumor SPORE CA151129 Career Development Award, a pilot award from the UAB-HudsonAlpha Center for Genomic Medicine, and startup funds from UAB.
Additional support was provided by NIH grants NS100054, CA160821, CA138517, RR027822-01, NS47466 and AI027767.
Hjelmeland, Gillespie, Nabors, Darley-Usmar, Griguer and Nozell are all members of the UAB Comprehensive Cancer Center, one of the nation’s leading cancer research and treatment centers.