Indoor Tanning May Be an Addiction Abetted by Both Genetic and Psychiatric Factors

WASHINGTON — A combination of elevated symptoms of depression along with modifications in a gene responsible for dopamine activity, important to the brain’s pleasure and reward system, appear to influence an addiction to indoor tanning in young, white non-Hispanic women.

That finding comes from a new study, reported by researchers at Georgetown Lombardi Comprehensive Cancer Center and published online June 11 in Annals of Behavioral Medicine.

Excess exposure to ultraviolet radiation can lead to melanoma and non-melanoma skin cancer. Most UV exposure is from the sun, but exposure from indoor tanning is common in certain people and accounts for 10 percent of skin cancer cases in the U.S. There will be an estimated 96,480 new cases of melanoma in the United States and 7,230 deaths from the disease in 2019.

This study compiled survey responses from 292 non-Hispanic white women in the Washington, D.C. area, 18 to 30 years of age, who used indoor tanning beds, sunlamps, or sun booths. The survey asked questions about values and behaviors that might predispose a person to a tanning addiction, as well as a series of questions to determine if they had symptoms of depression.

The researchers also collected saliva samples to obtain DNA to look for 34 single nucleotide polymorphisms (SNPs) in five different genes. SNPs are changes in one of the base molecules on a strand of DNA. The specific SNPs that researchers looked at were in genes known to be related to pathways that reward addictive behavior.

“By demonstrating that genes in behavioral reward pathways are associated with tanning addiction, we are providing stronger evidence that tanning addiction is a cancer risk behavior in need of intervention,” says lead author Darren Mays, PhD, MPH, an associate professor of oncology and member of the Cancer Prevention and Control Program at Georgetown Lombardi. “This finding adds to a growing body of evidence from animal studies and neuroimaging studies that have been done in humans.”

The researchers adjusted their analyses based on indoor tanning frequency, value of appearance, and depressive symptoms. They found a more than two-fold increased odds of indoor tanning addiction in modifications to the rs4436578 SNP and a slightly less than two-fold increased odds of addiction in modifications to the rs4648318 SNP. When looking at whether the SNPs interacted with depressive symptoms to increase the risk of indoor tanning-addiction, they found a more than 10-fold increase if there were modifications to the rs4436578 SNP and a more than 13-fold increase in the rs4648318 SNP. This knowledge should be helpful if screening for risk of addiction is shown to be beneficial in reducing the chance that people will engage in a cancer-causing activity.

Mays work in tanning addiction continues with a study, just getting underway, that will explore the effectiveness of text messaging as an intervention to help young women quit if they are addicted to indoor tanning. The research is funded by the Prevent Cancer Foundation.

“This grant will enable us to test behavioral interventions in young women who are addicted to indoor tanning,” Mays says. “We have used text messaging to intervene in other behaviors and have found that the personalized conversation we can deliver through this medium can help people take steps to quit.”

In addition to Mays, authors include Jaeil Ahn, PhD, and Bingsong Zhang, MS, from the Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center and Michael B. Atkins, MD, David Goerlitz, MS, and Kenneth P. Tercyak, PhD, from Georgetown Lombardi.

Media Contact

Brendan McNamara 
Office: 703-558-1593
Cell: 571-314-2942
[email protected]

National Cancer Institute Renews Prestigious Designation of Georgetown Lombardi Comprehensive Cancer Center

(Washington, D.C) - MedStar Georgetown University Hospital is proud to announce that the National Cancer Institute (NCI) has once again designated its research partner, Georgetown Lombardi Comprehensive Cancer Center, with its coveted distinction, "comprehensive cancer center."

First awarded to Georgetown Lombardi in 1974, MedStar Georgetown University Hospital serves as one of the cancer center’s primary hospital affiliates in Washington D.C.  Additionally, for the first time, MedStar Washington Hospital Center was also named as a Georgetown Lombardi primary hospital affiliate. 

"As the only NCI-designated comprehensive cancer center in the District of Columbia, we’re able to offer a comprehensive suite of services to our patients, providing them with research-inspired cancer care that they simply can't get anywhere else," says Dr. Louis M. Weiner, director of Georgetown Lombardi and the MedStar Georgetown Cancer Institute.

The MedStar Georgetown Cancer Institute combines medical expertise, the latest therapies, and research across the region. "What makes us special is the concept of cura personalis, or the care of the whole person. We don't treat diseases – we use evidence-based medicine to treat people in the context of their own lives, families, and communities. Having cancer is very frightening. Being a cancer patient can be a lonely journey.  At our hospital, you're going to be treated like a person, not like a disease," says Dr. Weiner. 

Of the 1,500 cancer programs in the United States, only 50 have this prestigious designation and Georgetown Lombardi is the only such center in the Washington, D.C. area.  

In order to renew its NCI designation, the cancer program in 2018 went through a rigorous, peer-reviewed grant renewal process conducted by cancer center experts from across the country. The renewal occurs every three to five years.

M. Joy Drass, MD, Executive Vice President and Chief Operating Officer of MedStar Health, says, "As the clinical partner for Georgetown Lombardi, our patients receive personalized care from physicians who are also, through innovative clinical trial research, offering breakthrough advancements in diagnostics, new technologies, and novel therapeutics. Our long-standing partnership provides patients with unparalleled access to a multidisciplinary team of experts, clinicians, and researchers who are leading the way in how cancer is detected and treated."

The NCI approved Georgetown Lombardi as a "consortium center" reflecting an integrated cancer research program with John Theurer Cancer Center, part of Hackensack Meridian Health in New Jersey. MedStar Georgetown, Georgetown Lombardi, and John Theurer began their clinical and research relationship in 2013 through which the world-class Bone Marrow and Blood Stem Cell Transplant Program at MedStar Georgetown was established. Because of this program MedStar Georgetown has been able to offer patients with blood cancers the latest in bone marrow transplantation, CAR T cell therapy and other new immunotherapies that require the infusion of cells into people to attack cancer.

Cancer-fighting technologies like proton therapy, which opened at MedStar Georgetown in 2018, and CyberKnife that has been used to treat cancers at the hospital since 2002 are also examples of the cutting-edge care available to treat patients in the region. 

The NCI designation as a comprehensive cancer center indicates that Georgetown Lombardi excels in laboratory science, clinical research and population-based programs, along with robust translational research that bridges these areas. It also demonstrates expansive public education and outreach capabilities, which focus on the community.

The populations in Washington, D.C., and in Bergen County, New Jersey, where the John Theurer Cancer Center is located have some of the highest cancer incidence and death rates in the country. Georgetown Lombardi researchers are working on new ways to address the underlying causes so that strategies to address these health disparities can be implemented and refined.

Edward B. Healton, MD, MPH, Executive Vice President for Health Sciences and Executive Dean of the medical school at Georgetown University Medical Center underscores the critical role of Georgetown Lombardi in the communities it serves.

"An important aspect of the research, outreach and education activities carried out at Georgetown Lombardi focuses on eliminating disparities in minority and medically underserved populations," Healton says. "This is especially important in the communities served by both Georgetown and Hackensack, as our special collaboration has the potential to be deeply impactful."

Media Contact

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

Brendan McNamara 
Media Relations Specialist
Office: 703-558-1593
[email protected]

Researchers Decode How Cancer Drug Works in Brains of Parkinson’s Disease Patients

WASHINGTON  — Laboratory analysis from the first arm of a phase II clinical trial testing the use of nilotinib in patients with Parkinson’s disease demonstrates precisely how the agent increases levels of dopamine in the brains of study participants, says a research team at Georgetown University Medical Center. Symptoms of Parkinson’s, such as motor dysfunction, are a result of a dopamine loss.

In the journal Pharmacology Research & Perspectives, investigators report that a single low dose of the leukemia drug, nilotinib (Tasigna® by Novartis), reduces levels of a toxic protein that prevents the brain from utilizing dopamine that is stored in tiny vesicles, or pockets, in brain areas that may control movement.

The researchers say nilotinib appears to rev up the ability of immune cells within the brain to reduce the constant flow of the misshapen alpha-synuclein protein produced by damaged neurons, allowing normal alpha-synuclein to facilitate release of stored dopamine. 

“We detect the drug in the brain producing multiple effects, including improving dopamine metabolism reducing both inflammation and toxic alpha-synuclein. This is unprecedented for any drug now used to treat Parkinson’s disease,” says the study’s senior author, Charbel Moussa, MBBS, PhD, director of the Laboratory for Dementia and Parkinsonism, and scientific and clinical research director of the Translational Neurotherapeutics Program at Georgetown University Medical Center.

The research team examined cerebral spinal fluid (CSF) and plasma collected from patients participating in the clinical trial to examine Parkinson’s disease biomarkers. The CSF was collected after a single dose of nilotinib or placebo was administered.

Researchers examined levels of dopamine breakdown products, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the CSF that bathes the brain and spinal cord of patients, after nilotinib or placebo. They also looked at levels of TREM-2, which reflects the immune response to inflammation.

Without nilotinib treatment, DOPAC and HVA were at low levels in the CSF of all patients. These molecules are produced when dopamine is broken down, or metabolized. A low level suggests a low level of dopamine is being used in the brain.

Investigators divided participants into five groups to test different drug levels (150, 200, 300 or 400 mg.) or a placebo. After a single dose of nilotinib, they found DOPAC and HVA were elevated in patients who received nilotinib compared to placebo, suggesting the brain was utilizing substantially more dopamine. The optimal dose of nilotinib for elevating DOPAC and HVA, they found, was 200 mg.

“When the drug is used, levels of these breakdown molecules quickly rise. This is what we also found in our preclinical studies and proof of concept clinical trial,” says Moussa. “This is exciting because this kind of potential treatment for Parkinson’s could increase use of a patient’s own dopamine instead of using or periodically increasing drugs that mimic dopamine.”

They also found 150 mgs dose of nilotinib treatment led to a significant reduction of alpha-synuclein in the blood, outside of the CSF. Alpha-synuclein is typically very high, and may be toxic, in the blood of Parkinson’s disease patients.

In addition, the single dose of nilotinib (200 mg.) significantly increased the CSF level of TREM-2 in patients. “This suggests an elevated beneficial immune activity that targets misfolded alpha-synuclein for destruction.

“The TREM-2 findings fit neatly with DOPAC and HVA findings,” Moussa says.

He explains that under normal circumstances, the brain stores as much dopamine neurotransmitter as it can and uses it regularly to transmit messages across neurons. Research suggests that normal alpha-synuclein helps maintain the vesicles that dopamine is stored in and helps release the neurotransmitter when needed. But in Parkinson’s disease, dopamine-secreting neurons produce alpha-synuclein that is folded up (misfolded), and so cannot mediate dopamine re-cycling and breakdown. Eventually, more and more dopamine-secreting neurons emit the tangled protein and die.

In preclinical studies, Moussa says nilotinib appears to trigger brain cells (including immune cells and neurons) to attack the misfolded protein that is being produced, allowing normal alpha-synuclein to access and release dopamine from storage vesicles. Hence the increase in TREM-2 and dopamine breakdown chemicals in the central spinal fluid, Moussa says. Dopamine produced in the brain is then recycled, stored in vesicles and available for future use. The cycle repeats itself over and over.

Dr. Fernando Pagan
Dr. Fernando Pagan

Fernando Pagan, MD, principal investigator of the clinical trial and first author of the paper says the scientific evaluation of nilotinib’s effect suggest it can reduce toxic alpha-synuclein and brain inflammation, while protecting dopamine and dopamine-secreting neurons. Pagan is medical director of Georgetown’s Translational Neurotherapeutics Program and director of the Movement Disorders Clinic at MedStar Georgetown University Hospital.

 “Whether or not, or how much, the drug demonstrates improved clinical outcomes will be determined when the phase II clinical trial results are in,” he says.

###

Additional study authors included Michaeline L, Hebron, MS, Barbara Wilmarth, CRNP, Yasar Torres-Yaghi, MD, Abigail Lawler, MD, Elizabeth E Mundel, MD, Nadia Yusuf, MD, Nathan J Starr, DO, Joy Arellano, RN, Helen H. Howard, RN, Margo Peyton, Sara Matar, BS, Xiaoguang Liu, MD, PhD, Alan J. Fowler, Sorell L. Schwartz, PhD, and Jaeil Ahn, PhD.

Georgetown holds an issued US patent for the use of nilotinib for the treatment of certain neurodegenerative diseases and has other pending patent applications in US and foreign jurisdictions. Moussa is also the named inventor on this related intellectual property.

This study was supported by the Lasky-Barajas Family Fund and other donors. Novartis, the maker of nilotinib, provided nilotinib and matching placebo free of cost to Georgetown University for all participants while on the study.

Media Contact

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

Brendan McNamara 
Media Relations Specialist
Office: 703-558-1593
[email protected]

Large Study Reveals Long-Term Outcomes for Prostate Cancer Patients Treated with High Dose, Short Term Radiation like CyberKnife Radiotherapy

WASHINGTON –– A large, national study examining a radiation treatment for prostate cancer––popular because it delivers a high dose of therapy in a very short time frame––supports its routine use. 

The study, conducted at cancer centers around the United States including at Georgetown Lombardi Comprehensive Cancer Center, looks at long term follow up data for stereotactic body radiotherapy (SBRT) used to treat more than 2,100 men with prostate cancer that had a low or intermediate risk of recurring.

The results were published Feb. 8 in the journal JAMA Network Open.

At MedStar Georgetown University Hospital, the therapy is delivered by a system called CyberKnife, which delivers high doses of radiation precisely aimed to minimize the involvement of healthy surrounding tissue.

Radiation oncologist Sean P. Collins, MD, PhD, says curative treatment is a shared goal along with maintaining a person’s quality of life.  Side effects, including impotence, can occur with all treatments for prostate cancer and can happen years after treatment.

“While it is necessary to observe these men for decades, our interim seven-year data show that survival and side effects are comparable to other forms of radiotherapy,” says Collins, director of the CyberKnife Prostate Program at MedStar Georgetown University Hospital and an associate professor of radiation medicine at Georgetown University. 

The National Comprehensive Cancer Network, which establishes cancer treatment guidelines, classified SBRT as an alternative to conventional therapy, but had noted a lack of long term follow up data. There is much more experience with conventionally fractionated radiation therapy, delivered five times a week for up to nine weeks, and brachytherapy, in which radioactive seeds are implanted in the prostate.

“Our findings give us great confidence that CyberKnife should become a standard option for some men who want to avoid the hassle and inconvenience of standard therapy,” Collins says.

 

###

Collins reports receiving grants from and being a paid consultant for Accuray Inc., the maker of CyberKnife.

 

Media Contact

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

Brendan McNamara 
Media Relations Specialist
Office: 703-558-1593
[email protected]

Georgetown Study Investigates Memory Improvement Through Nicotine Dosing

WASHINGTON --  Can nicotine slow or stop memory loss in people experiencing mild memory problems, or mild cognitive impairment (MCI)? A new study being conducted at Georgetown University Medical Center aims to find out.

Recent studies have suggested that one of the causes of memory disorders may be a reduction in a particular chemical substance in the brain. This chemical substance, known as acetylcholine, is thought to act on certain brain cells in a specific way, helping us to remember and use memories as well as affect our mood.

In people with MCI (and Alzheimer’s disease), the level of acetylcholine may be changed, and this may impair brain functioning. Preliminary studies have suggested that shorter-term administration of nicotine appears to improve memory in patients with mild memory loss and early Alzheimer’s disease (AD). It has been known for years that nicotine imitates many of the actions of acetylcholine.

To expand on this finding, a clinical trial led by Georgetown’s principal investigator, R. Scott Turner, MD, PhD, will explore whether nicotine may act to improve memory loss symptoms over the longer term and whether it may help to delay the progression of memory loss symptoms.

“We are increasingly able to detect those at risk for future Alzheimer's disease in order to perhaps slow or stop their progression to dementia,” says Turner. “About 10-15% of those diagnosed with mild cognitive impairment (MCI) will advance to dementia each year most commonly due to Alzheimer's disease – with a total risk of greater than 50% after 5 years. This new study is seeking volunteers with MCI to test whether treatment with a daily Nicotine skin patch can slow or stop further cognitive decline.”

This phase 2 randomized clinical trial is being conducted at approximately 30 to 40 clinical trial sites across the United States and will enroll 300 participants. Participants will wear a skin patch, containing either nicotine or placebo, for approximately 16 hours per day for two years.

Half of the participants will receive transdermal nicotine (nicotine by skin patch) called a “nicotine patch” with a dose of 7 mg per day increasing to 21 mg per day. The other half (the control group) will receive an identical patch, which does not contain an active dose of nicotine, called a “placebo patch.” The placebo patch contains a small amount of nicotine that cannot pass into the skin or be absorbed by the body.

Given that this is a randomized trial, neither the investigator nor the participant will know which group they are in.

During the first visit, participants will undergo standard physical and cognitive testing with the addition of an electrocardiogram (ECG). They will also be given a memory and thinking skills test that will be written as well as administered on an electronic device.

Some side effects could include sleepiness, diarrhea, stomach ache, muscle pain or joint pain  (reported by 3-9 percent of patients using the nicotine patch) and reddening or irritation of the skin where the patch is applied (reported by 17 percent of patients using the patch).

“Since we don't know all the possible risks and benefits as yet of Nicotine patch treatment in individuals with MCI, we advise against taking the drug for this purpose outside of the study,” says Turner.

Study participants must be between the ages of 55-90 and have a study partner who can accompany them to all appointments.

Full study criteria are available at ClinicalTrials.gov.

To learn more about this or other clinical trials, please contact Carolyn Ward, program coordinator of the Memory Disorders Program at (202) 784-6671, [email protected].

The study is sponsored by the National Institute on Aging and is being conducted by the

Alzheimer’s Therapeutic Research Institute (ATRI) with Vanderbilt University through a grant from the National Institute on Aging (NIA).  Turner conducts additional clinical research supported by funding to Georgetown University from Lilly, Biogen, Merck, Acadia, and Toyama as well as the National Institutes of Health and Department of Defense.

 

Media Contact

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

Brendan McNamara 
Media Relations Specialist
Office: 703-558-1593
[email protected]

For Some Bladder Cancer Patients, Simple Test Could Reduce Over-Treatment, Ease High Cost

WASHINGTON — Bladder cancer is relatively common and imposes the highest per patient cost on the U.S. health care system than the management of any other cancer type. Now, a new test could be key to reducing the cost of care while at the same time, relieving some patients of unneeded over-treatment, say investigators led by Georgetown Lombardi Comprehensive Cancer Center researchers.

Deciding whether to treat bladder cancer aggressively has been difficult — predictive diagnostic data is limited.  Up to 70 percent of patients treated for early stage lesions that have not invaded the bladder wall will experience recurrence of these lesions, and 20 percent of these patients will develop an invasive cancer. 

Because clinicians do not know which tumors will become dangerous, they err on the side of caution and perform an extremely intensive post-surgery surveillance regimen, including cystoscopy (a lighted optical scope that examines the inside of the bladder) as frequently as every three months for two years after removal of the tumor, and every 6-12 months for the years after.

The Georgetown-led investigators offer a new solution to the dilemma. They have found that a fairly simple test that significantly improves the identification of bladder tumors that will likely become invasive.

The study, published in Clinical Cancer Research, “validates this test that helps predict whether an early stage bladder cancer will recur and progress,” says the study’s senior author, Todd Waldman, MD, PhD, a professor of oncology at Georgetown.

Working with researchers from the U.S. and Denmark, Waldman has found that, compared with using current diagnostic procedures, the new test is 2.4 times more accurate in identifying tumors likely to recur after treatment, and 1.9 times more accurate at predicting which tumors will likely to progress, invade the bladder wall and spread.

The test involves examining bladder tumors that had been removed during initial surgery for over expression of the STAG2 gene, which Waldman earlier identified as key to development of potentially deadly bladder tumors.

Checking for STAG2 is a “very simple and very robust” procedure for pathologists who routinely examine excised tumors, Waldman says. His studies have described how to run this test.

Using the test could, in some cases, spare patients constant surveillance and, in others, support forgoing aggressive treatment that can produce significant side effects, the researchers say.

So Waldman and his colleagues have worked on a diagnostic test for years. This study summed up several of those clinical studies, concluding that using the test “offers additional two-fold predictive discrimination,” Waldman says.

“We are closer to our goal of lowering the risk of both aggressive bladder cancer and over-surveillance and treatment side effects in bladder cancer patients,” he says. “In principle, it might be possible to reduce the frequency of post-resection surveillance and therapy in patients whose cancer is STAG2-negative, and, conversely, treat patients and keep up high frequency surveillance in patients who have positive test results.”

The study’s first author is Alana Lelo, an MD/PhD candidate at Georgetown University School of Medicine.  Additional Georgetown authors include Deborah L. Berry, PhD, Brent Harris, MD, PhD, George Philips, MD, Krysta Chaldekas, and Jung-Sik Kim, PhD. Frederik Prip, Lars Dyrskjøt, PhD, Jørgen Bjerggaard Jensen, MD, are from Aarhus University Hospital, Denmark; Jeffry Simko, MD, PhD, and David Solomon, MD, PhD, are from the University of California San Francisco School of Medicine; Ciaran Mannion, MD, and Pritish Bhattacharyya, MD, are from Hackensack University Medical Center, New Jersey, and Anagha Kumar, MD, is from MedStar Health Research Institute in Washington D.C.

The authors declare no potential conflicts of interest.

This work was supported by the National Cancer Institute grants (R01CA169345, T32CA009686, DP5OD021403), and Cancer Center Support Grant (P30CA051008) to the Histopathology and Tissue Shared Resource); the Danish Cancer Society; the National Center For Advancing Translational Sciences of the National Institutes of Health (TL1TR001431); and institutional funds from the John Theurer Cancer Center at Hackensack University Medical Center.

Media Contact

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

Brendan McNamara 
Media Relations Specialist
Office: 703-558-1593
[email protected]

Family History Increases Breast Cancer Risk Even in Older Women: Weighing Screening Options

WASHINGTON Family history of breast cancer continues to significantly increase chances of developing invasive breast tumors in aging women — those ages 65­ and older, according to research published in JAMA Internal Medicine. The findings could impact mammography screening decisions later in life.

The large study of more than 400,000 women is the first to specifically look at family history as a breast cancer risk factor in two groups of women, age 65-74 and 75 and older, says the research team, led by Dejana Braithwaite, PhD, associate professor of oncology at Georgetown University School of Medicine and a member of Georgetown Lombardi Comprehensive Cancer Center.

“Family history of breast cancer does not decline as a breast cancer risk factor as a woman ages. The relationship didn’t vary based on whether a first-degree relative’s diagnosis was made in a woman age 50 or younger, or older than age 50,” Braithwaite says. “This means that women with that first-degree family history — breast cancer in a mother, sister, or daughter — should consider this risk factor when deciding whether to continue mammography screening as they age.”

Currently, the U.S. Preventive Services Task Force (USPSTF) recommends mammography screening every two years between ages 50 and 74 for women at average risk. After age 75, the evidence is insufficient to assess risk and benefit of mammography, according to USPSTF’s most recent update in 2016.

The American Cancer Society recommends yearly mammograms in women age 45, and then biennial screening at age 55 and on “as long as a woman is in good health.”

“As breast cancer screening guidelines change from age-based to risk-based, it is important to know how standard risk factors impact breast cancer risk for women of different ages,” said Karla Kerlikowske, MD, senior author of the new study and a member of the UC San Francisco Helen Diller Family Comprehensive Cancer Center.

“The goal of our work is to provide evidence that helps inform breast cancer screening guidelines for older women,” Braithwaite says. “Older women who are in good health and have a first-degree family history may consider a screening mammogram even as they age beyond the screening recommendations for average risk women.”

Researchers from Washington, California, Wisconsin, Vermont, New Hampshire and North Carolina participated in the research by examining 1996-2012 records from the Breast Cancer Surveillance Consortiums (BCSC) registries in their regions.

The team found that while age is the strongest risk factor for breast cancer — any adult woman in the general population has a baseline 12 percent risk of developing the disease — first-degree family history can almost double that risk.

Overall, a first-degree family history leads to an absolute increase in 5-year risk of breast cancer ranging from 1.2 to 10.3 percentage points depending on breast density and age. For example, in women 65-74 years old with scattered areas of dense tissue in their breasts, the team found an increased 5-year risk of breast cancer that ranged from 15.1 percent in women without a family history of the disease to 23.8 percent in women whose first degree female relatives had developed breast cancer.

Similarly, among women 75 years or older with the same scattered breast density, 5-year cumulative risk of breast cancer increased from 15.9 percent for women without a family history to 23.1 percent for women with a family history.

Researchers also discovered that breast density, one of the strongest risk factors for breast cancer, did not attenuate the association of family history of breast cancer and breast cancer risk in the women studied as a whole. But when broken into age groups, fatty breasts added a little risk to women age 65-74 years with a family history; in the older cohort, the association was flipped — dense breasts added slight risk.

Study co-authors include: Diana L. Miglioretti, PhD, from the University of California, Davis; Weiwei Zhu, MS, and Diana S. M. Buist, PhD, Kaiser Permanente Washington Health Research Institute in Seattle; Joshua Demb, MPH, Elad Ziv, MD, Jeffrey A. Tice, MD, and Louise C. Walter, MD, of the University of California, San Francisco; Amy Trentham-Dietz, PhD,   of the University of Wisconsin at Madison; Brian Sprague, PhD of the University of Vermont College of Medicine;  Tracy Onega, PhD, of Dartmouth; and Louise M. Henderson, PhD, of the University of North Carolina, Chapel Hill.

The authors report having no personal financial interests related to the study.

This work was supported by a National Institutes of Health, National Cancer Institute–funded Program Projects (P01 CA154292, 1R01CA207361-01A1). Data collection was additionally supported by the Breast Cancer Surveillance Consortium (HHSN261201100031C).

Media Contact

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

 

Brain Chemistry Profiles Shows Chronic Fatigue Syndrome, Gulf War Illness as Unique Disorders

WASHINGTON  — Researchers at Georgetown University Medical Center have found distinct molecular signatures in two brain disorders long thought to be psychological in origin — chronic fatigue syndrome (CFS) and Gulf War Illness (GWI).

In addition, the work supports a previous observation by GUMC investigators of two variants of GWI. The disorders share commonalities, such as pain, fatigue, cognitive dysfunction and exhaustion after exercise.

Their study, published in Scientific Reports, lays groundwork needed to understand these disorders in order to diagnosis and treat them effectively, says senior investigator, James N. Baraniuk, MD, professor of medicine at Georgetown University School of Medicine. Narayan Shivapurkar, PhD, assistant professor of oncology at the medical school worked with Baraniuk on the research.

The changes in brain chemistry — observed in levels of miRNAs that turn protein production on or off — were seen 24 hours after riding a stationary bike for 25 minutes.

“We clearly see three different patterns in the brain’s production of these molecules in the CFS group and the two GWI phenotypes,” says Baraniuk. “This news will be well received by patients who suffer from these disorders who are misdiagnosed and instead may be treated for depression or other mental disorders.”

Chronic fatigue syndrome affects between 836,000 and 2.5 million Americans, according to a National Academy of Medicine report. The disorder was thought to be psychosomatic until a 2015 review of 9,000 articles over 64 years of research pointed to unspecified biological causes. Still, no definitive diagnosis or treatment is available.

Gulf War Illness has developed in more than one-fourth of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War, Baraniuk and his colleagues have reported in earlier work.

Gulf War veterans were exposed to combinations of nerve agents, pesticides and other toxic chemicals that may have triggered the chronic pain, cognitive, gastrointestinal and other problems, Baraniuk says. Although the mechanisms remain unknown, the study provides significant insights into brain chemistry that can now be investigated.

This study focused on spinal fluid of CFS, GWI and control subjects who agreed to have a lumbar puncture. Spinal taps before exercise showed miRNA levels were the same in all participants. In contrast, miRNA levels in spinal fluid were significantly different after exercise. The CFS, control and two subtypes of GWI groups had distinct patterns of change. For example, CFS subjects who exercised had reduced levels of 12 different mRNAs, compared to those who did not exercise.

The miRNA changes in the two GWI subtypes add to other differences caused by exercise. One subgroup developed jumps in heart rate of over 30 beats when standing up that lasted for two to three days after exercise. Magnetic resonance imaging showed they had smaller brainstems in regions that control heart rate, and did not activate their brains when doing a cognitive task. In contrast, the other subgroup did not have any heart rate or brainstem changes, but did recruit additional brain regions to complete a memory test. The two groups were as different from each other as they were from the control group.

Finding two distinct pathophysiological miRNA brain patterns in patients reporting Gulf War disease “adds another layer of evidence to support neuropathology in the two different manifestations of Gulf War disease,” he says.

Baraniuk adds that miRNA levels in these disorders were different from the ones that are altered in depression, fibromyalgia, and Alzheimer’s disease, further suggesting CFS and GWI are distinct diseases.

The study was supported by funding from The Sergeant Sullivan Center, Dr. Barbara Cottone, Dean Clarke Bridge Prize, Department of Defense Congressionally Directed Medical Research Program (CDMRP) W81XWH-15-1-0679, and National Institute of Neurological Diseases and Stroke R21NS088138 and RO1NS085131.

Baraniuk and Shivapurkar are named as inventors on a patent application that has been filed by Georgetown University related to the technology described.

 

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

Two Agents Deliver Knockout Punches to Ewing Sarcoma

WASHINGTON When combined with an already FDA-approved chemotherapy, a novel agent developed by researchers at Georgetown Lombardi Comprehensive Cancer Center, appears to halt the ability of Ewing sarcoma to grow and progress.

The finding, in cell lines and animal models, warrants clinical investigation to see if the combination would be an effective treatment as well as a less toxic alternative to current therapy for the rare bone cancer, the researchers say.

The study, published October 3 in the journal Science Signaling (Inhibition of the oncogenic fusion protein EWS-FLI1 AQ1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewing’s sarcoma), tests a combination of YK-4-279, the compound developed at Georgetown, with vincristine in laboratory and mice studies. Vincristine is one of the chemotherapy drugs now used to treat Ewing sarcoma.  

“Each of the two drugs impacts the cancer cell’s ability to survive, but they do it in a way that magnifies their effectiveness compared to if they were used alone. It’s like a left hook followed by an uppercut,” says the study’s senior investigator, Jeffrey Toretsky, MD, the new chief of Pediatric Hematology Oncology at MedStar Georgetown University Hospital, and researcher at Georgetown Lombardi.

In the United States, about 500 children and young adults are diagnosed with Ewing sarcoma annually. Between 60 to 70 percent of patients survive more than five years, but with many late effects from treatment. Patients with Ewing sarcoma are currently treated with a combination of five different chemotherapy drugs, which often damages nerves and few treatments lead to a cure when the cancer progresses, Toretsky says.

Ewing sarcoma is caused by the exchange of DNA between two chromosomes. The resulting EWSR1-FLI1 gene produces a fusion protein, EWS-FLI1, responsible for cancer’s growth. In 2006, Toretsky and his team discovered that the fusion protein binds to another protein, RNA helicase A (RHA), which is important for cancer progression.

YK-4-279 directly inhibits EWS-FLI1. Toretsky’s work on YK-4-279 led to the eventual development of TK216, a first-in-class small molecule that is now being studied by Oncternal Therapeutics in a clinical trial in patients with relapsed or refractory Ewing sarcoma.

In this study, Toretsky led a team of researchers that tested 69 different anti-cancer drugs to find an agent that would work synergistically with YK-4-279. They discovered that together, the drugs produce a “microtubule catastrophe” in Ewing sarcoma cancer cells.

Microtubules are tube-like structures that help cells keep their shape and act like highways that transport cellular proteins. They also pull apart chromosomes when they divide, and it is this action that is particularly affected by the drug combo, Toretsky says.

“Cancer needs to grow, and to do that, the cells need to divide and multiply. This is the step both drugs target, but in different ways,” he says.

According to Toretsky, Oncternal is planning to test the combination of TK216 and vincristine in patients.

Co-authors include Georgetown researchers Stefan K. Zöllnerm MD (the study lead author), Saravana P. Selvanathan, PhD, Garrett T. Graham, PhD, Ryan M. T. Commins, MD, Sung Hyeok Hong, DVM, PhD, research fellow Eric Moseley, college student Sydney Parks, medical student Jessica N. Haladyna, Hayriye V. Erkizan, PhD, and Aykut Üren, PhD; Uta Dirksen, MD, from the Essen University Hospital, Germany; and Michael D. Hogarty, MD, from the Children’s Hospital of Philadelphia.

The Georgetown researchers are funded by the Children’s Cancer Foundation, Nick Currey Fund, St. Baldrick’s Foundation, Alan B. Slifka Foundation, CureSearch, Go4theGoal, Liddy Shiver Sarcoma Initiative, as well as a Burroughs Wellcome Clinical Scientist Award in Translational Research and the NIH (RC4CA156509, RO1CA133662, and R01CA138212).

Georgetown University owns the underlying YK-4-279 technology and related intellectual property invented by Toretsky, Üren, et al., and has licensed the technology to Oncternal for development as a potential therapeutic agent for cancer, including Ewing sarcoma. Toretsky is a paid scientific advisor to Oncternal.                                           

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]

Protein Associated with Parkinson’s Disease Linked to Human Upper GI Tract Infections

WASHINGTON  —Acute and chronic infections in a person’s upper gastrointestinal tract appear to be linked to Parkinson’s disease, say scientists at Georgetown University Medical Center and their collaborators at the National Institutes of Health and other institutions.

Their study, published in the Journal of Innate Immunity, finds that alpha-Synuclein (αS), the protein implicated in Parkinson’s disease and other forms of neurodegenerative diseases, is released when an infection occurs in the upper GI tract (the esophagus, stomach and duodenum) inducing an immune response as part of the body’s innate immune system. The researchers say that these findings suggest that frequent or chronic upper GI infections could overwhelm the body’s capacity to clear αS, leading to disease.

image-of-brainThis largely federally-funded study helps clarify the function of αS, which is poorly understood, says the study’s senior investigator, Michael Zasloff, MD, PhD, professor of surgery and pediatrics at Georgetown University School of Medicine and scientific director of the MedStar Georgetown Transplant Institute.

This research builds upon prior studies that showed in autopsied material from individuals at very early as well as later stages of Parkinson’s, that the buildup of αS actually begins in the enteric nervous system (nerves in the GI tract). Animal studies have further shown that microbes in the GI tract can induce formation of toxic aggregates in the enteric nervous system, which can then travel up to the brain.

Zasloff and his colleagues studied biopsy samples, collected at the University of Oklahoma Health Sciences Center, from 42 children with upper GI distress. They also looked at another population of 14 MedStar Georgetown University Hospital patients who received an intestinal transplant. This second group had documented cases of infection by Norovirus, a common cause of upper GI infection.

The biopsies showed that expression of αS in enteric nerves of the upper GI tract in these children positively correlated with the degree of acute and chronic inflammation in the intestinal wall. Some highly monitored transplant patients expressed αS as Norovirus was infecting them.

Researchers also showed that human αS could potently attract human immune cells such as macrophages and neutrophils and could “turn on” dendritic cells to alert the immune system of the specific pathogen encountered.

As Zasloff explains, “When expressed in normal amounts following an infection of the upper GI tract, αS is a good molecule. It is protective. The nervous system within the wall of the GI tract detects the presence of a pathogen and responds by releasing αS. αS then attracts white blood cells to the site where it has been released. In addition, αS produced in one nerve can spread to others with which it communicates thereby protecting a large field. By this means, the nervous system can protect both itself as well as the GI tract as a whole in the setting of an infection.”

He adds, “It is well known from animal studies that αS produced in the enteric nervous system can use the nerves connecting the GI tract to the brainstem as an escalator, trafficking αS from the gut to the brain and spreading to centers within the central nervous system.

“But too much αS — such as from multiple or chronic infections — becomes toxic because the system that disposes of αS is overwhelmed, nerves are damaged by the toxic aggregates that form and chronic inflammation ensues. Damage occurs both within the nervous system of the GI tract and the brain.”

Zasloff says the new findings “make sense” of observations made in Parkinson’s disease patients, such as the presence of chronic constipation from damage to the enteric nervous system that develops decades before brain symptoms become apparent and that chronic upper GI distress is relatively common in people who develop Parkinson’s.

Zasloff adds that the publication of this study coincides with the start of a clinical trial targeting the accumulation of αS in the enteric nervous system. The phase 1/2a study is examining the safety, tolerability, pharmacokinetics, and pharmacodynamics of an oral drug, ENT-01, a synthetic version of squalamine, a natural steroid made by the dogfish shark, to relieve constipation associated with Parkinson's disease. Research recently published by Zasloff and collaborators demonstrated that squalamine both reduced the formation of toxic αS clumps and their toxicity, in animal experiments. The clinical trial, being conducted in the US, is sponsored by Enterin, Inc.


The study’s lead author was Ethan Stolzenberg MD, PhD, from the University of Oklahoma and its co-senior author was Denise Barbut, MD, FRCP, Enterin, Inc.

Other scientists contributing to the study include De Yang MD, PhD, Joost J. Oppenheim, MD, and Ad Bax, PhD from the National Institutes of Health, E.Y. Lee, and Gerard C. L. Wong, PhD, from the University of California, Los Angeles. Collaborators from Georgetown are Deborah Berry, PhD, Alexander Kroemer, MD, Supti Sen, Stuart Kaufman, MD, Thomas M. Fishbein, MD, and Brent Harris, MD, PhD.

Zasloff is founder, chairman and CEO of Enterin and Barbut is co-founder of Enterin, president and chief medical officer of the company.

The study was funded by the Intramural Research Program of the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (ZIADK029047), the University of Oklahoma, and UCLA training grants from the National Institute of General Medical Sciences (T32GM008185, T32GM008042).

Media Contact

Marianne Worley
Director of Media Relations
Office: 703-558-1287
Pager: 202-405-2824
[email protected]n.edu