Day: June 22, 2023

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Repurposed Cancer Drug Might Treat Cardiac Arrhythmias

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Ruxolitinib, a drug that is already approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers and skin conditions, is effective at inhibiting CaMKII, a protein kinase linked to cardiac arrhythmias.

In a new study published in Science Translational Medicine, researchers invented a new reporting technique to monitor activity of CaMKII while screening the effects of nearly 5000 FDA-approved drugs on human cells that expressed the enzyme. The screen identified five previously unknown CaMKII inhibitors; ruxolitinib, which is used to treat cancers of the blood and bone marrow, along with skin conditions like atopic dermatitis and vitiligo, was the most effective.

CaMKII, or Calcium and calmodulin-dependent protein kinase II, is critical to cardiomyocytes, the muscle cells of the heart, where it maintains the balance of calcium. Activation of CaMKII helps facilitate rapid changes in heart activity, such as initiating a fight-or-flight response in the body. Overactivation can lead to impaired heart function and cell death, which can in turn lead to poor heart health outcomes like arrhythmia.

CaMKII is perhaps best known, however, for its role in the brain, where it is believed to play key roles in learning and memory. This has slowed the development of CaMKII inhibitors to treat arrythmia, for fear they could impact cognitive function.

“Finding an FDA approved drug means that millions of people have been taking CaMKII inhibitors, and in the case of ruxolitinib, there are no reported major problems with the brain,” said Mark Anderson, MD, PhD, a senior author of the paper. “That should give pharma and biotech companies confidence that they could carry out development of a CaMKII inhibitor program, because the biggest obstacle seems to be surmountable.”

The research began in Anderson’s lab at Johns Hopkins University Oscar Reyes Gaido, the study’s first author and an MD-PhD student in the lab, developed a new tool to measure activity of CaMKII in living cells. He started with a protein called green fluorescent protein (GFP), originally derived from jellyfish, that emits green light. He then engineered the GFP tag to detect CaMKII activation, making a new reporter called CaMKAR (CaMKII Activity Reporter). When this reporter was inserted into human heart cells, it helpfully glowed bright green whenever CaMKII became active, allowing researchers to monitor enzyme activity.

“This biosensor will be very useful for studying how CaMKII activity changes in both healthy and pathological contexts. Existing methods can measure CaMKII activity, but they lack the versatility and resolution to track in real time and with high sensitivity,” Reyes Gaido said. “This has been a real obstacle for studying enzyme biology in general, so this gives the field an important new tool.”

Using this tool, the researchers conducted a drug repurposing screen to test the effects of 4,475 approved compounds on cultured human cardiomyocytes. This identified five previously unknown CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. Of the five, ruxolitinib was the most effective at inhibiting CaMKII activity in cell and mouse models of CaMKII-driven arrhythmias. A 10-minute application of the drug was enough to prevent catecholaminergic polymorphic ventricular tachycardia (CPVT), a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. Crucially, the mice treated with ruxolitinib did not show any adverse cognitive effects when they were tested with memory and learning tasks.

Anderson said that new drugs based on ruxolitinib could be used in several ways to treat heart conditions. One would be what he called the “pill in a pocket” scenario. In the early stages of atrial fibrillation, people could take the medication occasionally as symptoms arise. Patients with CPVT are often resistant to standard treatments, and a ruxolitinib-based treatment could provide another option. Finally, there is evidence that inhibiting CaMKII during a heart attack can prevent heart muscle from dying, so emergency responders could potentially administer such a drug as part of standard practice.

“There’s been a long search for fundamental pathways that could be targets for therapeutics in arrhythmias,” Anderson said. “This could be a finding that will translate relatively rapidly into people now since it’s already been proven to be safe in humans.”

Source: University of Chicago

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Restoring the Integrity of the Blood–Brain Barrier

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A new paper published in Nature Communications describes a treatment that restores intercellular signalling and which could be instrumental in restoring the barrier’s normal function. Key to the process is ‘frizzled’, a key protein receptor implicated in blood-brain abnormalities.

When the blood-brain barrier isn’t working properly, a variety of conditions can crop up. Barrier-invading cancer cells can develop into tumours, and multiple sclerosis can occur when too many white blood cells slip pass the barrier, leading to an autoimmune attack on the protective layer of brain nerves, hindering their communication with the rest of the body.

“A leaky blood-brain barrier is a common pathway for a lot of brain diseases, so to be able to seal off the barrier has been a long sought-after goal in medicine,” said senior author Calvin Kuo, MD, PhD, professor of hematology.

Methods of repairing the blood-brain barrier remain understudied, according to Kuo. But the recent paper he and colleagues led describes a possible treatment.

“We have evaluated a new therapeutic class of molecules that can be used to treat a leaky blood-brain barrier; previously, there were no treatments directed at the blood-brain barrier specifically,” Kuo said.

The researchers started their quest by looking at WNT signalling, a communication pathway used by cells to promote tissue regeneration and wound healing. WNT signalling helps maintain the blood-brain barrier by promoting cell-to-cell communication that lines brain blood vessels.

“There’s a lot of historical data that indicated that the WNT signalling pathway would be important for maintaining the blood-brain barrier,” Kuo said. “The opportunity arose to test a novel WNT signalling pathway that would turn on signalling in the blood-brain barrier by binding very selectively to a receptor called frizzled.”

Scientists have been focusing on ‘frizzled’, a protein receptor that initiates the WNT pathway, for blood-brain barrier therapies since mouse mutations in the frizzled gene cause blood-brain barrier abnormalities.

How it’s made

Many different molecules bind to frizzled protein receptors, so to narrow their search for a potential therapeutic molecule, the researchers selected only those that specifically target cells that line the brain’s blood vessels.

Chris Garcia, PhD, a professor of molecular and cellular physiology as well as the Younger Family Professor, developed prototype therapeutic WNT pathway molecules in the lab, including a molecule that activates the frizzled receptor FZD4. Building off of the work of Garcia and Kuo, collaborators at a research company created L6-F4-2, a FZD4 binding molecule that activates WNT signalling 100 times more efficiently than other FZD4 binders.

When the team, including Jie Ding, a research scientist and the lead author of the paper, activated WNT signaling at a higher rate, they saw an increase in blood-brain barrier strength.

Keeping the barrier up

The researchers wanted to study what happens when the natural molecular key for frizzled is missing, and whether it can be replaced successfully with L6-F4-2. So they turned to Norrie disease, a genetic abnormality that results in a leaky blood-retinal barrier.

The blood-retinal barrier performs the same function for the eye as the blood-brain barrier does for the brain. In Norrie disease, the development of blood vessels of the retina is hindered, resulting in leaky blood vessel connections, improper development and blindness.

Norrie disease results from mutations in the NDP gene, which provides instructions for making a protein called Norrin, which is the key that fits the lock of the FZD4 receptor and turns it on. In the study’s mice, the gene is inactivated, and the key is missing causing a leaky barrier and blindness. The scientists replaced the missing Norrin protein with L6-F4-2, which they call a surrogate.

When L6-F4-2 replaced the missing Norrin protein, the blood-retinal layer was restored in the mice. Researchers knew this because they imaged the blood vessels and found them to be denser, and less leaky, than before treatment. Scientists also showed that, for the blood-brain barrier surrounding the mice cerebellum L6-F4-2 replaced Norrin and activated WNT signalling.

Next, the researchers wanted to study a more common human condition — ischemic stroke (in which blood vessels and the blood-brain barrier are damaged, and fluid, blood and inflammatory proteins involved in cellular communication can leak into the brain. They found that L6-F4-2 reduced the severity of stroke and improved survival of mice compared with mice that had untreated strokes. Importantly, L6-F4-2 reversed the leakiness of brain blood vessels after stroke. Mice treated with L6-F4-2 had increased stroke survival, compared to those that were not treated.

The finding shows that, in mice, the blood-brain barrier could be restored by drugs that activate FZD receptors and the WNT signalling pathway.

Because a variety of disorders have their origin in blood-brain barrier dysfunction, Kuo is excited about the treatment potential for a variety of other neurological diseases, such as Alzheimer’s, multiple sclerosis and brain tumours.

“We hope this will be a first step toward developing a new generation of drugs that can repair the blood-brain barrier, using a very different strategy and molecular target than current medications,” Kuo said.

Source: Stanford Medicine

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Losing the Y Chromosome to Age Drives Bladder Cancers but Improves Immunotherapy

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Chromosomes. Credit: NIH

As men age, some of their cells lose their Y chromosome and this loss hampers the body’s ability to fight cancer, according to new research from Cedars-Sinai Cancer. The study, published in Nature, found that loss of the Y chromosome helps cancer cells evade the immune system, resulting in aggressive bladder cancer. Somehow, this also renders the disease more responsive to immune checkpoint inhibitors.

Based on their research, investigators are developing a test for loss of the Y chromosome in tumours with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” said corresponding author Dan Theodorescu, MD, PhD, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.

In men, loss of the Y chromosome has been observed in several cancer types, including 10%–40% of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.  

The investigators then reviewed data on two groups of men. One group had muscle invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.

To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.

Cancer cells were grown in vitro and not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing T-cells. In both cases, tumours with and without the Y chromosome grew at the same rate.

In mice with intact immune systems, tumours lacking the Y chromosome grew at a much faster rate than did tumours with the intact Y chromosome.

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

Based on their results derived from human patients and laboratory mice, Theodorescu and his team also concluded that tumours missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors. This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body’s immune system to fight the cancer.

“Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said co-first author Hany Abdel-Hafiz, PhD, associate professor at Cedars-Sinai Cancer.

Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.

“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumour cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, MB, ChB, dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.

“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.

“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”

Source: Cedars-Sinai Medical Center

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Game-changing Therapy Targets Colon Cancer that has Spread to the Liver

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Physicians at Cedars-Sinai Cancer are now using a unique therapy, called hepatic artery infusion (HAI) pump chemotherapy, that offers hope to colorectal cancer patients whose disease has spread and who now have inoperable liver tumours. The system, which was developed over two decades ago, is only now being adopted more widely, also spares the rest of the body from much of the chemotherapy drugs’ toxicity.

“Many of these patients are not candidates for curative surgery and we now have a meaningful option for treating them,” said Cristina Ferrone, MD, chair of the Department of Surgery at Cedars-Sinai and a specialist in the care of patients with complex hepato-pancreato-biliary disorders. “This therapy has been shown to extend both life and quality of life.”

Colorectal cancer is the fourth-leading cause of cancer-related death in the US. In as many as 25% of patients diagnosed with the disease, the cancer spreads to the liver, where it can be difficult to treat. However, more than half of patients receiving hepatic artery infusion pump therapy go on to receive curative surgery, studies have shown.

Cedars-Sinai Cancer and associate professor of Surgery at Cedars-Sinai, sat down with the Cedars-Sinai Newsroom to explain this lifesaving therapy.

How do the pumps work?

We surgically place the pump underneath the skin, outside of the abdominal cavity, and it is attached to tubing that enters the abdominal cavity and goes into the gastroduodenal artery. That artery feeds into the hepatic artery, which supplies blood to the liver. During surgery, we block blood flow from the gastroduodenal artery from going into portions of the small intestine so that the therapy flows only to the liver.

The pump has a soft centre, allowing its internal reservoir to be filled through the skin via a syringe. After surgery, the patient comes in every two weeks and we refill the pump, which then allows the chemotherapy drug to flow directly into the liver via the arterial supply.

Which patients are likely to benefit from hepatic artery infusion pump therapy?

This therapy is designed for patients, based on the distribution of the metastatic disease (where are the tumours and how many), for whom curative surgery is not an option at the time of diagnosis. The best we had been able to offer these patients was lifelong chemotherapy that had potential systemic toxicities, and that never quite reduced their tumour size to the point that we could surgically remove it. This therapy offers an additional option for liver-directed therapy that can potentially make patients candidates for surgery by specifically targeting the liver disease.

What are the advantages of the hepatic artery infusion pump over traditional chemotherapy delivery?

A majority of these tumours derive their blood supply from the hepatic arterial system, and delivering chemotherapy to the tumours through the hepatic arterial system allows us to give higher doses of specific chemotherapeutic agents without exposing the patient to their systemic toxicities. Data shows that up to 60% of appropriately selected patients receiving hepatic artery infusion pump chemotherapy were then able to receive curative surgery. Patients can often continue receiving systemic chemotherapy in combination with hepatic artery infusion pump chemotherapy.

Are hepatic artery infusion pumps used to treat other types of liver cancer?

Some patients with cholangiocarcinoma are currently treated with HAI pumps, but this is not yet standard of care. Colon cancer is the second most common cancer, and colon cancer that has metastasized to the liver affects a significant number of patients. And we have seen good outcomes with those patients. Other types of cancers that metastasise to the liver are significantly more challenging to treat, and thus far, we don’t think this therapy will benefit those patients.

Is this a new therapy?

Hepatic artery infusion pumps have actually been around for about 25 to 30 years, but until quite recently only a few medical centres were using them. But more and more centres are realising that this therapy can truly benefit patients, and it is becoming more widely available.

Source: Cedars-Sinai Medical Center

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Forming Supportive Connections for Multiple Sclerosis Sufferers

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This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Multiple sclerosis (MS), an unpredictable, often disabling disease of the central nervous system with symptoms ranging from numbness and tingling to blindness and paralysis,1 is estimated to affect 2.8 million people around the world.2 Most people with MS are diagnosed between the ages of 20 and 50 years, with at least two to three times more women than men being diagnosed with the disease.1

Non Smit, Chairperson of Multiple Sclerosis South Africa, stresses the importance of generating extensive awareness to reach individuals with MS as well as healthcare providers and therapists. “This inclusive approach aims to establish a support system and platform that addresses crucial issues such as treatment accessibility, advocacy, epidemiology, and financial assistance,” says Smit.

The progress, severity, and specific symptoms of MS in any one person cannot yet be predicted; the disease varies greatly from person to person, and from time to time in the same person.1 Although MS can be very debilitating, it is estimated that about two-thirds of affected persons are still able to walk, although many may need an aid such as a cane or crutches.1

Dr Andile Mhlongo, Medical Advisor, Specialty Care at Sanofi South Africa, says: “There are no hard and fast rules about what life with MS will mean for each patient, because everybody experiences MS differently, depending on which part of the brain is affected. Symptoms range from problems with mobility to problems with vision, extreme tiredness and thinking – but these are just a few examples. It mostly affects young people, and if untreated can have a devasting impact on the lives of patients and their families.”

In terms of diagnosis, in early MS elusive symptoms that come and go might indicate any number of possible disorders. Some people have symptoms that are very difficult to interpret. While no single laboratory test is yet available to prove or rule out MS, magnetic resonance imaging (MRI) is a great help in reaching a definitive diagnosis.2

MS comes in several forms, including clinically isolated syndrome, relapsing-remitting MS, secondary progressive MS and primary progressive MS.3 The course is difficult to predict: some people may feel and seem healthy for many years after diagnosis, while others may be severely debilitated very quickly. Most people fit somewhere in-between.3

Clinically isolated syndrome (CIS) is the first episode of neurological symptoms experienced by a person, lasting at least 24 hours. They may experience a single sign or symptom, or more than one at the same time. CIS is an early sign of MS, but not everyone who experiences CIS goes on to develop MS.3

In relapsing-remitting MS (RRMS) people experience attacks or exacerbations of symptoms, which then fade or disappear. The symptoms may be new, or existing ones that become more severe. About 85% of people with MS are initially diagnosed with RRMS.3

Secondary progressive MS (SPMS) is a secondary phase that may develop years or even decades after diagnosis with RRMS. Most people who have RRMS will transition to SPMS, with progressive worsening of symptoms and no definite periods of remission.3

Primary progressive MS (PPMS) is diagnosed in about 10–15% of people with MS. They have steadily worsening symptoms and disability from the start, rather than sudden attacks or relapses followed by recovery.3

While there is no medicine that can cure MS, treatments are available which can modify the course of the disease. Sanofi has been a partner in the MS community since 2012, through the introduction of two treatments. One of these is an oral formulation for patients with relapsing forms of MS and the other is an infusion therapy for patients with rapidly evolving, severe relapsing-remitting MS.

“Sanofi continues to be a partner through research and development to bring about therapies to improve the management of this disease. Sanofi also supports various initiatives that bring education to patients and healthcare providers and the MS community in general,” says Mhlongo.

Advances in treating and understanding MS are being achieved daily and progress in research to find a cure is encouraging. In addition, many therapeutic and technological advances are helping people with MS to manage symptoms and lead more productive lives.2

For further information on MS, visit: https://www.sanofi.com/en/our-science/rd-focus-areas/neurology-rd or https://www.multiplesclerosis.co.za

References

  1. Multiple Sclerosis SA. What is multiple sclerosis? Available from: https://www.multiplesclerosis.co.za/ms-information/what-is-ms, accessed 29 May 2023.
  2. MS International Federation. About World MS Day. Available from: https://worldmsday.org/about/, accessed 29 May 2023.
  3. MS International Federation. Types of MS. Available from: https://www.msif.org/about-ms/types-of-ms/?gclid=Cj0KCQjw4NujBhC5ARIsAF4Iv6fOHSQYim5KoJidw7_9ig8HBcC3FRKWBmXViloS6H-__GPuavAsTgoaAuJjEALw_wcB, accessed 31 May 2023.
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IBD Patients Have an Increased risk of Ischaemic Stroke

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Credit: American Heart Association

In a nationwide Swedish study of more than 85 000 patients with biopsy-confirmed inflammatory bowel disease (IBD), researchers saw an increased risk of stroke, especially ischaemic stroke, compared to the general population. The results are published in Neurology.

IBD is a chronic intestinal disease with a relapsing-remitting manner, including Crohn’s disease (CD), ulcerative colitis (UC), and IBD-unclassified. Prior studies have suggested that IBD patients have a greater risk of thromboembolic events, but evidence for long-term risk of stroke remains scarce. A recent postmarketing safety study on tofacitinib, a new drug approved for IBD treatment, found an increased stroke risk.

The researchers, from Karolinska Institutet and Örebro University (Sweden), conducted a cohort study by linking a nationwide histopathology cohort (the ESPRESSO study) to national healthcare registers in Sweden to explore whether patients with a biopsy-confirmed IBD had an increased long-term risk of stroke compared to their IBD-free siblings or the general population.

During an average follow-up of 12 years, 3720 of IBD sufferers had a stroke (32.6/10 000 person years), compared with 15 599 of the IBD-free people (27.7/10 000 person-years). When accounting for other factors, such as heart disease, hypertension and obesity, they found that people with IBD were 13% more likely to have a stroke than those without IBD. The risk stayed elevated even 25 years after IBD diagnosis, equating to one additional stroke case per 93 IBD patients. The excess risk was mainly driven by ischaemic stroke rather than haemorrhagic stroke.

The risk for ischaemic stroke was significantly increased across all IBD subtypes (ie, CD, UC, and IBD-U). Sibling comparison analyses confirmed the main findings, suggesting the excess risk of stroke may be independent of familial factors.

Clinical implications

“Due to the excess risk of stroke in IBD patients, screening and management of traditional stroke risk factors in IBD patients could be more urgent to prevent fatal CVD complications”, says first author Jiangwei Sun, postdoc at the Department of Medical Epidemiology and Biostatistics.

“These findings highlight the need for clinical vigilance about the long-term excess risk of cerebrovascular events in IBD patients”, adds last author Jonas F Ludvigsson, professor at Karolinska Institutet and pediatrician at Örebro University Hospital.

Source: Karolinska Institutet