Cancer therapy shows promise for psoriasis treatment

HDAC inhibitors, already widely used to treat cancer, may be an effective therapy for psoriasis as well, scientists report.

They have shown that HDAC3 inhibitors are particularly adept at increasing expression of aquaporin-3, or AQP3, a channel that transports glycerin, a natural alcohol and water attractor, which helps skin look better and aids healthy production and maturation of high-turnover skin cells.

“We’ve found that HDAC3 normally inhibits expression of AQP3 and we think we can use this knowledge to treat patients with psoriasis,” said Dr. Vivek Choudhary, molecular biologist and physiologist in the Department of Physiology at the Medical College of Georgia at Augusta University.

MCG scientists knew that AQP3 levels were lower in psoriasis than in healthy skin, said Choudhary, corresponding author of the study in the Journal of Investigative Dermatology. The protein helps skin cells proliferate, differentiate into the right kind of cells and get to the right location in the body. It also aids the skin’s hydration, wound recovery and elasticity. Histone deacetylase, which they found suppresses AQP3, helps regulate gene expression and protein function.

Since the immune system is believed to play a key role in psoriasis, many current treatments generally suppress the immune response, which increases the risk of infections, even cancer. MCG scientists hope they can one day instead directly enhance the presence of AQP3 or maybe its key cargo glycerin.

Psoriasis is one of the most common skin disorders, with red, flaky patches most often erupting on the elbows, knees, scalp and back, said Dr. Wendy B. Bollag, cell physiologist in the MCG Department of Physiology and the study’s senior author.

Like cancer, inflammation and excessive proliferation of cells are a psoriasis hallmark. That common ground and other emerging clues got the scientists thinking about the treatment potential of HDAC inhibitors. But first they had to establish a relationship.

When they introduced a broad-acting HDAC inhibitor to normal skin cells, or keratinocytes, – both mouse and human – they found expression of AQP3 went up within 24 hours, the first time the relationship had been noted.

They reiterated that AQP3 was critical because when it was missing, there was no commensurate increase in glycerin. AQP3 knockout mice also further clarified AQP3’s role in skin hydration, elasticity and wound healing and that it is glycerin – rather than water – that is most key to these healthy functions.

They also found that p53, a known, natural tumor suppressor that also supports cell differentiation, helps the HDAC inhibitors enable more AQP3 and ultimately more glycerin, Choudhary said. HDACs also are known to inhibit p53 activity. However overexpressing p53 by itself did not result in increased functional levels of AQP3, the scientists found.

The MCG scientists first used the HDAC inhibitor, suberoylanilide hydroxamic acid, or SAHA, which was approved by the Food and Drug Administration more than a decade ago to treat cutaneous T cell lymphoma, which has symptoms that can include dry, itchy skin as well as enlarged lymph nodes.

“We think this is one of the ways it works,” Bollag said of SAHA and their new findings. They also used several other HDAC inhibitors and found the ones that suppressed HDAC3 were also most effective at increasing AQP3.

AQP3 is adept at hauling glycerin, the backbone of many lipids and typically a key ingredient in skin lotion. Bollag’s lab reported in the Journal of Investigative Dermatology in 2003 that glycerin helps skin cells mature properly. Inside skin cells, phospholipase D – an enzyme that converts fats or lipids in the external protective cell membrane into cell signals – and AQP3 interact. AQP3 hands off glycerin, which produces phosphatidylglycerol, which, in turn, aids skin cell differentiation.

“We think phosphatidylglycerol is the key,” Bollag said of the positive results. “If you don’t have enough, you may have psoriasis.”

The Bollag lab and others also had found that AQP3, which is present in psoriasis, appears rather immature and out of place, largely inside the cell cytoplasm instead of on the protective, outer cell membrane. The inner location puts quite a damper on its normal mature function of transporting glycerin, water and other substances through the membrane.

“If you use antibodies to visualize where AQP3 is in the keratinocytes, you will see it nicely outlining the cells because it’s right there on the plasma membrane,” Bollag said. “So clearly it’s normally expressed in keratinocytes but the fact that we can upregulate it even more with an HDAC3 inhibitor suggests that normally HDAC3 keeps it in check.”

Cambridge, Massachusetts-based biotech company Shape Pharmaceuticals Inc., currently has a topical version of an HDAC inhibitor in clinical trials for cutaneous T cell lymphoma. If psoriasis patients end up taking HDAC inhibitors, low doses or a topical application likely would help avoid some side effects, including nausea, Bollag said.

One way HDAC inhibitors help fight cancer is by temporarily loosening DNA, increasing the expression of tumor-suppressing genes and making the tumor more vulnerable. HDAC inhibitors also are being explored for their potential in treating neurological diseases such as Huntington’s.

Others have provided evidence that dysregulation of AQP3 contributes to psoriasis and AQP3 is linked to other skin diseases as well like atopic dermatitis – the most common type of eczema and vitiligo, which results in white patches on the skin.

Interestingly, even though psoriatic cells are known for their propensity to replicate, it’s hard to grow an adequate number of cells for scientific study: they increase a certain amount then go quiet. There also is no real animal model of psoriasis. Moving forward, the MCG scientists may try developing a model using a topical drug for genital warts since some patients who take it develop psoriasis.

Healing wounds with cell therapy

Diabetic patients frequently have lesions on their feet that are very difficult to heal due to poor blood circulation. In cases of serious non-healing infections, a decision to amputate could be made. A new therapeutic approach, presented recently in the Journal of Investigative Dermatology by Canadian researchers affiliated with the University of Montreal Hospital Research Centre (CRCHUM), could prevent these complications by promoting wound healing.

The solution isn’t what you might expect, not just another antibiotic ointment or other prescription medication. It’s the approach that’s different, a way to heal through personalized medicine. “We discovered a way to modify specific white blood cells — the macrophages — and make them capable of accelerating cutaneous healing,” explained nephrologist Jean-François Cailhier, a CRCHUM researcher and professor at the University of Montreal.

It has long been known that macrophages play a key role in the normal wound healing process. These white cells specialize in major cellular clean-up processes and are essential for tissue repair; they accelerate healing while maintaining a balance between inflammatory and anti-inflammatory reactions (pro-reparation).

“When a wound doesn’t heal, it might be secondary to enhanced inflammation and not enough anti-inflammatory activity,” explained Cailhier. “We discovered that macrophage behaviour can be controlled so as to tip the balance toward cell repair by means of a special protein called Milk Fat Globule Epidermal Growth Factor-8, or MFG-E8.”

Cailhier’s team first showed that when there is a skin lesion, MFG-E8 calls for an anti-inflammatory and pro-reparatory reaction in the macrophages. Without this protein, the lesions heal much more slowly. Then the researchers developed a treatment by adoptive cell transfer in order to amplify the healing process.

Adoptive cell transfer consists in treating the patient using his or her own cells, which are harvested, treated, then re-injected in order to exert their action on an organ. This immunotherapeutic strategy is usually used to treat various types of cancer. This is the first time it has been shown to also be useful in reprogramming cells to facilitate healing of the skin.

“We used stem cells derived from murine bone marrow to obtain macrophages, which we treated ex vivo with the MFG-E8 protein before re-injecting them into the mice, and we quickly noticed an acceleration of healing,” said Dr. Patrick Laplante, Cailhier’s research assistant and first author of the study.

Added Dr. Cailhier, “the MFG-E8 protein, by acting directly upon macrophages, can generate cells that will orchestrate accelerated cutaneous healing.”

The beauty of this therapy is that the patient (in this case the mouse) is not exposed to the protein itself. Indeed, as Dr. Cailhier explained, “if we were to inject the MFG-E8 protein directly into the body there could be effects, distant from the wound, upon all the cells that are sensitive to MFG-E8, which could lead to excess repair of the skin causing aberrant scars named keloids. The major advantage [of this treatment] is that we only administer reprogrammed cells, and we find that they are capable of creating the environment needed to accelerate scar formation. We have indeed discovered the unbelievable potential of the macrophage to make healing possible by simple ex vivo treatment.”

What now remains to be done is to test this personalized treatment using human cells. Thereafter, the goal will be to develop a program of human cell therapy for diabetic patients and for victims of severe burns. It will take several years of research before this stage can be reached.

This advanced personalized treatment could also make all the difference in treating cases of challenging wounds. According to the World Health Organization, diabetes affects 8.5% of the global population, and amputation rates of the lower extremities are 10 to 20 times higher in diabetics. “If, with this treatment, we can succeed in closing wounds and promoting healing of diabetic ulcers, we might be able to avoid amputations,” Dr. Cailhier said.

“Serious burn victims could also benefit,” he added. “By accelerating and streamlining the healing of burns, we may be able to reduce the infections and keloids that unfortunately develop much too often in such patients.” Cancer patients requiring extensive reconstruction surgery could also benefit, he said.

 

Penn Medicine Launches First Apple ResearchKit App for Sarcoidosis Patients

App combines patient resources with research

Penn Medicine today launched its first Apple ResearchKit app, focused on patients with sarcoidosis, an inflammatory condition that can affect the lungs, skin, eyes, heart, brain, and other organs. The effort marks Penn’s first time using modules from Apple’s ResearchKit framework, as part of the institution’s focus on mobile health and innovative research strategies.

ResearchKit is an open source software framework designed specifically for medical research that helps doctors and scientists gather data more frequently and more accurately from participants using an iPhone. Since its launch two years ago, valuable data collected from the iPhones of patients with Parkinson’s disease, breast cancer, and asthma who opt in to use these applications, has poured into medical centers investigating better ways to study and treat these diseases.

Developed by Misha Rosenbach, MD, an assistant professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, and Daniel O’Connor, a fourth-year Penn medical student, in collaboration with Marc Judson, MD, at Albany Medical College as well as the Foundation for Sarcoidosis Research, the app will deliver informational resources to patients, supplying links to disease information and advocacy groups, and directing them to specialists in their area based on their phone’s GPS. Patients will have the ability to opt in to a research study which can provide researchers with a trove of data about this rare disease. Optional, once-a-month surveys will query users about, for example, their symptoms and flare ups, how sarcoidosis affects their lives, and medications. The app will also optionally pull data naturally tracked through sensors on iPhone – from the weather to physical activity – to help the researchers spot any trends.

Among potential queries the technology will allow investigators to explore: When sarcoidosis is flaring, are patients walking fewer steps? Do they miss work? Does their disease flare after a week’s worth of sunny days? Does geographic location affect symptoms? Is there a seasonal variability? How quickly do patients respond to treatments?

“There’s a great opportunity that has never been done,” Rosenbach said. “In traditional research, you can’t see patients every day, but in app-based research you can suddenly get all this information about the disease in real-time and over time, from many different patients all over the world. It gives us the power to do sarcoidosis research in a way that has never been done.”

One of the biggest challenges in medical research is numbers. Researchers are faced with a shortage of patients for clinical studies. Even in a more common research space like cancer, studies have shown only 3 to 5 percent of patients volunteer to participate. But it’s especially hard in rare disease research because of a much smaller pool of patients. Sarcoidosis, which occurs in the lungs for about 90 percent of patients, is diagnosed in anywhere between 10 to 30 out of 100,000 Americans each year. It can affect nearly anyone, but disproportionately affects African Americans, particularly black women.
The largest study to date, the ACCESS trial (A Case-Control Etiologic Sarcoidosis Study), enrolled about 800 patients over a three-year period across 20 medical centers in the United States, and still failed to completely answer many critical questions, Rosenbach said.
“This new app has the potential to build up a larger cohort of more diverse patients in a shorter amount of time,” he said. “There’s a motivated and engaged group of sarcoidosis patients who are active online, but there’s a whole host of them out there we don’t know about. This app, which can securely, privately, and anonymously collect data, casts a wide net that may engage those people, and funnel valuable, much-needed information to researchers.”

The exact cause of sarcoidosis is unclear, but many researchers agree it starts from an immune response to some foreign material trigger, such as an atypical infection. When the body encounters a foreign material that it can’t fight off, it builds up a protective wall of inflammatory cells called a granuloma – lumps of cells. In sarcoidosis patients, this production never shuts off – it keeps going and going, resulting in numerous granulomas – that can damage organs, particularly the lungs.

With this project, researchers will determine whether the app is an effective method of studying the disease and collecting quality of life measurements used in today’s conventional clinical studies. Survey questions to enrollees can be tweaked throughout the process, if necessary, as new data rolls in or input from health care leaders and the sarcoidosis community emerges.

Data gathered from the app, the researchers said, could impact how tomorrow’s clinical studies are designed.

“We’re excited about future opportunities to repurpose the app for other rare diseases, as well,” O’Connor said. “With a strong app framework in place, ‘sarcoidosis’ could be swapped out for another disease, allowing wide networks of patients all over the country to participate in Penn studies without traveling to Philadelphia.”

Battling Psoriasis: Can-Fite Advances to Critical Worldwide Phase III Clinical Trial

Psoriasis, a skin disorder expressed by dry, red reptile-like scales, is autoimmune, meaning cells in the body attack cells supposed to help put down the ailment. Several medicines exist, but not without effects that lead to more problems. In what amounts to a psoriasis coup, Can-Fite BioPharma found a way to clear skin and restore quality of life to those with this miserable disease, inciting no adverse consequences, and contained in a simple pill.

A fast journey, Can-Fite recently set its Phase III plan to use Piclidenoson, formerly CF101, in front of Europe’s EMA, our equivalent of FDA but quicker. EMA was receptive. The pivotal study will have all the proper scientific controls in place, where doctors don’t know if they’re handing out Piclidenoson or sugar pills.
Most important, planned global trials in 400 patients will pit Piclidenoson against the wildly-popular and lucrative Otezla (a blockbuster bringing in billions), from Celgene Corp. for psoriasis. Prior head-to-head studies against Otezla proved favorable and were subsequently published in highly-respected Journal of Drugs in Dermatology. As in the former study, Phase III will seek improvement versus placebo under medical-vetted psoriasis scoring as a first endpoint; the second will expect to show Piclidenoson equal to Otezla in efficacy.
Biologics for psoriasis are dangerous. Injectables operate to harness the immune system but fall short – side effects like respiratory illness are rampant, to name a few. Can-Fite’s drug works better. Two biochemical helpers – IL 17 and IL 23 are key. Can-Fite has found a way to employ these crucial players in the autoimmune disease of inflammation that represent different internal pathways than competitors.

Psoriasis affects millions worldwide – a medical market of $4 billion and growing exponentially. Can-Fite’s drug has shown safety and efficacy in 1,000 patients so far.
Piclidenoson brings information from cells of the body to enable certain functions in the body. How Piclidenoson works is elegant: it targets a biologically essential adenosine receptor to stop action that may result in disease, specifically autoimmune disorders where blood and organs attack themselves. Because Piclidenoson only works on ‘bad’ cells that cause inflammation, ‘healthy’ cells are spared; hence, the lack of detrimental side effects.

Inquiring about Can-Fite’s choice of receptor to study, I spoke to Pnina Fishman, CEO and founder of Can-Fite, who replied: “The reason we selected A3AR stems out of findings showing it is highly expressed on diseased cells but low expressed on normal cells. This makes it a specific target. This receptor doesn’t play a physiological role and is expressed when a disease evolves. So it does not mediate any adverse events”.

Two psoriasis pharma stars light up the medical sky – Celgene’s compound and another heavy-hitter from Johnson & Johnson, Stelara, which lists as bad side effects the risk of life-threatening allergic reactions, skin cancer, and blood leakage into the brain that may kill. Yet the drug is about to rake in $3 billion in 2016.
Piclidenoson works differently than Otezla, which is based on an asthma drug as I describe in an earlier article, and whose close biochemical cousin is used for erectile dysfunction. Otezla’s common side effects include unbearable migraine, diarrhea and vomiting and even thoughts of suicide, which led 6% of clinical trial patients to voluntarily stop treatment of the drug (see box below for a comprehensive list of psoriasis treatments).

By contrast, Piclidenoson may cause slight sinus trouble and earache, although occurring in a very low percentage of patients.

Gene therapy for blistering skin disease appears to enhance healing in clinical trial

Grafting sheets of a patient’s genetically corrected skin to open wounds caused by the blistering skin disease epidermolysis bullosa appears to be well-tolerated and improves wound healing, according to a phase-1 clinical trial conducted by researchers at the Stanford University School of Medicine.

The results mark the first time that skin-based gene therapy has been demonstrated to be safe and effective in patients.

The findings will be published Nov. 1 in JAMA. Associate professors of dermatology Peter Marinkovich, MD, and Jean Tang, MD, PhD, share senior authorship of the study. Senior scientist Zurab Siprashvili, PhD, is the lead author.

For the study, four adult patients with recessive dystrophic epidermolysis bullosa, an excruciatingly painful genetic skin disease, received the skin grafts.

“Our phase-1 trial shows the treatment appears safe, and we were fortunate to see some good clinical outcomes,” said Tang. “In some cases, wounds that had not healed for five years were successfully healed with the gene therapy. This is a huge improvement in the quality of life for these people.”

People with epidermolysis bullosa lack the ability to properly produce a protein called type-7 collagen that is needed to anchor the upper and lower layers of the skin together. As a result, the layers slide across one another upon the slightest friction, creating blisters and large open wounds. The most severe cases are fatal in infancy. Other patients with recessive dystrophic EB can live into their teens or early adulthood with supportive care. Often these patients die from squamous cell carcinoma that develops as a result of constant inflammation in response to ongoing wounding.

The Stanford researchers showed that it was possible to restore functional type-7 collagen protein expression in patient skin grafts to stop blistering and allow wounds to heal. They also found that the protein continued to be expressed and that wound healing was improved during a year of follow up.

Looking to build upon results

The researchers seek to build upon these promising early results in a new trial that will include patients ages 13 and older.

“Moving into the pediatric population may allow us to intervene before serious chronic wounds and scars appear,” said Marinkovich, who directs the Stanford Blistering Disease Clinic. Repeated rounds of wounding and scarring on the fingers and palms, for example, often lead to fusion of the skin and the formation of what’s known as a “mitten hand.”

Siprashvili used a virus to deliver a corrected version of the type-7 collagen gene into batches of each patient’s skin cells that had been harvested and grown in the laboratory. He coaxed these genetically corrected cells to form sheets of skin about the size of an iPhone 5. The sheets were then surgically grafted onto the patient’s chronic or new wounds in six locations.

The researchers tracked the status of the grafts at one-, three- and six-month intervals for at least a year, checking to see if they stayed in place and caused wound closure. They also looked for any evidence of an immune reaction to the grafts, and whether the grafts continued to make the corrected type-7 collagen protein.

All 24 grafts were well-tolerated, the researchers found. Furthermore, they could detect expression of the type-7 collagen protein in the correct location of the skin in nine out of 10 tissue biopsies at three months. After 12 months, they were able to detect the collagen protein in five out of 12 biopsies.

Wound healing

Similar results were seen with wound healing. After three months, 21 of the 24 grafts were intact. This number dropped to 12 out of 24 after one year.

“Even a small improvement in wound healing is a huge benefit to the overall health of these patients,” said Tang. “For example, it may reduce the likelihood of developing squamous cell carcinoma that often kills these patients in young adulthood.”

Coupling grafts with hand surgery to break up scarred, fused tissue could help patients maintain the use of their hands, Marinkovich said.

Tang, Marinkovich and their colleagues will continue to monitor the patients in the phase-1 trial throughout their lifetimes to assess any long-term effects of the grafts.

The completion of the phase-1 trial and the potential to improve upon these outcomes is due to a concerted, long-term effort at Stanford to find ways to help young patients with this devastating disease.

The researchers are now starting a phase-2 clinical trial and are looking for new patients. For more information, send an email to tangy@stanford.edu or mpm@stanford.edu.

“This trial represents the culmination of two decades of dedicated clinical and basic science research at Stanford that began with the arrival of the former dean of the School of Medicine, Eugene Bauer, who set up the multidisciplinary EB Center at Stanford,” said Tang. “We have been working for a long time to get to this potential therapy into patients. We had to discover the genes and proteins involved and the responsible mutations. We then had to learn to deliver the corrected gene and grow those cells into sheets suitable for grafting.”

“We could not have reached this point without the support of the EB patients and their families,” said Marinkovich. “Since the time of my research training in the laboratory of Robert Burgeson, PhD, who discovered type-7 collagen, I’ve been deeply motivated to contribute to the EB community, and it is very satisfying to be able to finally see this molecular therapy come to fruition.”

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.