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.

 

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

 

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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.

 

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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.

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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).

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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.

 

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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.                                           

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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).

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Georgetown Announces Phase II Clinical Trial of Nilotinib for Parkinson’s Disease

WASHINGTON  – Georgetown University Medical Center (GUMC) today announces the launch of a phase II clinical trial to study the safety of the cancer drug nilotinib and its effects on clinical outcomes and biomarkers in people with Parkinson’s disease.  

GUMC is recruiting volunteers for the study in collaboration with its clinical partner, MedStar Georgetown University Hospital. 

The clinical trial is a phase II, randomized, double-blind, placebo-controlled study designed to evaluate the safety and tolerability of low doses of nilotinib, the efficacy on disease biomarkers, and clinical outcomes in people with mid-stage Parkinson’s disease. Fernando Pagan, MD, medical director of the GUMC Translational Neurotherapeutics Program and director of the Movement Disorders Clinic at MedStar Georgetown University Hospital will serve as principal investigator on this study.

As part of the year-long random ascending dose trial, a third of the participants will receive 150mg of nilotinib, another third will receive 300mg of nilotinib and the final third will receive a placebo (inactive drug). Clinical outcomes will be assessed at six and 12 months and compared to assessments at the start of the trial. A one-year open-label extension trial, in which all participants will be randomized to 150mg or 300mg nilotinib, is also planned upon completion of the placebo-controlled trial to evaluate nilotinib’s long-term effects.

The clinical trial follows a proof of concept study conducted at Georgetown (published July 11, 2016 in the Journal of Parkinson’s Disease) providing molecular evidence that nilotinib significantly increased brain dopamine (the chemical lost as a result of neuronal destruction) and reduced toxic proteins linked to disease progression in Parkinson’s disease or dementia with Lewy bodies. Twelve participants were enrolled in the initial study; one patient withdrew due to an adverse event. Researchers say the drug appeared to be safe and well tolerated in the remaining 11 participants who completed the study.

“The early proof of concept study conducted in 2015 and published in 2016 provided encouraging results, but we won’t know the exact effects of nilotinib on Parkinson’s disease until larger trials like this new one are complete,” says Pagan.

“I am pleased to offer this study to my patients, which demonstrates the importance of teaming Parkinson’s care with academic research. Only through clinical trials will we be able to move the field forward so that we can offer better treatments to our patients in the future,” he adds.

Nilotinib is approved by the U.S. Food and Drug Administration at much higher doses for the treatment of chronic myeloid leukemia (CML). In 2016, the U.S. Food and Drug Administration reviewed Georgetown’s investigational new drug application (IND) for the nilotinib study in Parkinson’s disease and informed GUMC investigators that the trial could proceed.

Human BrainThe Parkinson’s study and the recently announced Alzheimer’s clinical trial with nilotinib build on research from the GUMC Translational Neurotherapeutics Program led by Charbel Moussa, MB, PhD. He and his colleagues are examining tyrosine kinase inhibitors, like nilotinib, in the treatment of neurodegenerative diseases. Tyrosine kinases appear to play a role in neurodegeneration, protein clearance and inflammation. (Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases).

The Parkinson’s study is funded by the generous support of donors. Novartis, the maker of nilotinib, is providing nilotinib and matching placebo free of cost to Georgetown University for all participants while on the study.

More information can be found at ClinicalTrials.gov. Patients and families can sign up here to receive more information about the Parkinson’s study and other Georgetown neurodegenerative clinical trials.

 

Marianne Worley
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Georgetown Clinical Trial Testing Nilotinib in Alzheimer’s Disease Begins

WASHINGTON (January 24, 2017) – A clinical trial to examine the effect of nilotinib on clinical outcomes and biomarkers in people with mild to moderate Alzheimer’s disease has opened at Georgetown University Medical Center (GUMC).

The clinical trial is a phase II, randomized, double blinded, placebo-controlled study to evaluate the impact of low doses of the cancer drug nilotinib (Tasigna®). GUMC is conducting the study with its clinical partner, MedStar Georgetown University Hospital.

The rationale for using nilotinib is based on laboratory and clinical research conducted by the Georgetown Translational Neurotherapeutics Program (TNP). Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in the brain. Both are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear the Tau, Abeta and other toxic proteins.

“In a 2015 proof of concept study at Georgetown, patients with Parkinson’s disease or dementia with Lewy bodies were treated with nilotinib. As my colleagues reported, those who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers—the same biomarkers seen in Alzheimer’s,” explains Scott Turner, MD, PhD, medical co-director of the TNP, who will serve as principal investigator for the study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study give an even stronger rationale.”

“When used in higher doses for chronic myelogenous leukemia (CML), nilotinib forces cancer cells into autophagy or cell death. The dose used in CML treatment is significantly higher than what we will use in our Alzheimer’s study,” says Charbel Moussa, MB, PhD, scientific and clinical research director for the Translational Neurotherapeutics Program. “When used in smaller doses once a day, as in this study, it appears nilotinib turns on autophagy for about four to eight hours—long enough to clean out the cells without causing cell death. Toxic proteins that build up again then appear to be cleared when the drug is given again the next day.”

Moussa conducted the preclinical research that led to the discovery of nilotinib for the potential treatment of neurodegenerative diseases.

Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases.

The Alzheimer's Drug Discovery Foundation is supporting this clinical trial through a $2.1 million grant to Turner.  The study has also received private philanthropic support.

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.

To learn more about this clinical trial, please click here.  To learn about other Alzheimer’s clinical studies, please visit the Georgetown Memory Disorders Program website.


Meet Dr. Turner

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Study Tests New Breast Cancer Drug in African American Women

(Washington, D.C) — The first clinical trial to test a newly approved breast cancer drug specifically in African American patients is now enrolling at Georgetown Lombardi Comprehensive Cancer Center and will begin soon at five other institutions in Washington, DC, Maryland, Alabama and New Jersey.

The phase II study will evaluate the safety of palbociclib (Ibrance ®) in African American patients, including those who may have a low white blood cell count due to “benign ethnic neutropenia.” This condition is common in African-Americans, but it is unclear whether it increases a patient’s risk of infection while taking palbociclib, says the study’s leader, Filipa Lynce, MD, a physician researcher at Georgetown Lombardi Comprehensive Cancer Center.

The U.S. Food and Drug Administration approved palbociclib in February 2016 for ER+ HER2- breast cancer that has spread.

Because about three-fourths of the 1,137 patients tested in earlier clinical trials of palbociclib developed neutropenia (low white blood cell count) — including half of the patients who developed a more serious form of the disorder — the FDA guidelines for palbociclib use require the patient to have a normal white blood cell count.

That threshold forces the elimination of African-American women who have “benign ethnic neutropenia,” or a lower than normal white blood cell count, from receiving the drug.

The study Lynce is conducting explores the safety of the drug in all African American women, knowing that some may have benign ethnic neutropenia. “The assumption that African American women with this common condition could not safely use this drug needs to be fully tested,” says Lynce.

The study will enroll 35 patients with metastatic breast cancer at Georgetown Lombardi/MedStar Georgetown University Hospital (Washington, DC), MedStar Washington Hospital Center (Washington, DC), MedStar Union Memorial Hospital (Baltimore, MD) and MedStar Good Samaritan Hospital (Baltimore, MD), the University of Alabama at Birmingham Comprehensive Cancer Center, and at the John Theurer Cancer Center at Hackensack University Medical Center (Hackensack, New Jersey).

All patients will be given palbociclib and letrozole (Femara®). Both agents are pills that are taken once daily. Participants will be enrolled in the study for a maximum of 13 months.

The usual standard of care services required to monitor and treat the cancer — including examinations, scans and laboratory tests — will be performed as part of the study and billed to a patient’s insurance. The primary study drug, palbociclib, will be provided free of charge on the study, but the second drug, letrozole, will also be billed to insurance.

Lynce applied and received a $600,000 grant from Pfizer, Inc., the developer of palbociclib, to test the agent in African Americans.

I think this award shows how committed the company is to look at the safety of their drugs in minorities,” says Lynce. “One focus area of my research is to look at the safety and efficacy of medications used to treat breast cancer in populations that have not been included in clinical trials.

For more information about this or other cancer clinical trials at Georgetown Lombardi, please call 202-444-2223, and press 3.

Translational Science Award (UL1TR001409-01) from the National Institutes of Health.

Media Contact

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