Researchers at the University of Alabama at Birmingham have found that a plant-based diet is more effective in preventing breast cancer later in life for the child if the mother consumed broccoli while pregnant. The 2018 study out of the UAB College of Arts and Sciences and Comprehensive Cancer Center used epigenetics — the study of biological mechanisms that will switch genes on and off — as a mechanism to identify ways we can change human gene expressions in fatal diseases, including breast cancer.
“An important risk factor for breast cancer is individual genetic background, which is initially generated early in human life — for example, during the processes of embryogenesis and as a baby develops in a mother’s womb,” said Yuanyuan Li, corresponding author and assistant professor in the School of Medicine’s Department of Pharmacology and Toxicology at UAB. “Bioactive dietary components that are found in cruciferous vegetables like broccoli sprouts, cabbage and kale have been shown to reduce the risk of developing many common cancers through regulation of epigenetic mechanisms.”
The study, conducted in mice and recently featured in the National Cancer Institute’s Nutrition Frontiers, suggests that women who eat broccoli sprouts while pregnant could more effectively prevent their child from breast cancer development later in life as compared with consumption of early-life and adult broccoli sprout diets. Postnatal early-life broccoli sprout diets starting prior to puberty showed protective effects in prevention of breast cancer but were not as effective as the prenatal/maternal treatment. However, an adulthood-administered broccoli sprout diet did not reduce breast cancer.
“Our results suggest that the prenatal/maternal broccoli sprout diet may impact early embryonic development by regulating global gene expression through affecting epigenetic profiles resulting in differential susceptibility to breast cancer later in life,” said Trygve Tollefsbol, Ph.D., professor in the UAB Department of Biology and senior author on the study. “These results suggest that a temporary exposure to epigenetic-regulating dietary components such as cruciferous vegetables could be a key factor in reducing the risk of breast cancer.”
This study may lead to translational breast cancer chemopreventive potential by appropriate administration of key dietary components, leading to early breast cancer prevention in humans.
Doxorubicin is a chemotherapy drug widely used in ovarian, bladder, lung, thyroid and stomach cancers, but it carries a harmful side effect. The drug causes a dose-dependent heart toxicity that can lead to congestive heart failure.
University of Alabama at Birmingham researchers now describe an important contributor to that heart pathology — disruption of the metabolism that controls immune responses in the spleen and heart. These immune responses are vital for heart maintenance, repair and control of inflammation. This dysregulated immunometabolism impairs resolution of inflammation, and chronic, non-resolving inflammation leads to advanced heart failure.
Immunometabolism is the study of how metabolism regulates immune cell function, and it is a recent and growing aspect of immunology. Two key players in immunometabolism are immune-responsive enzymes called lipoxygenases and cyclooxygenases. These immune-sensitive enzymes create a variety of bioactive lipid mediators that regulate immune cell responses.
The UAB researchers, led by Ganesh Halade, Ph.D., an assistant professor in the UAB Department of Medicine’s Division of Cardiovascular Disease, used a mouse model to study the effect of doxorubicin on immunometabolism. In the mice, doxorubicin induced fibrosis in the heart, increased the programmed cell death called apoptosis and impaired the pumping of the heart. The drug also caused a wasting syndrome in the heart and the spleen.
Mounting research has shown that the spleen — which acts as a reservoir of immune cells that speed to the site of heart injury to begin clearance of damaged tissue — plays a leading role in the initiation of immune response after a heart attack. Now, Halade and colleagues have found that the doxorubicin is also involved in the deleterious response to the spleen.
First, the UAB researchers found that doxorubicin induced irreversible dysregulation that lowered levels of lipoxygenases and cyclooxygenases in the left ventricle of the heart. This reduced the levels of bioactive lipids mediators produced by these enzymes, mediators that usually would help resolve inflammation.
Third, doxorubicin caused an imbalance of the cell-signaling molecules called chemokines and cytokines, and this imbalance suggests suppressed defense capacity of spleen-leukocyte immune cells. Specifically, the researchers found decreased levels of tumor necrosis factor-alpha in the spleen, and they found decreased levels of the immune-cells reparative marker MRC-1, also known as CD206, in the heart.Second, in the spleen, doxorubicin also poisoned a special group of marginal zone immune cells called CD169+ macrophages, causing the spleen to diminish in size. This loss of specialized macrophages means an impaired host defense system because these unique macrophages usually coordinate the first-responders monocyte deployment plan to sites of injury or infection in order to synthesize bioactive lipids to activate the resolution of inflammation.
Thus, Halade says, doxorubicin appears to have a splenocardiac impact in this non-cancer model. Knowledge of this mechanism may help explore strategies that will preserve spleen and heart health during doxorubicin treatment in cancer models.
Co-authors with Halade of the paper, “Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters inflammation-resolution program in the myocardium,” published in the journal in American Journal of Physiology-Heart and Circulatory Physiology, are Jeevan Kumar Jadapalli, Griffin W. Wright and Vasundhara Kain, Division of Cardiovascular Disease, UAB Department of Medicine; and Mohammad Asif Sherwani and Nabiha Yusuf, UAB Department of Dermatology.
Support for research was provided by National Institutes of Health grant HL132989 and a UAB Pittman Scholar Award.
While blood and marrow transplants can save the life of a pediatric cancer patient, research out of the University of Alabama at Birmingham found that those patients may be at an increased risk of premature death even years or decades after the procedure as compared with the general population.
Smita Bhatia, M.D., MPH, professor of pediatric oncology at UAB and director for the Institute for Cancer Outcomes and Survivorship at the UAB School of Medicine, served as the senior author of findings from an observational study in the Journal of the American Medical Association Oncology. The study analyzed data regarding cause of death for nearly 1,400 patients who lived two years or more after undergoing an allogenic blood or marrow transplant in their childhood between the years of 1974 and 2010.
Leading causes of death in the patient cohort were infection and chronic graft-vs-host disease, patients’ primary disease, and subsequent cancers. The data also indicated that the rate of later death among these transplant patients has decreased over the last three decades. The authors say it is promising to know that mortality rates have dropped, and the research gives more insight as to what causes late mortality in this population, and how to help other patients moving forward.
“This study shows that, while we are able to save the life of the child during their cancer treatment, we need to continue to provide proactive follow-up care with these types of patients throughout the rest of their life, as they are still an at-risk population,” Bhatia said. “The high intensity of therapeutic exposures at a young age lends itself to cause morbidities and organ compromise once they reach adulthood.”
Authors include researchers from the University of Alabama at Birmingham, University of Minnesota and City of Hope.
With the start of the school year just around the corner, it is easy to overlook one of the most important things on any back-to-school checklist — making sure your child is vaccinated. Vaccinations protect children from serious diseases, ultimately protecting families, schools and communities by way of safe and effective immunizations.
Whether your child is entering day care for the first time, going to middle school or heading off to college, University of Alabama at Birmingham physicians are answering some of the most commonly asked questions about immunizations, giving parents the proper resources and information needed to ensure that their child is up-to-date on all necessary vaccinations.
What is the benefit to vaccinating my child?
Vaccination is the most important way to protect your infant, child and teenager from harmful diseases, many of which are preventable and can be life-threatening. Vaccine-preventable diseases exist throughout the world and can cause outbreaks at any given time, even in our own country.
“The best way to treat diseases is to prevent them in the first place, and the diseases on the vaccine schedule are all preventable for the vast majority of our population,” said David Kimberlin, vice chair of UAB’s Department of Pediatrics, co-director of the Division of Pediatric Infectious Diseases, and also the American Academy of Pediatrics liaison to the CDC Advisory Committee on Immunization Practices. “The scientific evidence and public health statistics are comprehensive and compelling — properly scheduled and dosed vaccines are safe and effective, and they’re the reason we don’t see diseases like measles or whooping cough running rampant across our country.”
UAB’s Department of Pediatrics strongly supports the use of vaccines according to the schedule recommended by the American Academy of Pediatrics and the Centers for Disease Control and Prevention.
Are vaccinations mandatory for my child to go to school? How do I know which vaccinations my child needs and when?
Depending on the state you live in, immunization requirements may vary, but all states and the District of Columbia agree that students must meet the minimum requirement for dosing each school year to attend public schools. In many states, including Alabama, state law requires an updated Certificate of Immunization be presented prior to entering any public school or child care center.
As of Aug. 22, 2014, all 50 states and D.C. require vaccinations for diphtheria, tetanus and pertussis, polio, measles, and rubella; 49 states and D.C. also require mumps vaccination; 48 states and D.C. require varicella (chickenpox) vaccination (Montana and Pennsylvania do not); and 45 states and D.C. require hepatitis B vaccination (Alabama, Maine, Montana, North Dakota and South Dakota do not) to enter kindergarten. Some states require Hib, PCV, flu and Hep A vaccines to enter kindergarten.
Are school vaccinations free?
“Vaccines are part of standard care for children and are covered by insurance,” said Rachael Lee, M.D., assistant professor in UAB’s Division of Infectious Diseases. “Here in Alabama, our state has created a vaccines for children program to ensure cost is never an issue for families.”
As Lee notes, if you are in a position where you may not have access to health insurance, your state health department is a great resource. It can direct you to services which can offer low-cost and/or free immunizations, as well as provide other health and preventive-related resources to you and your child.
Where do I take my child to get their vaccinations?
You can take your child to their pediatrician to get their necessary vaccinations; but vaccinations are also available at local pharmacies, health centers and local health departments. Each state and D.C. have their own vaccination requirements to attend public school. It is best to check with your specific state health department to determine what immunizations are required.
Lee notes that, as a physician and a mother, she knows that it can be challenging for any parent to get their child to understand why getting a shot is important — a conversation that a pediatrician can also have when it is time for yearly immunizations.
“Vaccinating children can be hard; but I have found that, with my kids, by showing them my bandage and sore arm after getting the flu vaccine, I feel like they understand more about the importance of protecting ourselves from sickness, which turns into a great learning opportunity,” Lee said.
I’m entering college and/or postgraduate schooling. Are vaccinations required?
For students entering college or returning to a higher-education setting, there are specific vaccinations necessary for enrollment, so it is recommended that you check with your specific university to see what immunizations are required. Life-threatening infections such as meningococcal disease occur more commonly in college-age people, and can be prevented through full vaccination.
At UAB, students are able to check what specific immunizations they need through Student Health Services, as immunization requirements differ depending on your program of study and when you began attending UAB. Students of all pre-graduate and postgraduate levels can receive vaccinations and TB testing at the UAB Student Health and Wellness Center.
What if my child has not been previously vaccinated? Is it too late to start?
If you have not vaccinated your children previously, it is important talk with your child’s pediatrician about getting caught up, because it is possible and is highly recommended.
Stephen Russell, M.D., associate professor of internal medicine and pediatrics in UAB’s School of Medicine, says he has had parents who have previously rejected vaccinating their children change their mind. Whether it was because of their own further research, personally experiencing the devastation of one of these preventable diseases within their own family or through a friend’s family — or simply a change of heart — these parents have come to his UAB Medicine-Leeds clinic with one question: Now that we want to have our child vaccinated, what do we do?
“If parents who have previously not vaccinated their children decide they want to get the vaccines and get their children caught up, it can be done, and it can be done in one visit,” Russell said. “Many parents don’t know that, the sooner a child is vaccinated, the more effective those vaccines will be. Pediatricians can quickly help families get back on the vaccine schedule in a safe and effective manner.”
The CDC has also developed a “catch-up” schedule that parents can work with their pediatrician to follow.
What if vaccinations are against my religious beliefs?
All major religions endorse vaccination, including Christianity, Judaism, Islam and Buddhism. While most states offer medical and religious exemptions to vaccinations, and some states allow philosophical exemptions, the American Academy of Pediatrics views nonmedical exemptions to school-required immunizations as inappropriate for individual, public health and ethical reasons and advocates for their elimination. Both Kimberlin and Russell strongly encourage parents who have either rejected vaccinating their children or neglected to get vaccinations according to the CDC schedule to talk to their pediatricians now, and to make arrangements to get their children the vaccinations they need before the school year begins.
“It’s difficult for me to understand fully why someone would reject a medical miracle for their child, and that’s what vaccines are,” Kimberlin said. “The very success of the vaccination program is probably a big part of why we as physicians face these obstacles today, because parents don’t see measles, polio and rubella the way they did 30, 40, 50 and 60 years ago. So, they don’t have the perspective that their mothers, grandmothers and great-grandmothers had when it was common to lose a child to one of these now-preventable diseases.”
How can I pull my or my child’s immunization records?
According to the CDC, there are a few places to look to find immunization records. They recommend starting with the following agencies or organizations, as they should have a copy of their records on file:
- Your child’s pediatrician or public health clinic
- Your child’s state health department
- Your child’s school or day care center
- Your child’s college, should they be of adult age
How can I protect my children from HPV-related cancers, and when should I get them vaccinated?
According to Isabel Scarinci, Ph.D., professor in the UAB Division of Preventive Medicine and associate director for Globalization and Cancer at the UAB Comprehensive Cancer Center, more than 31,000 people will be diagnosed with human papillomavirus (HPV)-related cancer this year. Many of these cancers occur in both men and women and could be prevented by the HPV vaccine.
“The good news is that we now have a vaccine that has been proven to be effective against the HPV virus and that could eliminate multiple HPV-related cancers,” Scarinci said.
The Center for Disease Prevention and Control recommends the HPV vaccine for boys and girls between 11 and 12 years of age but they can start as early as 9 years of age. If they are between 9 and 14, they only need two shots six-months apart. If they are older than 14, then three shots are required.
“Teens who did not get the vaccine or did not get all doses when they were younger should get it now,” Scarinci said. “I cannot underscore enough that boys also need to get the vaccine because approximately 40 percent of HPV-related cancers occur among men.”
Wrinkled skin and hair loss are hallmarks of aging. What if they could be reversed?
Keshav Singh, Ph.D., and colleagues have done just that, in a mouse model developed at the University of Alabama at Birmingham. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age.
Importantly, the mutation that does this is in a nuclear gene affecting mitochondrial function, the tiny organelles known as the powerhouses of the cells. Numerous mitochondria in cells produce 90 percent of the chemical energy cells need to survive.
In humans, a decline in mitochondrial function is seen during aging, and mitochondrial dysfunction can drive age-related diseases. A depletion of the DNA in mitochondria is also implicated in human mitochondrial diseases, cardiovascular disease, diabetes, age-associated neurological disorders and cancer.
“This mouse model,” Singh said, “should provide an unprecedented opportunity for the development of preventive and therapeutic drug development strategies to augment the mitochondrial functions for the treatment of aging-associated skin and hair pathology and other human diseases in which mitochondrial dysfunction plays a significant role.”
The mutation in the mouse model is induced when the antibiotic doxycycline is added to the food or drinking water. This causes depletion of mitochondrial DNA because the enzyme to replicate the DNA becomes inactive.
In four weeks, the mice showed gray hair, reduced hair density, hair loss, slowed movements and lethargy, changes that are reminiscent of natural aging. Wrinkled skin was seen four to eight weeks after induction of the mutation, and females had more severe skin wrinkles than males.
Dramatically, this hair loss and wrinkled skin could be reversed by turning off the mutation. The photos below show the hair loss and wrinkled skin after two months of doxycycline induction, and the same mouse a month later after doxycycline was stopped, allowing restoration of the depleted mitochondrial DNA.
Little change was seen in other organs when the mutation was induced, suggesting an important role for mitochondria in skin compared to other tissues.
The wrinkled skin showed changes similar to those seen in both intrinsic and extrinsic aging — intrinsic aging is the natural process of aging, and extrinsic aging is the effect of external factors that influence aging, such as skin wrinkles that develop from excess sun or long-term smoking.
Among the details, the skin of induced-mutation mice showed increased numbers of skin cells, abnormal thickening of the outer layer, dysfunctional hair follicles and increased inflammation that appeared to contribute to skin pathology. These are similar to extrinsic aging of the skin in humans. The mice with depleted mitochondrial DNA also showed changed expression of four aging-associated markers in cells, similar to intrinsic aging.
The skin also showed disruption in the balance between matrix metalloproteinase enzymes and their tissue-specific inhibitor — a balance of these two is necessary to maintain the collagen fibers in the skin that prevent wrinkling.
The mitochondria of induced-mutation mice had reduced mitochondrial DNA content, altered mitochondrial gene expression, and instability of the large complexes in mitochondria that are involved in oxidative phosphorylation.
Reversal of the mutation restored mitochondrial function, as well as the skin and hair pathology. This showed that mitochondria are reversible regulators of skin aging and loss of hair, an observation that Singh calls “surprising.”
“It suggests that epigenetic mechanisms underlying mitochondria-to-nucleus cross-talk must play an important role in the restoration of normal skin and hair phenotype,” Singh said, who has a secondary UAB appointment as professor of pathology. “Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wildtype level by restoration of mitrochondrial DNA.”
Co-authors with Singh for the paper, “Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function,” published in the Cell Death and Disease, a Nature online journal, are Bhupendra Singh, Trenton R. Schoeb and Prachi Bajpai, UAB Department of Genetics; and Andrzej Slominski, UAB Department of Dermatology.
This work was supported by Veterans Administration grant 1I01BX001716 and National Institutes of Health grants CA204430, AR071189-01A1 and AR073004.
At UAB, Singh holds the Joy and Bill Harbert Endowed Chair in Cancer Genetics, and Slominski holds the Endowed Professorship in Basic Research in the Department of Dermatology.
Mickey Nunn mowed his grass this summer. That might not seem like much, but it was the first time in more than three years. The 66-year-old from a small town near Gadsden, Alabama, was diagnosed with prostate cancer in 2008. It got worse over the years, and the traditional therapies just were not working. He underwent 42 radiation treatments and 17 rounds of chemotherapy.
“Nothing was working,” Nunn said. “I was nearly bedridden, in pain and not getting any better.”
His PSA scores were sky-high. PSA, or prostate-specific antigen, is a protein produced by the prostate gland. The PSA test indicates the amount of the protein in a man’s blood — a score higher than 4 is considered a risk factor for prostate cancer. Even after all that radiation and chemotherapy, Nunn’s PSA score was 99.
Nunn was a patient at the University of Alabama at Birmingham Comprehensive Cancer Center. He did not know it, but he was about to benefit from a new research program in precision oncology — using the genetic makeup of a patient’s tumor to determine the optimum therapy for that patient.
“Precision oncology is a relatively new concept, and it is changing how we provide cancer care,” said Eddy Yang, M.D., Ph.D., professor and vice chair of translational sciences in the UAB Department of Radiation Oncology, deputy director of the Hugh Kaul Precision Medicine Institute, and director of the UAB Molecular Tumor Board. “We used to treat a patient based on the type of tumor — one size fits all. With precision oncology, we treat based on the genetic signature of that tumor, not necessarily its location in the body.”
UAB expanded its precision oncology efforts in May 2017 with a partnership with Strata Oncology to provide tumor profiling for patients with advanced or rare cancers. In some cases where the tumor profiling does not yield a treatment match, further analysis could be performed with another test using blood from the patient.
“Tumors can shed cells and DNA into the blood stream, so we can send a blood sample for analysis,” Yang said. “It’s a simple blood draw and less invasive than a biopsy. We then look for key mutations or changes in the copy number of cancer driver genes. We can then turn to medications that are known to target these mutations.”
Early in 2017, Nunn saw a TV news story about such testing and told his wife he would be interested in participating if they could find where the work was being done. She promised to make some calls, but Yang’s office beat her to it. Knowing that Nunn’s cancer was not responding to traditional therapy, they called to tell him he was a candidate for UAB’s precision oncology trials.
Following analysis of Nunn’s blood, Yang determined that his tumor, based on its genetic signature, might respond to a drug already on the market for ovarian cancer, olaparib, marketed under the name Lynparza.
“I had already told my doctors I was willing to try any new medicine they suggested,” Nunn said. “They told me I matched well to this ovarian cancer drug, and I said ‘let’s do it.’”
So they tried it. And it is working.
Nunn reports his PSA number dropped from 99 to 64 after just one month on olaparib. By mid-summer, it had fallen to just over 10.
“I feel the best I have in 10 years,” Nunn said. “I used to have bad back pain, but I was able to stop taking my pain medicine just three days after starting on olaparib. Now I can get out, work in the yard and take care of the house like I used to.”
Nunn says the whole experience has been a godsend to him.
“I really consider myself blessed, to have had the opportunity to take part in this research effort and to see the effect the drug has had on reducing my PSA numbers,” he said. “This all goes through God and I believe it was all meant to be.”
“In the past, when we began testing a new drug or therapy, we typically saw a response rate in Phase 1 studies of 10, maybe 20 percent of patients,” Yang said. “With genetic-based studies, we are seeing a drug response rate much higher in patients who match to therapy, which is very exciting.”
Yang says precision medicine is complicated. Informatics is the key, as it requires a lot of data.
“We need data about the tumor and about the patient,” he said. “We need information on the living environment, diet and other co-morbidities. We need to expand the knowledge base and find the necessary ways to integrate all this information in our treatment strategies so we can more effectively treat each individual patient.”
Three new UAB entities are helping Yang push to make precision oncology the new standard of care. UAB created the Hugh Kaul Precision Medicine Institute, the UAB Informatics Institute and the UAB HudsonAlpha Center for Genomic Medicine in 2015. All three are paving the way for significant growth and acceleration of personalized medicine in Alabama, the region and beyond.
These programs, housed in the School of Medicine, are pulling together scientists and physicians from a variety of disciplines to bear on a multitude of diseases and disorders. The goal is to expand research into the genetic factors related to diseases and create precisely targeted treatments based on a patient’s individual genetic makeup.
“I like where things are going,” Yang said. “Perhaps the most important key in this groundbreaking effort is that the physicians and the patients will be equipped with information upfront and sooner about their cancer, and that can go a long way.”
A viral immunotherapy using a herpes virus to treat brain tumors has been shown to be safe and well-tolerated in a pediatric study from the University of Alabama at Birmingham and Children’s of Alabama. The findings, presented today at the International Symposium on Pediatric Neuro-Oncology in Denver, also showed preliminary evidence of effectiveness in killing malignant tumor cells.
The virus, known as G207, is derived from the herpes virus responsible for cold sores. The virus is genetically altered so that it infects only tumor cells. When infused into a malignant brain tumor, the virus enters the tumor cells and replicates. This kills the cell and releases the virus’s progeny to hunt out other tumor cells. Additionally, the virus induces a strong immune response by the body’s immune system, which can attack the tumor.
Six pediatric subjects have been treated with G207 in the current trial. No dose-limiting toxicities or serious side effects occurred. Five of the six patients had evidence of tumor killing by the virus, including a patient who is over 18 months out with an ongoing response to the therapy without any other treatment.
“Our findings indicate that G207 is safe and tolerable in children with progressive malignant brain tumors,” said Gregory Friedman, M.D., primary investigator of the study and an associate professor in the UAB Division of Pediatric Hematology-Oncology in the Department of Pediatrics, and Children’s of Alabama and an associate scientist in the UAB Comprehensive Cancer Center. “Preliminary evidence of efficacy is very promising to date. The next phase of the study will test the safety of G207 combined with a single low dose of radiation, which is being used to enhance virus replication and the immune response against the tumor, within 24 hours of virus inoculation.”
Brain tumors are the most common solid tumor in children, and aggressive types like glioblastoma have an extremely low survival rate: as low as 10 percent five years after diagnosis. Even tumors successfully treated by surgery, radiation and/or chemotherapy have a high rate of recurrence and eventual death.
The use of genetically-engineered oncolytic viruses, those that selectively kill cancer cells as a treatment for brain tumors and other cancers, is the product of more than 20 years of research at UAB by James Markert, M.D., MPH, chair of UAB’s Department of Neurosurgery and senior scientist in the UAB Comprehensive Cancer Center. The concept was described in the literature in 2001 by Markert and his colleagues. A second-generation virus, called M032, has been developed by Markert and collaborators Yancey Gillespie, Ph.D., professor of neurosurgery, and Richard Whitley, M.D., distinguished professor of pediatric infectious disease, and is in clinical trials at UAB in adults with glioblastoma, the most deadly of primary brain tumors.
Friedman says the ability of the virus to kill a cancer cell is valuable, but the real benefit comes from its effect on the immune system. Cancer cells are very good at avoiding detection by the immune system’s killer T cells, meaning that the body does not recognize or mount a vigorous immune response to brain tumors. G207 appears to stimulate the immune system, provoking a robust and continued immune response in some patients.
M032 takes that a step further by introducing a cytokine called Interleukin-12, which acts on nearby lymphocytes and natural killer cells to induce an even stronger antitumor immune response. It also inhibits angiogenesis — the creation of new blood vessels — thereby shutting off the blood supply to tumor cells, denying oxygen and essential nutrients.
“High-grade glioma is a devastating diagnosis,” Friedman said. “We have made very little progress in developing effective therapies over the past 10-15 years. Viral immunotherapy shows great promise at treating all types of malignant brain tumors, although this approach needs to be studied further. But, I think we are on the cusp of a major development.”
Funding for the clinical trial is being provided by the United States Food and Drug Administration, and funding to develop this therapy has been provided by the NIH/NCI, Department of Defense, St. Baldrick’s Foundation, Rally Foundation for Childhood Cancer Research, Cannonball Kid’s Cancer Foundation, Hyundai Hope on Wheels, Vs. Cancer Foundation and the Truth 365.
A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy.
Paradoxically, the sending cells in this signaling are glioblastoma cells that are undergoing programmed cell death, or apoptosis, according to research by a team at institutes in the United States, Russia and South Korea.
The dying cancer cells send their signals by means of extracellular vesicles induced and released during apoptosis. These vesicles — small, membrane-bound blobs known as exosomes — carry components that alter RNA splicing in the recipient glioblastoma cells, and this altered splicing promotes therapy resistance and aggressive migration.
This mechanism thus becomes a possible target for new therapies to treat glioblastoma, a primary brain cancer, and the mechanism may apply to other cancer types as well.
“Clinically, our data may provide the rationale to the molecular targeting of RNA splicing events or specific splicing factors for novel cancer therapies,” said Ichiro Nakano, M.D., Ph.D., leader of the international study being published in Cancer Cell. “This may lead to decreased acquisition of therapy resistance, as well as reduction in the migration of cancer cells.”
Nakano is an academic neurosurgeon at the University of Alabama at Birmingham who conducts both brain tumor translational research and clinical brain tumor surgery. He is professor of neurosurgery in the UAB School of Medicine and a senior scientist for the UAB Comprehensive Cancer Center.
Glioblastoma exhibits invasive behavior, abrupt growth and poor patient survival. As the number of the cancer cells rapidly increases, abundant apoptotic tumor cells are intermingled with neighboring proliferating tumor cells. The apoptotic cells can account for up to 70 percent of the tumor cell population.
The discovery of this unusual cell-to-cell communication began with a simple experiment — injecting a combination of lethally irradiated human glioblastoma cells, which makes them apoptotic, and “healthy” glioblastoma cells into a mouse xenograft model. This combination led to much more aggressive tumor growth, as seen in brain scans, compared to “healthy” glioblastoma cells or irradiated glioblastoma cells alone. The combination was also more therapy-resistant.
The UAB researchers and colleagues found that, after induction of apoptosis, glioblastoma cells shed significantly higher numbers of exosomes with larger average sizes.
Those apoptotic exosomes, when combined with “healthy” glioblastoma cells, significantly increased tumor growth in the xenograft model and cell motility in bench experiments. Also, while the “healthy” glioblastoma cells alone had a clear border between the tumor and adjacent normal tissue in the xenograft, the glioblastoma cells co-injected with apoptotic exosomes invaded into adjacent brain tissue. Exosomes shed by non-apoptotic cells did not have these effects.
To discover the mechanism underlying these changes, the researchers looked at what was inside the apoptotic exosomes. The vesicles were enriched with spliceosomal proteins and several U snRNAs — parts of the cellular machinery that remove introns from pre-messenger RNA.
These are normally confined to the nuclei of cells; but the Nakano team found that, as the glioblastoma cells underwent apoptosis, the spliceosomal proteins were transported out of the nucleus to the cell cytoplasm, where they could be packaged into vesicles for release.
Glioblastoma cell subtypes include the proneural subtypes and the mesenchymal subtype. Recent data have shown that, after therapy, glioblastoma cells shift from the less aggressive proneural subtype to the more aggressive and therapy-resistant mesenchymal subtype. The researchers found that apoptotic exosomes induced substantial alternate RNA splicing in recipient cells that resembled the splicing patterns found in the mesenchymal glioblastoma subtype.
Part of this was caused by the splicing factor RBM11, which is encapsulated in the vesicles. The researchers found that exogenous RBM11 caused upregulation of endogenous RBM11 in the recipient cells and activated glycolysis. Overexpression of RBM11 increased the migration of glioblastoma cells.
They also found that RBM11 altered RNA splicing to produce an isoform of the protein cyclinD1 that promotes DNA repair and an isoform of the protein MDM4 that has significantly higher anti-apoptotic activity. These changes can make the cells more therapy-resistant.
Examination of the Cancer Genome Atlas database showed that elevated expression of those two isoforms is associated with poor prognoses for glioblastoma patients.
Finally, the Nakano-led team looked at paired glioblastoma specimens of primary and recurrent tumors from matched patients. In most of the 43 pairs of matched samples, the RBM11 protein levels were substantially higher in the recurrent glioblastoma compared to the original, untreated tumors. In two other patient cohorts, they found that the higher RBM11 levels correlated with poor post-surgical survival for glioma patients.
Beside Nakano, co-authors of the paper, “Apoptotic cell-derived extracellular vesicles promote malignancy of glioblastoma via intercellular transfer of splicing factors,” are Marat S. Pavlyukov, Hai Yu, Soniya Bastola, Mutsuko Minata, Suojun Zhang, Jia Wang, Svetlana Komarova, Jun Wang, Shinobu Yamaguchi and Heba Allah Alsheikh, UAB Department of Neurosurgery; Victoria O. Shender, Ksenia Anufrieva, Nadezhda V. Antipova, Georgij P. Arapidi, Vadim Govorun, Nikolay B. Pestov and Mikhail I. Shakhparonov, the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Yeri Lee, Yong Jae Shin and Do-Hyun Nam, Sungkyunkwan University School of Medicine, Seoul, Korea; Ahmed Mohyeldin, Junfeng Shi and L. James Lee, Ohio State University, Columbus, Ohio; Dongquan Chen, UAB Division of Preventive Medicine; Sung-Hak Kim, Chonnam National University, Gwangju, Korea; and Evgeniy G. Evtushenko, Lomonosov Moscow State University, Moscow, Russia.
This work was supported by NIH grants NS083767, NS087913, CA183991 and CA201402; Russian Foundation for Basic Research grants 16-04-01414, 16-04-01209 and 17-29-06056; and Russian Science Foundation grants 17-75-20205 and 16-14-10335; and by the Scholarships of the President of the Russian Federation SP-4811.2018.4.
At UAB, Nakano surgically cares for brain tumor patients. For any questions about his clinical program, call 205-996-2098 during working hours or 205-572-9703 at night or on weekends.
After an eight-year struggle to figure out why a lump formed under her jaw, to say Valerie Powell believes all things work together for good is an understatement.
In 2009, Powell, program coordinator in the University of Alabama at Birmingham’s Department of Radiation Oncology, noticed a tiny nodule near the hook of her jaw that had not been there before. She assumed it must be a side effect of the several Novocain shots she received at the dentist for a cavity filling. After calling her doctor, Powell received regular CT scans, which provided no further insight.
After six years, Powell’s mother was diagnosed with breast cancer, which led to Powell’s wanting another CT scan for her nodule.
“I figured after Mom’s diagnosis and the fact this little nodule had obviously gotten angrier in size and tenderness that I should check on things again,” she said.
Her doctors determined that she had an extra piece in her parotid gland and advised her not to worry.
Things began to change for Powell after she landed her program coordinator job in UAB Radiation Oncology in March 2017. She started researching oncology protocols as part of her duties, and the first protocol she reviewed was a salivary gland tumor study, which persuaded her to try another CT scan from a different clinic, which also proved to be inconclusive. She also received an MRI, which showed the same results.
Powell knew something was wrong and demanded answers.
“I was pretty frustrated, so I emailed one of our radiation oncologists at UAB and explained that two doctors at a different local hospital were unable to figure out what it was,” she said. “I asked if he could take a look at my scans.”
Soon after, Powell found herself scheduling an appointment with Department of Otolaryngology Chair and Comprehensive Cancer Center Senior Scientist William Carroll, M.D. The nodule in question was diagnosed as pleomorphic adenoma — a common benign salivary gland tumor.
“We scheduled surgery to remove the tumor because Dr. Carroll said he would remove it no matter what if I were his family member,” she said. “From the moment I met Dr. Carroll, he did feel like family. He’s always been patient and understanding, and he’s always done his absolute best to make sure I left his office confident and comfortable with the care I was receiving, and I would say that that’s hard to find.”
After the tumor was removed and pathology tests returned, it was determined that the tumor wasn’t actually benign; it was malignant.
“I was flooded with questions in my head like ‘Why did a CT, an MRI and a needle biopsy all confirm that my tumor was benign when it was in fact cancerous,’” Powell said. “Why was this happening to me at 28 when I’ve barely been married two and a half years, and why had no one paid more attention to this knot in my neck for the last seven years since it had shown up?”
The more she thought about it, Powell says, her faith reassured her that things worked out the way they were supposed to.
“I was supposed to go into surgery knowing it was benign because my little heart couldn’t have handled going into surgery knowing that I had let something dangerous live inside of me for that long,” she said. “God knew I needed the excitement of getting it out to carry me into that operating room with peace and a feeling of security.”
In September of 2017, Powell began seeing Sharon Spencer, M.D., professor in the Department of Radiation Oncology and senior scientist with the Comprehensive Cancer Center, for her radiation treatments. It was a familiar setting for Powell since she walked the path every day to her office, which resides just a few steps from patient care areas. She worked closely with Spencer in the months leading up to her diagnosis and treatment.
“This was kind of a neat plot twist in the workplace because I showed up to see Dr. Spencer as a patient instead of needing her signature,” Powell said.
After six weeks of daily radiation, Powell’s co-workers threw her a party to celebrate her final day of treatment.
“When I saw 50-plus people crammed in our break room yelling congrats at me, I lost it,” Powell said. “People from every single department — physicians, residents, billing, check-in, dosimetry, therapy, social work, administration and physics. They had all come for me, and right in the middle was my precious husband, K.T., my parents and my brother.”
Powell credits many people — at work and at home — who helped dry her tears, listened to her worries, and saw how the effects of radiation affected her physically and mentally. She says it was a hard road, but it was exactly where she was supposed to be.
“This was the road that led me to the career I never knew I needed,” she said, “and the career move that saved my life.”
Powell hopes to empower cancer patients and survivors through her blog where she documented her treatment and recovery. Click here to follow her journey.
Nearly 80 million Americans — one out of every four people — are infected with the human papillomavirus, and more than 31,000 will be diagnosed with an HPV-related cancer this year. Despite the availability of a vaccine to prevent the infections that cause these cancers, HPV vaccination remains low in the United States.
The UAB Comprehensive Cancer Center has partnered with 69 other National Cancer Institute-designated cancer centers to issue a statement urging for increased HPV vaccination and screening to eliminate HPV-related cancers, starting with cervical cancer. These institutions collectively recognize insufficient vaccination as a public health threat and call upon the nations’ health care providers, parents and adolescents to take advantage of this rare opportunity to eliminate several different types of cancer in men and women.
“We have the opportunity to eliminate multiple HPV-related cancers beginning with cervical cancer,” said Michael Birrer, M.D., Ph.D., director of the UAB Comprehensive Cancer Center. “To accomplish this goal, we need to utilize our most important tool — HPV vaccination. We hope our collective action as NCI-designated cancer centers will educate and motivate the public and highlight this tremendous opportunity we have to eliminate a preventable cancer.”
Vaccination rates remain significantly lower than other recommended adolescent vaccines in the United States. According 2016 data from the Centers for Disease Control, less than 50 percent of girls and 38 percent of boys completed the recommended vaccine series. Research shows there are a number of barriers to overcome to improve vaccination rates, including a lack of strong recommendations from physicians, and parents’ not being properly informed that this vaccine protects against several types of cancer in men and women. HPV causes multiple cancers, including cervical, anal, oropharyngeal (middle throat) and other genital cancers.
UAB Division of Gynecologic Oncology and senior medical officer for the cancer service line at the UAB Comprehensive Cancer Center, has tested several HPV vaccines. He was one of the first to test Gardasil, the first U.S. Food and Drug Administration-approved vaccine for the prevention of cervical cancer and genital warts. Huh was a lead author with a multinational study of a new nine-valent HPV vaccine that has even further potential to dramatically reduce rates of cervical cancer and perhaps eliminate cervical cancer screening altogether.UAB has been at the forefront of conducting groundbreaking cancer research, especially in developing the HPV vaccine. Warner Huh, M.D., director of the
“There is no question that the vaccine works,” Huh said. “We now have a second-generation vaccine that protects against 90 percent of the HPV that are associated with cervical cancer. This vaccine can literally eradicate the majority of cervical cancer, if given widely and appropriately.
“We need health care providers to stand with us and recommend the HPV vaccine. Parents can join with us by asking their doctors about the vaccination.”
HPV experts from the nation’s top cancer centers, including the UAB Comprehensive Cancer Center, along with partners from the NCI, CDC and the American Cancer Society, are meeting June 7-8 in Salt Lake City to discuss a path forward to eliminating cancers caused by HPV, including ways to reduce barriers to vaccination, as well as share education and training strategies to improve vaccination rates.
“In addition to being at the forefront of research, the UAB Cancer Center along with multiple stakeholders across the state established the Alabama HPV Vaccination Coalition, which has been a model for other states across the country,” said Isabel Scarinci, Ph.D., professor in the UAB Division of Preventive Medicine and associate director for Globalization and Cancer at the UAB Comprehensive Cancer Center.
“This movement is no longer just in the hands of the medical community, as cervical cancer screening and vaccination discoveries are already in existence,” she said. “There are many socio-economic and cultural reasons that stand in the way of adherence. But I am optimistic that we can legitimately move the needle as the scientific, public and private sectors combine efforts and expertise, with Alabama’s being one of the leaders in this effort.”
This is the third year that all NCI-designated cancer centers have come together to issue a national call to action. All 70 cancer centers unanimously share the goal of sending a powerful message to parents, adolescents and health care providers about the importance of HPV vaccination for the elimination of HPV-related cancers.