Genetic risk factor for equine eye cancer identified

Squamous cell carcinoma (SCC) is the most common cancer found in equine eyes and the second most common tumor of the horse overall. Thanks to a recent genetic study led by UC Davis, horse owners can now identify horses at risk for ocular SCC and make informed breeding decisions.

In the cover article for the International Journal of Cancer, scientists announced the discovery of a genetic mutation in horses that is hypothesized to impact the ability of damage specific DNA binding protein 2 (DDB2) to carry out its standard role. Normally, the protein conducts DNA surveillance, looking for UV damage and then calling in other proteins to help repair the harm.

“The mutation is predicted to alter the shape of the protein so it can’t recognize UV-damaged DNA,” said Dr. Rebecca Bellone, an equine geneticist at the Veterinary Genetics Laboratory and associate adjunct professor at UC Davis School of Veterinary Medicine. “We believe this is a risk factor because cells can’t repair the damage and accumulate mutations in the DNA that lead to cancer.”

Several equine breeds, including Haflingers, have a higher occurrence of limbal SCC, the form of the disease that originates in the junction between the cornea–the clear surface of the eyeball–and the conjunctiva that covers the white of the eye. A former study, conducted by Bellone and one of her research partners, Dr. Mary Lassaline, found that about 26 percent of SCC-affected horses in a retrospective study were Haflingers.

“The fact that we see this type of cancer in a relatively small breed with a narrow pedigree makes it a good model to study,” said Lassaline, associate professor of clinical equine ophthalmology at the UC Davis School of Veterinary Medicine.

Ocular SCC can lead to vision loss and even loss of the eye. In advanced cases, SCC can be locally invasive and spread to the orbit and eat away at bone and eventually the brain–leading to loss of life. These recent study results offer a huge application in identifying horses at risk for developing SCC on two fronts.

“One, it’s important for the individual horse with a known risk and we can be more vigilant about exams as well as protecting their eyes from UV exposure,” Lassaline said. “If detected early, we can remove the tumor and save the eye. Secondly, that knowledge is important for making informed breeding decisions.”

Scientists at the UC Davis Veterinary Genetics Laboratory were able to develop a genetic test for horses based on the research. The test determines if a horse carries the mutation or has two copies of the risk variant, putting it at highest risk for cancer.

In addition to improving the health of horses, this study may have implications for human health as well. The gene found to be associated with equine SCC is also linked in humans to xeroderma pigmentosum complementation group E–a disease characterized by sun sensitivity and increased risk of cutaneous SCC and melanoma.

“There is an interesting parallel in humans with mutation in this protein,” Bellone said. “Now we have the ability to understand why it’s affecting the eyes of horses as well as the skin of humans.”

‘Sticky’ Particles Promise More Precise Drug Delivery for Brain Cancer

A Yale research team has found that by tinkering with the surface properties of drug-loaded nanoparticles, they can potentially direct these particles to specific cells in the brain.

By making nanoparticles bioadhesive, or “sticky,” the researchers have answered a long-standing question: Once you get the particles to the brain, how do you get them to interact with the cancer cells there? Their findings are published May 19 in Nature Communications.

“Until now, research has focused on whether you can load the nanoparticles with drugs and whether we can get them into the brain at all, without thinking too much about what cells they go to,” said senior author W. Mark Saltzman, the Goizueta Foundation Professor of Chemical and Biomedical Engineering, professor of cellular and molecular physiology, and member of the Yale Cancer Center. “This is the first exploration of the particles’ affinity for different cells.”

The ability for nanoparticles to deliver drugs to specific areas of the body holds great promise for fighting cancer and other diseases while minimizing the side effects of drugs that are often very toxic, according to scientists. Their use in treating brain cancer, though, has been particularly challenging. That’s partly due to the blood-brain barrier, which acts to keep foreign elements out of the brain. Researchers have been able to get nanoparticles to penetrate the brain in recent years with help from a polymer coating that gives the particles “stealth” properties, allowing the particles to hide from the body’s immune system. Those same stealth properties, however, also keep cells from recognizing the particles.

“So they’re just kind of in the space between the cells, and not really doing what they’re supposed to be doing,” said co-lead author Eric Song, a graduate student at the Yale School of Medicine.

The Yale researchers found that they could correct for this by altering the chemistry of the nanoparticles. In two groups of rats — ones with brain tumors and ones with healthy brains — the researchers found that differences in the particles’ surface chemistry played a significant role in whether the particles were internalized by cells in the brain.

They covered one group of particles with polymers rich in aldehydes, which chemically bind to amines — a compound found in most proteins. These bioadhesive particles were most likely to be taken up by cells of all types in the brain: Tumor cells were among those that internalized the bioadhesive particles at a particularly high rate.

These results suggest that tailoring the chemical properties of particles provides an opportunity to control the distribution of the drugs they’re carrying, said the researchers. Further, they believe that the particles could be tailored for specific therapies to improve efficacy in target cells, and minimize toxicity to the cells they’re not targeting.

Study redefines HPV-related head and neck cancers

Much of what we thought we knew about the human papilloma virus (HPV) in HPV-related head and neck cancers may be wrong, according to a newly published study by Virginia Commonwealth University (VCU) researchers that analyzed data from The Human Cancer Genome Atlas. Head and neck cancers involving HPV are on the rise, and many experts believe we are seeing the start of an epidemic that will only get worse in the coming years.

The Cancer Genome Atlas is a collaboration between the National Cancer Institute (NCI) and the National Human Genome Research (NHGR) Institute that makes publicly available genomic information on tumor samples from 33 different types of cancers. Its aim is to help the cancer research community improve the prevention, diagnosis and treatment of cancer.

It is thought that there are two main forms of HPV-related cancers, episomal and integrated. In episomal variants, the HPV genome replicates independently. Integrated HPV has become part of the DNA of the host cell and relies on it for replication. Previously, it was believed that most HPV-related head and neck cancers had integrated HPV, as is what is believed with HPV-related cervical cancers. However, Windle’s study, recently published in the journal Oncotarget, found that HPV DNA is maintained separate from the human genome in the majority of HPV-related head and neck cancers, though, in many cases, the HPV genome can acquire a small piece of human DNA making it look like integrated HPV. This viral-human hybrid represents a new category of episomal HPV in HPV-related cancers.

“Our work challenges the idea that finding HPV DNA joined to human DNA means that HPV is integrated. With this new view of the state of HPV, we conclude that episomal HPV is the predominant state in HPV-related head and neck cancers,” says Brad Windle, member of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, professor at the Philips Institute for Oral Health Research at the VCU School of Dentistry and co-principle investigator on the study. “This is an important distinction because patients with episomal HPV cancer respond better to therapy than patients with integrated HPV cancer.”

Windle’s team analyzed the genomes of all 520 HNC samples in The Cancer Genome Atlas and found that 72 were HPV positive. The large majority of these cancers had a common type of the virus known as HPV16 present, so they focused on that virus type. The data showed that 75 percent of the HPV16 samples had the HPV genome in the episomal state, and about half of the genomes contained a piece of human DNA within their circular structure.

The researchers also found that 73 percent of the tumor samples were still dependent on proteins known as E1 and E2 for replication. This is important because when the HPV genome integrates with human DNA, expression of the HPV E2 protein–essential for independent replication–is lost. The presence of E2, or lack thereof, in tumor biopsies could be a reliable way for physicians to determine the cancer type and provide a more accurate prognosis.

“Perhaps our most striking outcome is the potential to target the E1 and E2 proteins for diagnosis and treatment,” says Windle. With nearly three quarters of these cancers dependent on E1 and E2 for replication, we could develop drugs that target these proteins and promote cell death.”

Windle’s team plans to continue studying the integration of HPV in HPV-related head and neck cancers, and suggests that viral-human DNA hybrid HPV should be further explored in HPV-related cervical cancers. His team is currently working with Massey clinicians in order to use this information to assess patients’ prognosis in the clinic.

Long Term Survival Indicated for Advanced Stage Colorectal Cancer Patients who Survive at Least Two Years

Improvements in chemotherapy and liver surgery have resulted in increased overall survival in patients with advanced stage colorectal cancer in recent decades. In order to better predict outcomes for these patients, researchers at Rutgers Cancer Institute of New Jersey conducted a retrospective analysis and found that stage IV colorectal cancer patients who survived at least two years have a better prognosis than originally thought. Results of the work will be presented as part of a poster presentation at the American Society of Clinical Oncology Annual Meeting being held in Chicago early next month.

“With patients in this population living longer, it is imperative we refine prognostic information to more accurately predict survival.  This data will assist multi-disciplinary cancer management teams in making treatment decisions that ultimately will impact a patient’s quality of life,” notes Darren Carpizo, MD, PhD, surgical oncologist and director of the Hepatobiliary Program at Rutgers Cancer Institute and senior investigator of the work (pictured).

Investigators examined data on more than a thousand stage IV colorectal cancer patients seen at Rutgers Cancer Institute between 2005 and 2015. This included patients who had their cancer removed through surgery and were treated with follow-up therapies, as well as those patients who were not eligible for surgery. Complete data was available for 125 patients who survived for more than two years (75 had surgical removal of their cancer; 50 did not).  Median overall survival of patients who underwent surgery was not reached, while median overall survival for those who were not eligible for surgery was six years and three months.

“For those patients not eligible for initial surgery who survive two years, these findings indicate they may benefit from future surgery, if feasible, to treat remaining disease. For those patients who initially had surgery, this information may be helpful to identify patients who might benefit from repeat surgery to resect any recurrent metastatic disease,” adds Dr. Carpizo, who is also an associate professor of surgery and pharmacology at Rutgers Robert Wood Johnson Medical School.

Rutgers Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center. As part of Rutgers, The State University of New Jersey, Rutgers Cancer Institute is dedicated to improving the detection, treatment and care of patients with cancer, and to serving as an education resource for cancer prevention both at its flagship New Brunswick location and at its Newark campus at Rutgers Cancer Institute of New Jersey at University Hospital. Physician-scientists across Rutgers Cancer Institute also engage in translational research, transforming their laboratory discoveries into clinical practice that supports patients on both campuses.

Skin cancer on the rise

New diagnoses for two types of skin cancer increased in recent years, according to a Mayo Clinic-led team of researchers.

Their paper, published today in Mayo Clinic Proceedings, uses medical records from the Rochester Epidemiology Project to compare diagnoses of basal cell carcinoma and squamous cell carcinoma — both nonmelanoma skin cancers — between 2000 and 2010 to diagnoses in prior years. The Rochester Epidemiology project is a medical records linkage system and research collaborative in Minnesota and Wisconsin.

Age, sex lead to different diagnoses

The researchers report that, between 2000 and 2010, squamous cell carcinoma (also called cutaneous squamous cell carcinoma) diagnoses increased 263 percent, and basal cell carcinomas increased 145 percent. They compared the 2000-2010 period to two other segments of time: 1976-1984 and 1985-1992.

Women 30-49 experienced the greatest increase in basal cell carcinoma diagnoses; whereas, women 40-59 and 70-79 experienced the greatest increase in squamous cell carcinomas.

Men had an increase in squamous cell carcinomas between the first and second time period studied (1976-1984 and 1985-1992), but experienced a slight decline in the 2000-2010 period. However, for basal cell carcinomas, men over 29 showed similar increases in diagnoses in the 2000-2010 period then the two earlier periods.

Tanning: Beautifying or death-defying?

“We know that the sun and some artificial sunlight sources give off skin-damaging ultraviolet, or UV, rays,” says Christian Baum, M.D., a Mayo Clinic dermatologist and the study’s senior author. “This skin damage accumulates over time and can often lead to skin cancer.”

“Despite the fact that sunscreens and cautionary information have been widely available for more than 50 years, we saw the emergence of tanning beds in the 1980s, and tanning – indoors or out – was a common activity for many years.”

Although Dr. Baum notes that tanning has slowed, tanning beds still exist, and beaches will never be empty. But what people should remember is that the damage accumulates, he says, and “eventually those blistering sunburns of your youth and hot, reddened skin, and peeling shoulders of your adulthood can add up to one or more skin cancers.”

The authors also reported that shifts in exposure to UV light may be the reason for a location shift in where the cancer tumors are found. In the earlier time periods, both basal cell and squamous cell carcinomas were diagnosed more often on the head and neck. But, in the most recent time period, the records showed that basal cell tumors on the torso increased, as did squamous cell carcinomas on the arms and legs.

Dr. Baum says that the risk of cancer should provide the ultimate argument for using sunscreen – every day, year-round on all exposed skin.

“Use sunscreen,” says Dr. Baum. “This includes on your left arm for those who do a lot of driving. UV rays can penetrate car windows and exposed skin — even when the sun isn’t shining. UV rays bounce around under the clouds, off the snow, buildings, and more, causing damage — even on gray days.

More on the data

Using the Rochester Epidemiology Project medical records linkage system, the research team was able to identify nearly all of the Olmsted County, Minnesota, adult residents who received an initial diagnosis of the most common nonmelanoma skin cancers — basal or squamous cell carcinoma (or both), during the 2000-2010 period and the comparison years.

“There is no tumor registry for these types of cancer,” says Dr. Baum, “So it is difficult to have accurate estimates of the national or worldwide impact of these cancers. However, because the Rochester Epidemiology Project contains health care information for virtually all residents of Olmsted County since 1966, it provides a good proxy for information on many global population health concerns.”

First-In-Human Clinical Trial Aims to Extend Remission for Children and Young Adults With Leukemia Treated With T-Cell Immunotherapy

Phase 1 pilot study utilizes T-cell antigen presenting cells to prolong the persistence of cancer-fighting chimeric antigen receptor (CAR) T cells, reduce the relapse rate

After phase 1 results of Seattle Children’s Pediatric Leukemia Adoptive Therapy (PLAT-02) trial have shown T-cell immunotherapy to be effective in getting  93 percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) into complete initial remission, researchers have now opened a first-in-human clinical trial aimed at reducing the rate of relapse after the therapy, which is about 50 percent. The new phase 1 pilot study, PLAT-03, will examine the feasibility and safety of administering a second T-cell product intended to increase the long-term persistence of the patient’s chimeric antigen receptor (CAR) T cells that were reprogrammed to detect and destroy cancer.

The research team, led by Dr. Mike Jensen at the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, is exploring this strategy after discovering that of the patients who relapse in the PLAT-02 trial, about half of them have lost their CAR T cells. Lasting persistence of the CAR T cells is critical in combating a recurrence of cancer cells.

“While it’s promising that we’re able to get these patients who are very sick back into remission, we’re also seeing that the loss of the CAR T cells in some patients may be opening the door for the cancer to return,” said Dr. Colleen Annesley, an oncologist at Seattle Children’s and the lead investigator of the PLAT-03 trial. “We’re pleased to now be able to offer patients who have lost or are at risk of losing their cancer-fighting T cells an option that will hopefully lead to them achieving long-term remission.”

In the PLAT-03 trial, patients will receive “booster” infusions of a second T-cell product, called T antigen-presenting cells (T-APCs). The T-APCs have been genetically modified to express the CD19 target for the cancer-fighting CAR T cells to recognize. Patients will receive a full dose of T-APCs every 28 days for at least one and up to six doses. By stimulating the CAR T cells with a steady stream of target cells to attack, researchers hope the CAR T cells will re-activate, helping to ensure their persistence long enough to put patients into long-term remission.

PLAT-03 is now open to patients who first enroll in phase 2 of Seattle Children’s PLAT-02 trial and who are also identified as being at risk for early loss of their reprogrammed CAR T cells, or those who lose their reprogrammed CAR T cells within six months of receiving them.

The PLAT-03 trial is one of several trials that Seattle Children’s researchers are planning to open within the next year aimed at further improving the long-term efficacy of T-cell immunotherapy. In addition to the current T-cell immunotherapy trial that is open for children with neuroblastoma, researchers also hope to expand this promising therapy to other solid tumor cancers.

“We are pleased to be at a pivotal point where we are now looking at several new strategies to further improve CAR T-cell immunotherapy so it remains a long-term defense for all of our patients,” said Dr. Rebecca Gardner, Seattle Children’s oncologist and the lead investigator of the PLAT-02 trial. “We’re also excited to be working to apply this therapy to several other forms of pediatric cancer beyond ALL, with the hope that T-cell immunotherapy becomes a first line of defense, reducing the need for toxic therapies and minimizing the length of treatment to only weeks.”

To read about the experience of one of the patients in the PLAT-02 trial, please visit Seattle Children’s On the Pulse blog.

The T-cell immunotherapy trials at Seattle Children’s are funded in part by Strong Against Cancer, a national philanthropic initiative with worldwide implications for potentially curing childhood cancers. If you are interested in supporting the advancement of immunotherapy and cancer research, please visit Strong Against Cancer’s donation page.

For more information on immunotherapy research trials at Seattle Children’s, please call (206) 987-2106 or email immunotherapy@seattlechildrens.org.

Penn Study Identifies New Target to Fight Prostate, Lung Cancer

A newly identified molecular chain of events in a mouse model of prostate cancer highlights novel targets to treat it and other cancers. A team led by Marcelo Kazanietz, PhD, a professor of Systems Pharmacology and Translational Therapeutics, published in Cell Reports that the overexpression of a protein called PKCε with the loss of the tumor suppressor Pten causes the progression of prostate cancer.

This deadly combination produces an uptick in the levels of the cancer-promoting molecule CXCL13. When the team purposely disrupted CXCL13, or CXCR5, the cell-surface receptor it attaches to, the metastatic and tumor-forming characteristics of the mouse prostate cancer cells were impaired.

“In addition to providing evidence for a vicious cancer cycle driven by PKCε, our studies identified a compelling rationale for blocking the CXCL13-CXCR5 molecules as a new cancer treatment,” Kazanietz said. He and colleagues plan to identify compounds to block CXCR5 or CXCL13 with potential to be developed as anti-cancer agents. The researchers also suggested that CXCL13 levels in blood could be used as a biomarker to measure the precise state of prostate cancer progression in a patient.

The team’s next step will be to interfere with CXCR5/CXCL13 signals not only from the cancer cells but also from other cells in the tumor microenvironment that contribute to cancer growth.

Pulmonologists and oncologists have also observed that PKCε is overexpressed in lung cancer patients, but they do not fully understand its exact molecular consequences. In general, a high level of PKCε is associated with a poor prognosis.

“We are in the midst of extending these findings to lung cancer,” said Kazanietz, who is collaborating with Penn Medicine researchers David Feldser, PhD, an assistant professor of Cancer Biology, Steven M. Albelda, MD, a professor of Pulmonary, Allergy and Critical Care, and Evgeniy Eruslanov, PhD, a research assistant professor of Thoracic Surgery.

Widespread Hype Gives False Hope To Many Cancer Patients

(photo caption) Michael Uvanni of Rome, N.Y., sits in one of his interior design business showrooms. Uvanni was devastated when his brother, James Michael Uvanni III, 66, died from cancer following more than three years of specialized treatment. Given how optimistic his doctors were, he expected that his brother would be cured, or at least live a long time. (Mike Roy for KHN)

After Michael Uvanni’s older brother, James, was diagnosed with a deadly form of skin cancer, it seemed as if everyone told the family what they wanted to hear: Have hope. You can beat this, and we are here to help.

The brothers met with doctors at a half-dozen of the country’s best hospitals, all with impressive credentials that inspired confidence.

Michael Uvanni was in awe when he visited the University of Texas MD Anderson Cancer Center in Houston, one of the world’s most respected cancer hospitals. It was like seeing the Grand Canyon, said Uvanni, 66, of Rome, N.Y. “You never get used to the size and scope.”

Even the MD Anderson logo on buses and buildings — with “Cancer” crossed out in red, above the words “Making cancer history” — made the family’s battle seem winnable.

“I thought they were going to save him,” said Uvanni, an interior designer.

Patients and families are bombarded with the news that the country is winning the war against cancer. The news media hypes research results to attract readers. Drug companies promise “a chance to live longer” to boost sales. Hospitals woo paying customers with ads that appeal to patients’ fears and hopes.

“I’m starting to hear more and more that we are better than I think we really are,” said Dr. Otis Brawley, chief medical officer at the American Cancer Society. “We’re starting to believe our own bullshit.”

The consequences are real — and they can be deadly. Patients and their families have bought into treatments that either don’t work, cost a fortune or cause life-threatening side effects.

“We have a lot of patients who spend their families into bankruptcy getting a hyped therapy that [many] know is worthless,” Brawley said. Some choose a medicine that “has a lot of hype around it and unfortunately lose their chance for a cure.”

Although scientists have made important strides in recent years, and many early-stage cancers can now be cured, most of those with advanced cancer eventually die of their disease.

For Uvanni, hope gave way to crushing disappointment when his brother’s health declined and he died from metastatic melanoma in 2014.

“You get your hopes up, and then you are dropped off the edge of a cliff,” said Uvanni. “That’s the worst thing in the world.”

Caregivers like Uvanni can suffer prolonged grief and guilt if their loved ones are riddled with side effects and don’t survive as long as the family expected, noted Holly Prigerson, co-director of the Center for Research on End-of-Life Care at Weill Cornell Medical College.

For decades, researchers have rolled out new cancer therapies with great fanfare, announcing that science has at last found a key to ending one of the world’s great plagues, said Dr. Vinay Prasad, an assistant professor of medicine at Oregon Health & Science University. When such efforts fail to live up to expectations, the cancer world simply moves on to the next big idea.

Hyping early scientific results — based on lab tests or animal studies — can attract investors that allow researchers to continue their work. Positive results can lead biotech firms to be bought out by larger drug companies.

“It’s in the interest of almost every stakeholder in the health system to be optimistic about these therapies,” said Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.

Uvanni says his brother may have gotten more time from the many drugs he tried during his illness but that his quality of life was mostly terrible. (Mike Roy for KHN)

Of course, there is plenty of money to be made.

The U.S. spent nearly $88 billion treating cancer in 2014, with patients paying nearly $4 billion out-of-pocket, according to the American Cancer Society Cancer Action Network. Spending on cancer, a disease that most afflicts the aging, is predicted to soar as people live longer.

“While many people are trying to make patients’ lives healthier and longer and better, there are others that are exploiting their vulnerability,” said Dr. Leonard Saltz, chief of the gastrointestinal oncology service at New York’s Memorial Sloan Kettering Cancer Center.

Others argue that the excitement about cancer research is justified. A spokeswoman for the Pharmaceutical Research and Manufacturers of America, an industry group, said cancer patients have good reason for optimism.

“We continue to see great strides in identifying the genetic mutations and related factors that can drive the seemingly random formation of abnormal cells in cancer,” spokeswoman Holly Campbell said in a statement. “In the last decade, we’ve seen a number of scientific advances transform the landscape of many cancers.”

Promises To Cure Abound

Even the country’s top scientists sometimes get carried away.

In 1998, Nobel laureate James Watson — who co-discovered the structure of DNA — told The New York Times that scientists would “cure cancer in two years” using drugs that block tumor blood supplies. At that time, the drugs had succeeded only in mice.

In 2003, the director of the National Cancer Institute, Dr. Andrew von Eschenbach, announced a goal of “eliminating suffering and death due to cancer by 2015” by better understanding tumor genetics.

Last year, when President Barack Obama announced the Cancer Moonshot, which aims to accelerate and better coordinate research, he said, “Let’s make America the country that cures cancer once and for all.”

In a recent interview, von Eschenbach acknowledged he didn’t communicate his goal well.

“We all fall into that trap,” said von Eschenbach, now a senior fellow at the Milken Institute, a health and public policy think tank. “We’re offering what we have, but making it appear that it’s more than what it is.”

It’s easy to see how patients’ hopes are raised, said Timothy Turnham, former executive director at the Melanoma Research Foundation, an advocacy group. Researchers are frequently overly enthusiastic about early discoveries that have little chance of leading to a new drug.

“There is a disconnect between what researchers think is statistically significant and what is really significant for patients,” Turnham said. “Patients hear ‘progress,’ and they think that means they’re going to be cured.”

A Marketing Blitz

Uvanni said his brother’s experience was nothing like the sunny images in TV commercials, in which smiling cancer patients hug their grandchildren, hike in the mountains and lead dance classes.

A TV commercial for the Bristol-Myers Squibb drug Opdivo projects the words “a chance to live longer” on the side of skyscrapers, as a captivated crowd looks on. In much smaller type, a footnote reveals that lung cancer patients taking Opdivo lived just 3.2 months longer than others.

(Screenshot of Opdivo TV Commercial)

(Screenshot of Opdivo TV Commercial)

A TV ad for Merck’s Keytruda features reassuring images of a smiling, healthy patient hugging her family — not fighting for breath or struggling to walk. Although the commercial notes that the people in the ad are portrayed by actors, the commercial claims the drug provides “a chance for a longer life. It’s Tru.”

“Your heart sinks when you see those ads,” Uvanni said. Seeing the family depicted in the ad, he said “makes you wonder if they’re going down the same path that we did.”

The Keytruda ad notes that 71 percent of patients given the drug were alive “at the time of patient follow-up,” compared with 58 percent of those who received chemotherapy. The ad doesn’t mention that the “time of follow-up” was 11 months.

(Screenshot of Keytruda TV Commercial)

“It’s not false; it’s just incomplete,” said pharmacist Harold DeMonaco, a visiting scientist at the Massachusetts Institute of Technology in Boston. “They don’t give patients or the patients’ family enough information to make a reasonable decision.”

In an interview, Merck senior vice president Jill DeSimone said that the company aims to be responsible with its advertising, noting that the Keytruda ad reminds patients to talk to their doctors. “The physician is the ultimate decider on treatment,” DeSimone said.

In a statement, Bristol-Myers’ senior vice president Teresa Bitetti said that Opdivo ads play “an important role in educating patients about new treatment options and fostering informed conversations between patients and their doctors.”

Hospitals also have drawn criticism for overstating their success in treating cancer. In 1996, Cancer Treatment Centers of America, a for-profit chain, settled allegations from the Federal Trade Commission that “they made false and unsubstantiated claims in advertising and promoting their cancer treatments.”

The company’s current commercials — dozens of which are featured on their website — boast of offering “genomic testing” and “precision cancer treatment.”

The commercials don’t tell patients that these tests — which aim to pair cancer patients with drugs that target the specific mutations in their tumors — are rarely successful, Prasad said. In clinical trials, these tests have matched only 6.4 percent of patients with a drug, according to Prasad’s 2016 article in Nature. Because these drugs only manage to shrink a fraction of tumors, Prasad estimates that just 1.5 percent of patients actually benefit from precision oncology.

In a statement, Cancer Treatment Centers of America said, “We use national media to help educate cancer patients and their families about the latest diagnostic tools and treatment options. … All of our advertising undergoes meticulous review for clinical accuracy as well as legal approval to ensure we tell our story in an informative and responsible manner, and in compliance with federal guidelines.”

Spending on ads for hospitals that treat cancer soared 220 percent from $54 million in 2005 to $173 million in 2014, according to a 2016 article in JAMA Internal Medicine. Ads for Cancer Treatment Centers of America accounted for nearly 60 percent of all total cancer center advertising.

Targeting Melanoma

For more than a decade, the Food and Drug Administration approved no new treatments for metastatic melanoma. Patients typically died within a year of diagnosis.

Since 2011, however, the FDA has approved 11 new treatments, including several immunotherapies, which aim to harness the immune system to fight cancer. Last year, doctors leading a clinical trial announced that the median survival of patients taking the drug Keytruda had grown to two years. Forty percent of patients were alive three years later, according to the clinical trial, presented at the American Society of Clinical Oncology.

Researchers have tested immunotherapies against a variety of tumors, leading to approvals in lung cancer, kidney cancer, bladder cancer and others.

Such success has led doctors to label cancer immunotherapy as a “game changer.” N­­ewspapers and magazines call it a “breakthrough.” And hospitals laud them as “a miracle in the making.”

Yet these treatments — which were initially assumed to be gentler than chemotherapy — can provoke fatal immune system attacks on the lungs, kidneys, heart and other organs.

And there are no approved immunotherapies for tumors of the breast, colon, prostate and pancreas.

Only about 10 percent of all cancer patients can expect to benefit from immunotherapy, Prasad said.

Uvanni’s brother — who tried immunotherapy, as well as a number of other approved and experimental treatments — survived 3½ years after his diagnosis. That might lead many oncologists to describe his story as a success.

Uvanni sees no reason to celebrate. He wanted more than short-term survival for his brother.

“I thought we were going to have a treatment where we’d at least have a good block of quality time,” Uvanni said.

But treatments meant to control the cancer only made him sick. Some caused flu-like symptoms, with fever, chills and shakes. Others left him nauseated, unable to eat or move his bowels. Others caused dangerous infections that sent him to the emergency room.

“I hope that if something like that happens to me,” Uvanni said, “I would be strong enough to say no to treatment.”’

Kaiser Health News, a nonprofit health newsroom whose stories appear in news outlets nationwide, is an editorially independent part of the Kaiser Family Foundation.

Beta Blocker Shows Cancer-Fighting Properties

The beta blocker carvedilol could one day be used in creams or sprays that prevent skin cancer

A new study finds that carvedilol, a drug typically used to treat high blood pressure, can protect against the sun-induced cell damage that leads to skin cancer. Researchers serendipitously discovered the beta blocker’s cancer-fighting properties after making an error in the lab.

Sherry Liang, a graduate student at the Western University of Health Sciences College of Pharmacy, will present the new findings at the American Society for Pharmacology and Experimental Therapeutics annual meeting during the Experimental Biology 2017 meeting, to be held April 22-26 in Chicago.

“What began as an experimental error led to a very interesting scientific discovery,” said Ying Huang, PhD, coleader of the research team with Bradley T. Andresen, PhD. “Our research could lead to the development of a class of new cancer-preventive agents.”

Carvedilol’s cancer-fighting properties were discovered when a former graduate student in Huang’s lab was studying whether carvedilol and similar beta blockers might increase cancer risk. The student inadvertently tested carvedilol’s anticancer effect rather than its ability to promote cancer, finding that carvedilol surprisingly showed some protective effects against skin cancer.

The researchers then conducted experiments with cell cultures and mice to see if carvedilol could prevent skin cancer caused by ultraviolet-B (UVB), the portion of sunlight that tends to damage the skin’s top epidermal layers and plays a key role in skin cancer development.

The researchers found that carvedilol exhibited a protective effect in cultured mouse skin cells exposed to UVB and in hairless mice given the drug after UVB exposure. The experiments showed that carvedilol acted by protecting cells against the cancer-causing DNA damage and cell death produced by UVB. Hairless mice exposed to UVB and given carvedilol showed decreases in both the severity and number of tumors that developed compared to those not given carvedilol. The mouse studies also showed that carvedilol delayed skin tumor formation more than sunscreen.

The researchers also discovered that not all beta blockers show cancer preventive properties, indicating that the cancer-fighting beta blockers likely act on not yet identified molecules. “We have preliminary data indicating that the cellular targets for carvedilol are not related to the beta-adrenergic receptors that are the commonly accepted targets for all beta blockers,” said Andresen. “They likely target unexpected mechanisms involved in cancer development.”

The researchers aim to incorporate carvedilol or similar beta blockers into a skin cream or spray that could hopefully be used to prevent skin cancer arising from UV light exposure. The treatment would act on the skin without affecting blood pressure and heart rate, which are commonly altered by beta blockers. Understanding carvedilol’s mechanisms of action could also allow scientists to design completely new treatments that target these mechanisms without introducing any cardiovascular effects.

Nanoparticles Reprogram Immune Cells to Fight Cancer

Researchers at Fred Hutchinson Cancer Research Center have developed biodegradable nanoparticles that can be used to genetically program immune cells to recognize and destroy cancer cells — while the immune cells are still inside the body.

In a proof-of-principle study to be published April 17 in Nature Nanotechnology, the team showed that nanoparticle-programmed immune cells, known as T cells, can rapidly clear or slow the progression of leukemia in a mouse model.

“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Fred Hutch’s Dr. Matthias Stephan, the study’s senior author. “The reprogrammed cells begin to work within 24 to 48 hours and continue to produce these receptors for weeks. This suggests that our technology has the potential to allow the immune system to quickly mount a strong enough response to destroy cancerous cells before the disease becomes fatal.”

Cellular immunotherapies have shown promise in clinical trials, but challenges remain to making them more widely available and to being able to deploy them quickly. At present, it typically takes a couple of weeks to prepare these treatments: the T cells must be removed from the patient and  genetically engineered and grown in special cell processing facilities before they are infused back into the patient. These new nanoparticles could eliminate the need for such expensive and time consuming steps.

Although his T-cell programming method is still several steps away from the clinic, Stephan imagines a future in which nanoparticles transform cell-based immunotherapies — whether for cancer or infectious disease — into an easily administered, off-the-shelf treatment that’s available anywhere.

“I’ve never had cancer, but if I did get a cancer diagnosis I would want to start treatment right away,” Stephan said. “I want to make cellular immunotherapy a treatment option the day of diagnosis and have it able to be done in an outpatient setting near where people live.”

The body as a genetic engineering lab

Stephan created his T-cell homing nanoparticles as a way to bring the power of cellular cancer immunotherapy to more people.

In his method, the laborious, time-consuming T-cell programming steps all take place within the body, creating a potential army of “serial killers” within days.

As reported in the new study, Stephan and his team developed biodegradable nanoparticles that turned T cells into CAR T cells, a particular type of cellular immunotherapy that has delivered promising results against leukemia in clinical trials.

The researchers designed the nanoparticles to carry genes that encode for chimeric antigen receptors, or CARs, that target and eliminate cancer. They also tagged the nanoparticles with molecules that make them stick like burrs to T cells, which engulf the nanoparticles. The cell’s internal traffic system then directs the nanoparticle to the nucleus, and it dissolves.

The study provides proof-of-principle that the nanoparticles can educate the immune system to target cancer cells. Stephan and his team designed the new CAR genes to integrate into chromosomes housed in the nucleus, making it possible for T cells to begin decoding the new genes and producing CARs within just one or two days.

Once the team determined that their CAR-carrying nanoparticles reprogrammed a noticeable percent of T cells, they tested their efficacy. Using a preclinical mouse model of leukemia, Stephan and his colleagues compared their nanoparticle-programming strategy against chemotherapy followed by an infusion of T cells programmed in the lab to express CARs, which mimics current CAR-T-cell therapy.

The nanoparticle-programmed CAR-T cells held their own against the infused CAR-T cells. Treatment with nanoparticles or infused CAR-T cells improved survival 58 days on average, up from a median survival of about two weeks.

The study was funded by Fred Hutch’s Immunotherapy Initiative, the Leukemia & Lymphoma Society, the Phi Beta Psi Sorority, the National Science Foundation and the National Cancer Institute.

Next steps and other applications

Stephan’s nanoparticles still have to clear several hurdles before they get close to human trials. He’s pursuing new strategies to make the gene-delivery-and-expression system safe in people and working with companies that have the capacity to produce clinical-grade nanoparticles. Additionally, Stephan has turned his sights to treating solid tumors and is collaborating to this end with several research groups at Fred Hutch.

And, he said, immunotherapy may be just the beginning. In theory, nanoparticles could be modified to serve the needs of patients whose immune systems need a boost, but who cannot wait for several months for a conventional vaccine to kick in.

“We hope that this can be used for infectious diseases like hepatitis or HIV,” Stephan said.  This method may be a way to “provide patients with receptors they don’t have in their own body,” he explained.  “You just need a tiny number of programmed T cells to protect against a virus.”

New Study Offers Hope for More Effective Treatment of Leukemia Article in Nature Immunology shows that activation of a specific protein could lead to acute lymphoblastic leukemia

The discovery of a protein signature that is highly predictive of leukemia could lead to novel treatments of the leading childhood cancer, according to new study showing that competition among certain proteins causes an imbalance that leads to leukemia.

The new study in the journal Nature Immunology reveals that the activation of a protein known as STAT5 causes competition among other proteins that leads to acute lymphoblastic leukemia (ALL). If a drug could be developed to prevent the initial activation of STAT5 and restore the natural balance of proteins, ALL could potentially be treated more effectively.

Blood cancers account for nearly 10 percent of all newly diagnosed cancer cases in the United States. Childhood acute lymphoblastic leukemia – a type of cancer in which the bone marrow produces too many immature lymphocytes (a type of white blood cell) – accounts for three out of every four cases of leukemia and is the most common in children under age five.

Prior research shows that certain genetic mutations common in Leukemia have a role in driving the disease. Authors of the article “Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival” found that by forcing the activation of STAT5 in mice (constitutively activated alleles forced by the researchers) always produced Leukemia.

“The major outcome of this story is that a signature emerged from looking at the level of activated proteins compared to other proteins that’s very predictive of how a patient will respond to therapy,” says Seth Frietze, assistant professor in medical laboratory and radiation sciences at the University of Vermont, whose data analysis supported the finding that the ratio of activated STAT5 to IKAROS in patients is very prognostic and predictive of the outcome. “That’s a novel finding. If we could find drugs to target that activation that could be an incredibly effective way to treat Leukemia.”

Corresponding author Michael Farrar from the Department of Laboratory Medicine and Pathology at the University of Minnesota led a team of 10 researchers that employed an innovative methodology that combines unique mouse models and patient samples in combination with high-throughput DNA sequencing, epigenetic and proteomic analysis. The result was that patients with a high ratio of imbalanced proteins (STAT5 to IKAROS or NF-kB) had far worse prognosis.

Frietze, whose research focuses on how to overcome IKAROS mutations, put the finding in perspective by explaining that “tumor sequencing is currently being used to both risk stratify patients and provide novel therapeutic targets. However, the ways in we are able to use that sequencing information is still limited. This study provides a new way to risk stratify patients, identifying those who are at higher risk or relapse and may therefore need more intense therapy to cure their disease.”

 

Liver Cancer Drug Shows Promise in Preventing Liver Fibrosis and Treating NASH

Namodenoson, a Phase II drug developed by Can-Fite BioPharma Ltd. (NYSE MKT: CANF), has shown in newly published data that it prevents liver (hepatic) fibrosis progression in preclinical studies.

“These latest study results add to the growing body of data that demonstrate Namodenoson’s potential efficacy in combating non-alcoholic fatty liver disease (NAFLD), the precursor to non-alcoholic steatohepatitis (NASH), indications for which there is currently no FDA approved drug. We are advancing Namodenoson into a Phase II trial in NAFLD and expect to commence patient enrollment in the coming months through leading medical institutions in Israel,” stated Can-Fite CEO Dr. Pnina Fishman.

NAFLD is characterized by excess fat accumulation in the form of triglycerides (steatosis) in the liver. According to a recent study published in Hepatology, an estimated 25% of the population in the U.S. has NAFLD, with a higher prevalence in people with type II diabetes. Incidence is increasing based on rising obesity rates. NAFLD includes a range of liver diseases, with NASH being the more advanced form, manifesting as hepatic injury and inflammation. According to the NIH, the incidence of NASH in the U.S. is believed to affect 2-5% of the population. The spectrum of NAFLDs resembles alcoholic liver disease; however, they occur in people who drink little or no alcohol. If untreated, NASH can lead to cirrhosis and liver cancer.

By 2025, the addressable pharmaceutical market for NASH is estimated to reach $35-40 billion.

Liver fibrosis is the excessive accumulation of scar tissue resulting from ongoing inflammation. It can result in diminished blood flow throughout the liver and is associated with NAFLD.

Recent preclinical studies in a mouse model of liver fibrosis demonstrated the anti-fibrotic effects of Namodenoson. The Namodenoson treated group exhibited normal liver under macroscopic view, no accumulation of fluid (ascites), a low fibrosis profile, and lower serum levels of transaminases as compared to the control group. In addition, liver protein extracts and mRNA for the alpha smooth muscle actin showed a significant anti-fibrotic effect in the Namodenoson treated group as compared to the control group.

These studies were conducted under the supervision of Prof. Rifaat Safadi M.D., a Key Opinion Leader in the field of liver diseases, and Director of Liver Unit, Institute of Gastroenterology and Liver Diseases, Hadassah University Hospital, Ein Kerem.

Prof. Safadi commented, “Lowering liver fat content and fibrosis are the main unmet needs in NASH. Today there is a huge market need for drugs that fight the worldwide NASH epidemic.”

“Namodenoson is uniquely compelling for its potential to treat NAFLD and NASH because its safety profile has already been de-risked, increasing the likelihood it can advance through late stage trials and into clinical use for this large and unmet need,” Dr. Safadi added. “In general, there is significant development risk for new potential drugs in development due to safety risks including drug induced liver injury (DILI), drug-to-drug interactions (DDI), and metabolites in safety testing (MIST). Namodenoson, however, has demonstrated a good safety profile and is low or negative for DILI, DDI and MIST.”

“In addition, Namodenoson recognizes the difference between diseased and normal cells, and targets only the diseased cells through the specific A3 adenosine receptor. This precision targeting is designed to lead to higher efficacy and safety by leaving healthy cells unaffected. We are all looking for drugs with this profile to treat NASH,” concluded Dr. Safari.

Can-Fite plans to commence patient recruitment for its Phase II trial of Namodenoson in NASH/NAFLD in the second quarter of 2017.

AACR: Phase II Trial Shows Rice Bran Promotes Microbiome Diversity, Slows Growth of Colorectal Cancer Cells

Today at the American Association for Cancer Research (AACR) Annual Meeting 2017, University of Colorado Cancer Center researchers at Colorado State University present results of a phase II clinical trial of 29 people exploring the effects of adding rice bran or navy beans to the diets of colorectal cancer survivors. After the 4-week randomized-controlled trial during which people added rice bran, navy bean powder or neither, both the rice bran and navy bean groups showed increased dietary fiber, iron, zinc, thiamin, niacin, vitamin B6, folate, and alpha-tocopherol. The rice bran group also showed increased microbiome richness and diversity. When researchers treated colorectal cancer cells with stool extracts from these groups, they saw reduced cell growth from the groups that had increased rice bran and navy bean consumption.

Previous work shows the ability of these diets to decrease colorectal cancer risk in animal models. The current trial confirms that people can eat enough bean- and rice bran-enhanced foods to promote gut health at levels shown to prevent colorectal cancer in animals.

Guidelines from the American Institute for Cancer Research recommend reducing the risk of cancer by eating more vegetables, fruits, whole grains and legumes, such as beans. Ryan has established from these studies that eating a half-cup of beans and 30 grams of rice bran per day is enough to see changes in small molecules that can confer protection against colorectal cancer.

“The simple message is, ‘Food is medicine,’ and we are looking at how to simplify that and make it apply to our everyday lives,” says study co-author Regina Brown, MD, assistant professor at the CU School of Medicine and oncologist for CUHealth.

Brown is long-time collaborator of CU Cancer Center investigator and CSU assistant professor, Elizabeth Ryan, PhD. The Ryan Lab in the CSU College of Veterinary Medicine and Biomedical Sciences studies the potential power of navy beans and rice bran to promote digestive health and to prevent metabolic alterations in obesity, heart disease and certain cancers.

“The evidence is there in animals and we can now study this in people. The question is, what are we doing to achieve adequate levels of intake of these foods?” Ryan said. “It’s not enough to say ‘I eat them once in a while.’ That’s not going to work, particularly if you are at higher risk. You have to meet a dose, just like you need a dose of a certain drug, you need to reach intake levels and consume increased amounts of these foods, and that’s where people, including me, are challenged. Not everyone wants to open up a can of beans and eat them every day.”

The two met about 10 years ago, when Ryan was a researcher in CSU professor Henry Thompson’s Cancer Prevention Lab, and Brown was practicing medicine in Fort Collins and caring for her mother, who had uterine cancer.

“It was kind of a novel partnership and had we not dug in our heels it could have died, but I told Elizabeth, ‘Your work is so interesting and so valuable. We have to take this translational research from the benchtop to the clinic.’ I guarantee, nine out of 10 of my patients, the first thing they ask is about their diet,” Brown said.

The study’s lead author is Erica Borresen, Ryan’s research associate and study coordinator, who worked with colorectal cancer survivors to make sure they ate their beans and rice bran provided in meals and snacks, and that they filled out their food logs and gastrointestinal health questionnaires. It was sometimes intimate and awkward, but so is getting a colonoscopy and being treated for colorectal cancer.

“Our participants donated their time and effort, and I want to make sure they understand they are appreciated,” said Borresen, who earned her Master of Public Health at the Colorado School of Public Health, and plans to become a physician’s assistant. “I came to realize I love the patient interaction – that’s one of my favorite parts about coordinating our studies.”

The next phase of Ryan’s research examines effects of the cooked navy bean powder and rice bran on the colon tissue of people who have already had colorectal cancer and are at high risk for recurrence.

“I really feel that there’s hope in this being a practical solution to improve gut health and specifically colorectal cancer prevention,” says Ryan.

Patients with Lung Cancers Responsive to Immunotherapy Drug Beat Standard Odds of Survival

More than seven years after the start of one of the first clinical trials of the immunotherapy drug nivolumab, researchers at the Johns Hopkins Kimmel Cancer Center report that the five-year survival estimate for a limited subset of people with advanced nonsmall cell lung cancer taking the drug is 16 percent, compared with a historical survival rate for that group of 1 to 4 percent.

A summary of the trial data, gleaned from follow-up information gathered on a total of 129 patients since it began in 2010, is scheduled for presentation April 3 at the American Association for Cancer Research Annual Meeting 2017 (abstract #CT077).

According to results of the data analysis of the 129 patients with advanced nonsmall cell lung cancer treated at more than 11 hospitals nationwide, including The Johns Hopkins Hospital, 16 survived at least 58 months (nearly five years). Twelve of the 16 received no further therapy and showed no evidence of worsening disease at the time the data were analyzed in November 2016. The other four received further chemotherapy or joined other clinical trials. Nine of the 16 are male.

“A small subset of nonsmall cell lung cancer patients appear to respond to nivolumab and have beaten the odds that most patients with this cancer face,” says Julie Brahmer, M.D., program leader at the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and director of the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview Medical Center campus. “Now, we need to figure out how to make more patients responsive to immunotherapy by exploring combinations of immunotherapy drugs and other treatment agents.”

“It’s clear that the patients who beat the survival odds are in some ways truly unique biologically, and the goal now is to discover exactly how immunotherapy is keeping their disease in check,” says Brahmer.

Applying their analysis more broadly, Brahmer and her colleagues estimate that 16 percent of patients with nonsmall cell lung cancer who receive nivolumab will survive beyond five years.

Thus far, Brahmer and the team of physicians who conducted the trial have not been able to identify specific genes or proteins shared by the 16 patients that could be linked to long-term survival.

Typically, says Brahmer, only 1 to 4 percent of patients with advanced nonsmall cell lung cancer survive five years, a form of lung cancer that strikes an estimated 222,500 Americans each year and accounts for 85 percent of all lung cancers in the United States.

Apart from nivolumab, which was approved by the U.S. Food and Drug Administration for lung cancer therapy in 2015 based on research led by Brahmer, standard treatments include various types of chemotherapy.

b Patients in the study received nivolumab once every two weeks for up to two “years. Brahmer says that defining which patients need continued therapy and which don’t not only would get the best treatments to each patient more quickly, but also present an opportunity for cost savings for patients who won’t benefit from the expensive drug, which can cost more than $100,000 per year.

Brahmer cautions that the study’s value is limited by the fact that patients who received nivolumab were not directly compared with patients who did not receive the drug.

Estetrol (E4) Shows Promise as a Safe, Effective Drug for Use in Advanced Prostate Cancer

The natural fetal estrogen estetrol, also called E4, is being tested as a new drug that may help treat advanced prostate cancer, according to an ongoing industry-sponsored study from the Netherlands. The final results will be presented in a poster on Saturday, April 1, at ENDO 2017, the annual scientific meeting of the Endocrine Society, in Orlando, Fla.

“E4 for the treatment of prostate cancer would offer a new and affordable option compared to current standard and new therapies. An important advantage of E4 is expected to be the avoidance of the hypoestrogenic side effects that occur with other types of testosterone-suppressing hormone therapy, including hot flushes and sweating, arthralgia, mood, sleep and cognition disturbances, and bone loss and fractures,” said Ellen Dutman, M.Sc., clinical research associate at Pantarhei Oncology BV in Zeist, the Netherlands, the company that is developing the drug.

“Furthermore, E4 treatment may not be as expensive as recently developed new prostate cancer therapies,” Dutman added.

“E4, a steroid produced by the human fetal liver during pregnancy only, is a potential candidate for the treatment of advanced prostate cancer, both as a single entity and for combination treatment with hormone therapy,” she said.

The hormone testosterone stimulates tumor growth and therefore maximal suppression of testosterone levels is the cornerstone of the endocrine treatment of prostate cancer. To test whether oral E4 lowers testosterone levels, Dutman and her colleagues conducted a double-blind, randomized, placebo-controlled study in 45 healthy male volunteers between 40 and 70 years of age at one medical center.

For each group of 15 men, 10 received the E4 and 5 received placebo for 28 days. The 10 men in the first group received one daily dose of 20 mg E4. And after that dose was found to be safe, the 10 men in the second group received 40 mg E4. That dose was found to be safe as well, and a third group of 10 men received a dose of 60 mg E4.

The results of the groups show promise. With 20 mg E4, 40 mg E4, and 60 mg E4 respectively, both total and free testosterone decreased: total testosterone absolute change: -3.74 nmol/L, -11.0 nmol/L, and -13.88 nmol/L respectively; and free testosterone absolute change: -0.059 nmol/L, -0.095 nmol/L, -and – 0.163 nmol/L respectively. Follicle-stimulating hormone (FSH) and estradiol (E2) levels also declined, while luteinizing hormone (LH) levels remained steady and sex hormone-binding globulin (SHBG) levels increased.

All three doses were well tolerated. Body weight and safety parameters did not change but libido decreased and nipple tenderness was reported.

“We expect that in the future, patients with advanced prostate cancer will have the opportunity to choose to be treated with E4, especially in combination with their current therapy,” Dutman said. “The addition of E4 will further improve the efficacy of their current therapy and have a positive impact on the quality of life of the patients.”

Estetrol is also being developed by Pantarhei Oncology for the treatment of advanced breast cancer. Mithra Pharmaceuticals in Belgium is developing E4 for contraception and menopausal hormone therapy in women.

First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

Q BioMed Gears up for Production of Cancer Pain Palliation Drug with Commercial Launch Expected in Q2 2017

Q BioMed Inc, a NYC-based biomedical acceleration and development company has begun process validation for the manufacturing of a non-narcotic analgesic treatment for pain associated with metastatic bone cancer. The drug, a generic Strontium Chloride 89 injection, provides long-lasting relief for patients suffering from debilitating bone pain due to metastatic cancer, typically caused by advanced-stage breast, prostate or lung cancer. It has been proven to provide a long-term effect — resulting in cancer pain relief and enhanced quality of life.

There are approximately 350,000 cases of patients living with bone metastases in the U.S. alone. In addition, 380,000 new diagnoses of patients with breast, prostate and lung cancer occur every year and approximately 1 in 3 of those will develop bone metastases.

The delivery of an affordable, non-narcotic pain therapy is a much needed and underutilized option for this patient population and coincides well with the recently passed 21st Century Cures Act combating opiate overuse and abuse. The Act, provides $1 billion in funding over the next two years for opioid addiction prevention and treatment programs to develop, promote and use non-narcotic alternative therapies.

The commercialization of the drug allows Q BioMed to deliver an effective and much needed alternative to hundreds of thousands of suffering patients. The company said in a statement that they are very pleased to offer this U.S. Food and Drug Administration approved therapy to patients in the very near term and are currently negotiating with US-based contract manufacturing organization (CMO) agreements and expect to have those completed along with the commercial launch in Q2 2017.

The company recently closed on its 2nd tranche of the $4,000,000 funding announced on November 30th 2016. The company received $1,000,000 on the 2nd closing bringing the total received to date to $2.5MM and expect to receive the remaining $1.5MM upon effectiveness of their recently filed registration statement on Form S-1.

Q BioMed is focused on licensing and acquiring biomedical assets across the healthcare spectrum. The company provides these target assets the strategic resources, developmental support, and expansion capital they need to ensure they meet their developmental potential, enabling them to provide products to patients in need.

Scientists Find Possible Achilles Heel of Treatment Resistant Cancers

Scientists identify two signaling proteins in cancer cells that make them resistant to chemotherapy, and show that blocking the proteins along with chemotherapy eliminate human leukemia in mouse models.

Reporting results March 20 in Nature Medicine, researchers at Cincinnati Children’s Hospital Medical Center suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy might cure several types of kinase-driven, treatment-resistant leukemia and solid tumor cancers.

These include acute myeloid leukemia (AML) fueled by the gene FLT3, lung cancers fueled by genes EGFR and PDGFR, HER2-driven breast cancers, and BCR-ABL-fueled chronic myeloid leukemia (CML), according to Mohammad Azam, PhD, lead investigator and a member of the Division of Experimental Hematology and Cancer Biology.

“We think that within the next five years our data will change the way people think about cancer development and targeted therapy,” Azam says. “This study identifies a potential Achilles heel of kinase-driven cancers and what we propose is intended to be curative, not just treatment.”

The weak spot is a common point of passage in cells (a signaling node) that appears to be required to generate cancer cells in both leukemia and solid tumors. The node is formed by the signaling proteins c-Fos and Dusp1, according to study authors. The researchers identified c-Fos and Dusp1 by conducting global gene expression analysis of mouse leukemia cells and human chronic myeloid leukemia (CML) cells donated by patients.

CML is a blood cancer driven by an enzyme called tyrosine kinase, which is formed by the fusion gene BCR-ABL. This fusion gene is the product of translocated chromosomes involving genes BCR (chromosome 22) and ABL (chromosome 9). Analysis of human CML cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive chemotherapy resistant cells.

Cancer sleeper cells

Cancer cells often become addicted to the mutated gene that causes them, such as BCR-ABL in kinase-driven chronic myeloid leukemia. Most chemotherapies work by blocking molecular pathways affected by the gene to shut down the disease process. In the case of CML, a chemotherapy called imatinib is used to block tyrosine kinase, which initially stops the disease. Unfortunately the therapeutic benefit is temporary and the leukemia comes back.

Azam and colleagues show in their CML models that signaling from tyrosine kinase – and growth factor proteins that support cell expansion (like interleukins IL3, IL6, etc.) – converge to dramatically elevate c-Fos and Dusp1 levels in the cancer cells.

Working together these molecules maintain the survival of cancer stem cells and minimal residual disease. The dormant cells wait around under the radar screen to rekindle the disease by acquiring additional genetic mutations after initially effective chemotherapy.

Azam says Dusp1 and c-Fos support the survival of cancer stem cells by increasing the toxic threshold needed to kill them. This means conventional imatinib chemotherapy will not eliminate the residual disease stem cells. Doctors can’t just increase the dose of chemotherapy because it doesn’t target the Dusp1 and c-Fos proteins that regulate toxic threshold.

Targeting c-Fos and Dusp1

After identifying c-Fos and Dusp1, the authors tested different treatment combinations on mouse models of CML, human CML cells, and mice transplanted with human leukemia cells. They also tested treatments on B-cell acute lymphoblastic leukemia (B-ALL).

The treatment combinations included: 1) solo therapy with just the tyrosine kinase inhibitor, imatinib; 2) solo treatment with just inhibitors of c-Fos and Dusp1; 3) treatment with all three combined – imatinib along with molecular inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression but the leukemia relapsed with the continued presence of residual disease cells. Treatment with c-Fos and Dusp1 inhibitors alone significantly slowed CML progression and prolonged survival in a majority of mice but wasn’t curative. Treatment for one month with c-Fos/Dusp1 inhibitors and imatinib cured 90 percent of mice with CML, with no signs of residual disease cells.

Azam and his colleagues also point to an interesting finding involving solo treatment with just the deletion of c-Fos and Dusp1. This eliminated expression of the signaling proteins and was sufficient to block B-ALL development, eradicating the disease in mouse models.

Next steps

The authors stress that because the study was conducted in laboratory mouse models, additional research is needed before the therapeutic strategy can be tested in clinical trials.
They are following up the current study by testing c-Fos and Dusp1as treatment targets for different kinase-fueled cancers, including certain types of lung cancer, breast cancers and acute forms of leukemia.

Drug Combination Delivered by Nanoparticles May Help in Melanoma Treatment

The first of a new class of medication that delivers a combination of drugs by nanoparticle may keep melanoma from becoming resistant to treatment, according to Penn State College of Medicine researchers.

CelePlum-777 combines a special ratio of the drugs Celecoxib, an anti-inflammatory, and Plumbagin, a toxin. By combining the drugs, the cells have difficulty overcoming the effect of having more than one active ingredient.

Celecoxib and Plumbagin work together to kill melanoma cells when used in a specific ratio. Researchers used microscopic particles called nanoparticles to deliver the drugs directly to the cancer cells. These particles are several hundred times smaller than the width of a hair and can be loaded with medications.

“Loading multiple drugs into nanoparticles is one innovative approach to deliver multiple cancer drugs to a particular site where they need to act and have them released at that optimal cancer cell killing ratio,” said Raghavendra Gowda, assistant professor of pharmacology, who is the lead author on the study. “Another advantage is that by combining the drugs, lower concentrations of each that are more effective and less toxic can be used.”

Celecoxib and Plumbagin cannot be taken by mouth because the drugs do not enter the body well this way and cannot be used together in the ratio needed because of toxicity.

CelePlum-777 can be injected intravenously without toxicity. Because of its small size, it also accumulates inside the tumors where it then releases the drugs to kill the cancer cells. Researchers report their results in the journals Molecular Cancer Therapeutics and Cancer Letters.

“This drug is the first of a new class, loaded with multiple agents to more effectively kill melanoma cells, that has potential to reduce the possibility of resistance development,” said senior author Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute. “There is no drug like it in the clinic today and it is likely that the next breakthrough in melanoma treatment will come from a drug like this one.”

The researchers showed the results of CelePlum-777 on killing cancer cells growing in culture dishes and in tumors growing in mice following intravenous injection. The drug prevented tumor development in mice with no detectable side effects and also prevented proteins from enabling uncontrolled cancer cell growth.

More research is required by the Food and Drug Administration before CelePlum-777 can be tested in humans through clinical trials. Penn State has patented this discovery and licensed it to Cipher Pharmaceuticals, which will perform the next series of FDA-required tests.

Breast Cancer Drug Dampens Immune Response, Protecting Light-Sensing Cells of the Eye

Tamoxifen could be repurposed to treat degenerative diseases of the retina

The breast cancer drug tamoxifen appears to protect light-sensitive cells in the eye from degeneration, according to a new study in mice. The drug prevented immune cells from removing injured photoreceptors, the light-sensitive cells of the retina in the back of the eye. The study, recently reported in the Journal of Neuroscience, suggests tamoxifen might work for the treatment of age-related macular degeneration (AMD) and retinitis pigmentosa (RP), blinding diseases that lack good treatment options. The study was conducted by researchers at the National Eye Institute (NEI), part of the National Institutes of Health.

Although commonly used for cancer treatment, tamoxifen is used in the laboratory as a tool to activate specific genes in genetically engineered mice. The tool allows researchers to turn genes on and off in specific tissues at will. Wai Wong, M.D., Ph.D., chief of NEI’s Unit on Neuron-Glia Interactions in Retinal Disease, and his team were using tamoxifen for this purpose when they noticed something odd. Xu Wang, Ph.D., staff scientist in the Wong laboratory and lead author of the study, observed that mice treated with tamoxifen gained resistance to light-induced eye injuries. Light injury, induced by exposing mice to short-duration, high-intensity light, normally leads to degeneration of photoreceptors. But in the tamoxifen-treated mice, the team unexpectedly observed little to no photoreceptor degeneration.

The team investigated the effects of tamoxifen on light-induced photoreceptor degeneration in normal mice and mice with a disease similar to RP. Live retinal imaging and tissue analyses showed significantly lower levels of photoreceptor degeneration, compared to control mice that did not received tamoxifen. Tamoxifen-treated mice also demonstrated higher photoreceptor function, compared to controls.

How was tamoxifen exerting this protective effect? In an earlier study in 2015, Wong showed that light injury triggers a neurotoxic immune response in the retina. “The immune system becomes alerted to the stressed photoreceptors and goes into culling mode, clearing them out of the retina,” he explained. Wong and his team surmised that tamoxifen was inhibiting this immune response, rather than protecting the photoreceptors directly.

To investigate this hypothesis, Wong’s team cultured microglia — immune cells in the retina — and found that tamoxifen reduced their ability to remove and kill photoreceptor cells. Tamoxifen also reduced levels of inflammatory cytokines — signaling molecules that trigger inflammation — produced by the microglia.

Tamoxifen did not appear to directly influence the physiology of photoreceptors or protect photoreceptors in the absence of microglia, suggesting that the inhibition of microglia is a key mechanism underlying tamoxifen’s protective effect. The investigators are currently studying at molecular level how tamoxifen is able to inhibit the microglia.

In August 2016, Wong’s laboratory filed a patent for use of tamoxifen in retinal degenerative disorders. The new use of the drug is unexpected, as tamoxifen’s only previously known association with the retina had been a low risk of retinopathy among breast cancer patients.

RP is a group of rare genetic disorders affecting the retina. Worldwide, RP affects about 1 in 4,000 people. Symptoms typically appear during childhood and slowly progress over many years, often causing blindness. AMD is a leading cause of vision loss among people age 50 and older. About two million Americans have AMD, which affects central vision.

The tamoxifen dose used in Wong’s mouse study was equivalent to eight times the FDA-approved dose for breast cancer. The researchers are currently investigating whether the protective effects are retained at lower doses.

The work “sets us up for a clinical trial in the not-so-distant future,” said Wong. “Translation to the clinic can happen reasonably rapidly because tamoxifen, as an FDA-approved drug, already has a well-characterized safety profile,” he explained.