Some Cancer Therapies May Provide a New Way to Treat High Blood Pressure

Drugs designed to halt cancer growth may offer a new way to control high blood pressure (hypertension), say Georgetown University Medical Center investigators. The finding could offer a real advance in hypertension treatment because although a number of high blood pressure drugs are now available, they work by different mechanisms that are not suited for all patients.

The study, published in the journal Hypertension, found that fibroblast growth factors, or FGFs, involved in increasing blood vessel growth so that cancer can grow, also have a systemic effect on blood pressure. The study suggests that just as oncologists use FGF inhibitors to control cancer, clinicians may be able to use FGF inhibitors to regulate blood pressure and control disease associated with hypertension.

“It’s rare that a single class of drugs can be used for such different conditions, but that is what our study strongly suggests,” says the study’s senior investigator, Anton Wellstein, MD, PhD, professor of oncology and pharmacology at Georgetown University School of Medicine and a researcher at Georgetown Lombardi Comprehensive Cancer Center.

Wellstein and his collaborators previously found that the FGF pathway, when switched on, drives growth of blood vessels that feed a growing tumor (angiogenesis).  The development of FGF inhibitors is based in part on their ability to inhibit angiogenesis. The current study took a deeper dive into the pathway and found that a protein, FGFBP1, modulates FGF. The gene that produces FGFBP1 to regulate FGF is known as FGF binding protein 1.

Wellstein had learned from a publication by a group in the United Kingdom that a population in Eastern Europe that had hypertension also had a variation of the FGFBP1 gene. Due to this gene variation in these individuals, FGFBP1 was over-expressed in kidney tissue, the major control hubs for blood pressure.

He decided to test the link between FGFBP1 and hypertension in a mouse model his laboratory at Georgetown had created that revealed the link between FGF and cancer. In these mice, FGFBP1 can be switched on or off.

Wellstein partnered with Christopher S. Wilcox, MD, PhD, professor of medicine at Georgetown and the George E. Schreiner Chair of Nephrology, and when investigators switched on FGFBP1 in mice, their blood pressure shot up. “It actually went up [30 mm Hg] from a normal blood pressure to pretty bad hypertension,” says Wellstein. “It was amazing.”

He adds that he turned the gene on “just to a level you see in people in the Eastern European group who have hypertension.” Wellstein also clarified that when a cancer switches on overproduction of the FGF pathway, in order to stimulate blood vessel production, that has only a local tumor effect, not a systemic one. Most patients using cancer treatment have normal blood pressure, he says.

Further research revealed that hypertension regulation by FGFBP1 occurred in the resistance vessels —the end portion of vessels in different tissues that control the flow to that tissue. The aberrant FGFBP1 gene increased the vessel response to a hormone (angiotensin II) that constricts the blood vessels, making blood pressure rise.

“FGF can control how sensitive the blood pressure regulation by angiotensin II is,” says Wellstein. “That tells us that if a person has hypertension, it is possible to target FGF signaling because it contributes to maintenance of high blood pressure by altering sensitivity to a major vasoconstrictive hormone, angiotensin II,” he says.

Investigators then used an FGF inhibitor in mice with a switched on FGFBP1 gene, and found the drug effectively lowered the sensitivity to angiotensin II in several vascular beds.

“Of course, we can’t say that this tactic will work in humans with hypertension, but it will be straightforward to test this rather surprising possibility to target a new mechanism of blood pressure control,” says Wellstein.

Finding a Key to Unlock Blocked Differentiation in Microrna-Deficient Embryonic Stem Cells

This aids goal to use stem cells in therapy, where an important hurdle is efficient differentiation.

The more than 200 different types of human cells have the same DNA but express different ensembles of genes. Each cell type was derived from embryonic stem cells, which are called pluripotent stem cells because they can differentiate to all those different cell fates.

One very active area of biology is cells that mimic these fountainhead embryonic stem cells, cells that are called induced pluripotent stem cells, or iPSCs. With genetic and biochemical tricks, researchers can reverse a differentiated cell — such as a skin fibroblast — into a pluripotent state.

Such iPSCs have the potential to create tissue for regenerative medicine, such as repair heart attacks, create models of human disease or make cells that enable drug screening. But future progress with iPSCs needs a much greater understanding of the basic biology of pluripotency and differentiation.

“For the goal of using stem cells in therapy, the most important step is differentiation from iPSCs,” said Rui Zhao, Ph.D., an assistant professor of biochemistry and molecular genetics at the University of Alabama at Birmingham. “We need to be able to differentiate the iPSCs into a disease-relevant cell type at high efficiency and high purity.”

In a study published in Stem Cell Reports, Zhao and colleagues have partly solved a long-unanswered basic question about stem cells — why are pluripotent stem cells that have mutations to block the production of microRNAs unable to differentiate?

Zhao and colleagues, including co-corresponding author Kitai Kim, Ph.D., of the Sloan Kettering Institute, have found a key that allows those microRNA-deficient pluripotent stem cells to differentiate into neural cells, including subtypes with markers for dopaminergic, glutamatergic and GABAergic neurons

“For many years, we did not know why these cells did not differentiate,” Zhao said. The answer for neural cell differentiation in the microRNA-deficient cells turned out to be simple — a single microRNA or a single protein.

In the Stem Cell Reports study, Zhao and colleagues show that a microRNA-302 mimic — delivered by a specially constructed lentivirus — was sufficient to enable neural differentiation of mouse embryonic stem cells that lacked Dgcr8, a vital gene for the processing of the more than 2,000 microRNAs in cells.

When they examined gene expression profiles in the differentiated cells, they saw changes in many gene sets regulated by p53, also known as tumor suppressor p53. This tumor suppressor has been called “the guardian of the genome” because of its many roles in preventing DNA damage and cancer.

Zhao, Kim and colleagues showed that microRNA-302 acted to reduce p53 expression in the microRNA-deficient embryonic stem cells by binding to the 3′ untranslated region of p53 mRNA.

They further showed that direct inhibition of p53 with the simian virus large T antigen or short hairpin RNA, or even deleting the p53 gene itself, allowed embryonic stem cells or iPSCs to proceed to neural differentiation without the need for microRNA-302. Thus, the differentiation barrier that prevents the neuronal lineage specification from microRNA-deficient stem cells is expression of p53.

The keys to unlock the paths cells to other cell lineage specifications from microRNA-deficient embryonic stem are still unknown, Zhao says.

Deadly Lung Cancers Are Driven by Multiple Genetic Changes

Blood-Based Cancer Tests Reveal Complex Genomic Landscape of Non-Small Cell Lung Cancers

A new UC San Francisco–led study challenges the dogma in oncology that most cancers are caused by one dominant “driver” mutation that can be treated in isolation with a single targeted drug. Instead, the new research finds one of the world’s most deadly forms of lung cancer is driven by changes in multiple different genes, which appear to work together to drive cancer progression and to allow tumors to evade targeted therapy.

These findings — published online on November 6, 2017 in Nature Genetics — strongly suggest that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient’s cancer and prevent drug resistance from arising.

“Currently we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment,” said Trever Bivona, MD, PhD, a UCSF Medical Center oncologist, associate professor in hematology and oncology, and member of the Helen Diller Family Comprehensive Cancer Center at UCSF.

Lung cancer is by far the leading cause of cancer death worldwide. Efforts to identify the genetic mutations that drive the disease have led to targeted treatments that improve life expectancy for many patients, but these drugs produce temporary remission at best — sooner or later, cancers inevitably develop drug resistance and return, deadlier than ever.

The new UCSF-led study — which analyzed tumor DNA from more than 2,000 patients in collaboration with Redwood City–based Guardant Health — is the first to extensively profile the genetic landscape of advanced-stage non–small cell (NSC) lung cancer, the most common form of the disease.

“The field has been so focused on treating the ‘driver’ mutation controlling a tumor’s growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumor can take to develop resistance to treatment,” said Bivona, who is also co-director of a new UCSF-Stanford Cancer Drug Resistance and Sensitivity Center funded by the National Cancer Institute. “This could also explain why many tumors are already drug-resistant when treatment is first applied.”

Potential New Autism Drug Shows Promise in Mice

Scientists have performed a successful test of a possible new drug in a mouse model of an autism disorder. The candidate drug, called NitroSynapsin, largely corrected electrical, behavioral and brain abnormalities in the mice.

NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

“This drug candidate is poised to go into clinical trials, and we think it might be effective against multiple forms of autism,” said senior investigator Stuart Lipton, M.D., Ph.D., Professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

The research, published on today in the journal Nature Communications, was a collaboration involving scientists at the Scintillon Institute; the University of California, San Diego School of Medicine; Sanford Burnham Prebys Medical Discovery Institute and other institutions. Lipton’s fellow senior investigators on the project were Drs. Nobuki Nakanishi and Shichun Tu of the Scintillon Institute in San Diego.

ASD is brain development disorder that affects 1 in 68 children in the United States alone. Because ASD has been diagnosed more often in recent years, most Americans now living with autism diagnoses are children—roughly 2.4 percent of boys and 0.5 percent of girls.

Genetic Analysis Leads to Potential Treatment

The new study stemmed from a 1993 study in which Lipton and his laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially important factor in brain development.

This breakthrough led Lipton and colleagues to the discovery that disrupting the mouse version of MEF2C in the brain, early in fetal development, causes mice to be born with severe, autism-like abnormalities. Since that discovery in mice in 2008, other researchers have reported many cases of children who have a very similar disorder, resulting from a mutation to one copy of MEF2C (human DNA normally contains two copies of every gene, one copy inherited from the father and one from the mother). The condition is now called MEF2C Haploinsufficiency Syndrome (MHS).

“This syndrome was discovered in people only because it was first discovered in mice—it’s a good example of why basic science is so important,” Lipton said.

MEF2C encodes a protein that works as a transcription factor, like a switch that turns on the expression of many genes. Although MHS accounts for only a small proportion of autism disorder cases, large-scale genomic studies in recent years have found that mutations underlying various autism disorders frequently involve genes whose activity is switched on by MEF2C.

“Because MEF2C is important in driving so many autism-linked genes, we’re hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism,” Lipton said, “and in fact we already have preliminary evidence for this.”

For the study, the researchers created a laboratory model of MHS by engineering mice to have—like human children with MHS—just one functioning copy of the mouse version of MEF2C, rather than the usual two copies. The mice showed impairments in spatial memory, abnormal anxiety and abnormal repetitive movements, plus other signs consistent with human MHS. Analyses of mouse brains revealed a host of problems, including an excess in key brain regions of excitatory signaling (which causes neurons to fire) over inhibitory signaling (which suppresses neuronal activity).

In short, these two important kinds of brain signals were out of balance. A similar excitatory/inhibitory (E/I) imbalance is seen in most forms of ASD and is thought to explain many of the core features of these disorders, including cognitive and behavioral problems and an increased chance of epileptic seizures.

The researchers treated the MHS-mice for three months with NitroSynapsin, an aminoadamantane nitrate compound related to the Alzheimer’s FDA-approved drug memantine, which was previously developed by Lipton’s group. NitroSynapsin is known to help reduce excess excitatory signaling in the brain, and the team found that the compound did reduce the E/I imbalance and also reduced abnormal behaviors in the mice and boosted their performance on cognitive/behavioral tests—in some cases restoring performance essentially to normal.

Lipton and colleagues are currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner.

The work also has support from parents of children with MHS. “We are all hanging on to the hope that one day our children will be able to speak, to understand and to live more independent lives,” said Michelle Dunlavy, who has a son with MHS.

In fact, Lipton’s group is also now using stem cell technology to create cell-based models of MHS with skin cells from children who have the syndrome—and NitroSynapsin appears to work in this ‘human context’ as well. Dunlavy and other parents of children with MHS recently organized an international, Facebook-based support group, which is coordinating to assist in Lipton’s research going forward.

In an amazing twist, the scientific team also found in Alzheimer’s disease models that the new NitroSynapsin compound improves synapse function, the specialized areas for communication between nerve cells. Thus, the ability of the drug to improve ‘network’ communication in the brain may eventually lead to its use in several neurological diseases.

New Player in Alzheimer’s Disease Pathogenesis Identified

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown that a protein called membralin is critical for keeping Alzheimer’s disease pathology in check. The study, published in Nature Communications, shows that membralin regulates the cell’s machinery for producing beta-amyloid (or amyloid beta, Aβ), the protein that causes neurons to die in Alzheimer’s disease.

“Our results suggest a new path toward future treatments for Alzheimer’s disease,” says Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP’s Neuroscience and Aging Research Center. “If we can find molecules that modulate membralin, or identify its role in the cellular protein disposal machinery known as the endoplasmic reticulum-associated degradation (ERAD) system, this may put the brakes on neurodegeneration.”

ERAD is the mechanism by which cells get rid of proteins that are folded incorrectly in the ER. It also controls the levels of certain mature, functional proteins. Xu’s team found that one of the fully formed, working proteins that ERAD regulates is a component of an enzyme called gamma secretase that generates Aβ.

This discovery helps fill in the picture of how Alzheimer’s disease, an incredibly complicated disorder influenced by many genetic and environmental factors. No therapies have yet been demonstrated to slow progression of the disease, which affects around 47 million people worldwide. Until such drugs are developed, patients face a steady, or sometimes rapid, decline in memory and reasoning.

Memory loss in Alzheimer’s results from the toxic effects of Aβ, which causes connections between neurons to break down. Aβ is created when gamma secretase cuts the amyloid precursor protein into smaller pieces. While Aβ is made in all human brains as they age, differences in the rate at which it is produced and eliminated from the brain and in how it affects neurons, means that not everyone develops dementia.

“We were interested in membralin because of its genetic association with Alzheimer’s, and in this study we established the connection between membralin and Alzheimer’s based on findings from the laboratory of a former colleague at SBP, Professor Dongxian Zhang,” Xu explains. “That investigation showed that eliminating the gene for membralin leads to rapid motor neuron degeneration, but its cellular function wasn’t clear.”

Using proteomics, microscopic analysis, and functional assays, the group provided definitive evidence that membralin functions as part of the ERAD system. Later, they found that membralin-dependent ERAD breaks down a protein that’s part of the gamma secretase enzyme complex, and that reducing the amount of membralin in a mouse model of Alzheimer’s exacerbates neurodegeneration and memory problems.

“Our findings explain why mutations that decrease membralin expression would increase the risk for Alzheimer’s,” Xu comments. “This would lead to an accumulation of gamma secretase because its degradation is disabled, and the gamma-secretase complex would then generate more Aβ. Those mutations are rare, but there may be other factors that cause neurons to make less membralin.”

Xu and colleagues also observed lower levels of membralin, on average, in the brains of patients with Alzheimer’s than in unaffected individuals, demonstrating the relevance of their findings to humans.

“Previous studies have suggested that ERAD contributes to many diseases where cells become overwhelmed by an irregular accumulation of proteins, including Alzheimer’s,” says Xu. “This study provides conclusive, mechanistic evidence that ERAD plays an important role in restraining Alzheimer’s disease pathology. We now plan to search for compounds that enhance production of membralin or the rate of ERAD to test whether they ameliorate pathology and cognitive decline in models of Alzheimer’s. That would further support the validity of this mechanism as a drug target.”

Scientists make a major breakthrough to treat fibrotic diseases that cause organ failure

Researchers from Duke-NUS Medical School (Duke-NUS) and the National Heart Centre Singapore (NHCS) have discovered that a critical protein, known as interleukin 11 (IL11) is responsible for fibrosis and causes organ damage. While it is surprising that the importance of IL11 has been overlooked and misunderstood for so long, it has now been very clearly demonstrated by this work.

A protein known as transforming growth factor beta 12 (“TGFB1”) has long been known as the major cause of fibrosis and scarring of body organs, but treatments based on switching off the protein have severe side effects. The scientists discovered that IL11, is even more important than TGFB1 for fibrosis and that IL11 is a much better drug target than TGFB1.

Fibrosis is the formation of excessive connective tissue, causing scarring and failure of bodily organs and the skin. It is a very common cause of cardiovascular and renal disease, where excessive connective tissue destroys the structure and function of the organ with scar tissue. Compared to other Asians, American, and Europeans, Singaporeans have a higher prevalence of coronary artery disease, hypertension, and diabetes, the three most common diseases that lead to heart failure. In addition, kidney failure is an epidemic in Singapore and around the world. Fibrosis of the heart and kidney eventually leads to heart and kidney failure, thus this breakthrough discovery — that inhibiting IL11 can prevent heart and kidney fibrosis — has the potential to transform the treatment of millions of people around the world.

The international team, led by Professor Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine, along with Assistant Professor Sebastian Schäfer, both from NHCS and Duke-NUS’ Programme in Cardiovascular and Metabolic Disorders, carried out the translational research to identify the key drivers of chronic fibrotic disease in heart, kidney, and other tissues. The team also includes researchers from Harvard University and University of California, San Diego/UCSD (USA), Max Delbrück Center for Molecular Medicine/MDC-Berlin (Germany), London Institute of Medical Sciences/MRC-LMS and Imperial College London (the UK), and the University of Melbourne (Australia).

“Fibrotic diseases represent a major cause of illness and death around the world. The discovery that IL11 is a critical fibrotic factor represents a breakthrough for the field and for drug development. It is an incredibly exciting discovery,” explained the study’s senior author, Professor Cook, who is also Director, National Heart Research Institute Singapore.

“Currently, more than 225 million people worldwide suffer from heart and kidney failure and there is no treatment to prevent fibrosis. The team is at the stage of developing first-in-class therapies to inhibit IL11 and this offers hope to patients with heart and kidney disease,” shared Professor Terrance Chua, Medical Director, National Heart Centre Singapore.

“This therapeutic target for fibrotic diseases of the heart, kidney and other organs may be exactly what we need to fill the unmet pressing clinical gap for preventing fibrosis in patients. We are proud to announce that the suite of intellectual property arising from this research has been licensed to a newly launched Singapore-funded biotechnology start-up Enleofen Bio Pte Ltd, which is co-founded by Professor Cook and Assistant Professor Schäfer,” said Professor Thomas Coffman, Dean of Duke-NUS Medical School.

No cardiovascular disease reduction with intensive blood pressure lowering treatment

Blood pressure lowering treatment does not reduce death or cardiovascular disease in healthy individuals with a systolic blood pressure below 140. This is shown in a systematic review and meta-analysis from Umeå University. The results, published in JAMA Internal Medicine, support current guidelines and contradict the findings from the Systolic Blood Pressure Intervention Trial (SPRINT).

Blood pressure treatment goals have been intensively debated since the publication of the SPRINT study in 2015. While current guidelines recommend a systolic blood pressure goal < 140 mm Hg, SPRINT found additional mortality and cardiovascular disease reduction with a goal < 120 mm Hg.

A systematic review and meta-analysis from Umeå University, published today in JAMA Internal Medicine, contradicts these findings. The Umeå study shows that treatment does not affect mortality or cardiovascular events if systolic blood pressure is < 140 mm Hg. The beneficial effect of treatment at low blood pressure levels is limited to trials in people with coronary heart disease.

“Our findings are of great importance to the debate concerning blood pressure treatment goals,” says Dr Mattias Brunström, researcher at the Department of Public Health and Clinical Medicine, Umeå University and lead author.

The study is a meta-analysis, combining data from 74 randomized clinical trials, including more than 300 000 patients. The researchers separated primary preventive studies from studies in people with coronary heart disease or previous stroke. The analysis found that the treatment effect was dependent on how high blood pressure was in previously healthy individuals. If systolic blood pressure was above 140 mm Hg, treatment reduced the risk of death and cardiovascular disease. Below 140 mm Hg, treatment did not affect mortality or the risk of first-ever cardiovascular events.

“Several previous meta-analyses have found that blood pressure lowering treatment is beneficial down to levels below 130 mm Hg. We show that the beneficial effect of treatment at low blood pressure levels is limited to trials in people with coronary heart disease. In primary preventive trials, treatment effect was neutral,” says Mattias Brunström.

Over the Counter Pain Medication as Effective as Opioids in ER Patients-Study

Emergency rooms are where many patients are first introduced to powerful opioid painkillers, but what if doctors offered over-the-counter pills instead? A new study tested that approach on patients with broken bones and sprains and found pain relievers sold as Tylenol and Motrin worked as well as opioids at reducing severe pain.

The results challenge common ER practice for treating short-term, severe pain and could prompt changes that would help prevent new patients from becoming addicted.

The study has limitations: It only looked at short-term pain relief in the emergency room and researchers didn’t evaluate how patients managed their pain after leaving the hospital.

But given the scope of the U.S. opioid epidemic — more than 2 million Americans are addicted to opioid painkillers or heroin — experts say any dent in the problem could be meaningful.

Results were published Tuesday in the Journal of the American Medical Association.

Long-term opioid use often begins with a prescription painkiller for short-term pain, and use of these drugs in the ER has risen in recent years. Previous studies have shown opioids were prescribed in nearly one-third of ER visits and about 1 out of 5 ER patients are sent home with opioid prescriptions.

“Preventing new patients from becoming addicted to opioids may have a greater effect on the opioid epidemic than providing sustained treatment to patients already addicted,” Dr. Demetrios Kyriacou, an emergency medicine specialist at Northwestern University, wrote in an accompanying editorial.

The study involved 411 adults treated in two emergency rooms at Montefiore Medical Center in New York City. Their injuries included leg and arm fractures or sprains. All were given acetaminophen, the main ingredient in Tylenol, plus either ibuprofen, the main ingredient in Motrin, or one of three opioids: oxycodone, hydrocodone or codeine. They were given standard doses and were not told which drug combo they received.

Patients rated their pain levels before taking the medicine and two hours later. On average, pain scores dropped from almost 9 on a 10-point scale to about 5, with negligible differences between the groups.

Ibuprofen and acetaminophen affect different pain receptors in the body so using the two drugs together may be especially potent, said Dr. Andrew Chang, an emergency medicine professor at Albany Medical College in upstate New York, who led the study.

He noted that a pill combining ibuprofen and acetaminophen is available in other countries; his findings echo research from Canada and Australia testing that pill against opioids for pain relief.

For cancer patients with HIV, immunotherapy appears safe

A new category of immunotherapies called checkpoint inhibitors that has been highly effective against many different cancers appears safe to use in patients with both advanced malignancies and HIV, a population excluded from earlier trials of such therapies, according to an early-phase trial.

Study Principal Investigator, Dr. Thomas Uldrick of the HIV & AIDS Malignancy Branch at the National Cancer Institute, will present late breaking results from the first 17 patients on a phase I study of pembrolizumab in patients with HIV and advanced cancers Friday at the Society for Immunotherapy of Cancer’s annual meeting in National Harbor, Maryland. The ongoing, multi-site study is being conducted by the NCI-funded Cancer Immunotherapy Trials Network, which is headquartered at Fred Hutchinson Cancer Research Center.

Cancer has become the leading cause of death for people with HIV. But until now, they and their physicians have had little data to guide them on whether they can safely use powerful new anti-cancer drugs called immune checkpoint inhibitors.

“During the development of these drugs, people with HIV were routinely excluded from studies due to concerns that they would not tolerate these medications or perhaps not benefit from them because of their underlying HIV and associated immune dysfunction,” Uldrick said. “The most important first step was to show that this class of drug would be safe in cancer patients with HIV.”

Study participants — who were on standard antiretroviral therapy to control their HIV infections and had various cancers that had failed to respond to standard therapies — received pembrolizumab (Keytruda), known since 2015 as “the Jimmy Carter drug” after it swiftly beat back melanoma that had spread to the former president’s brain and liver.

Pembrolizumab belongs to a type of immunotherapy that blocks a braking system cancers use to tamp down the immune response. Checkpoint inhibitors have been extremely effective in some patients with advanced cancers otherwise thought untreatable. The treatments have received U.S. Food and Drug Administration approval for melanoma, lung cancer, head and neck cancer, Hodgkin’s lymphoma, and kidney and bladder cancers.

“These drugs are the backbone of cancer immunotherapy at present and have been shown to be effective in subsets of virtually every different kind of cancer,” said Fred Hutch immunotherapy researcher Dr. Martin “Mac” Cheever, who leads the Cancer Immunotherapy Trials Network and is senior author of the new study. “For patients with HIV who are using effective antiretroviral therapy and have cancers for which these drugs are approved, there’s no reason not to consider these drugs as standard therapy.”

HIV and cancer

From the earliest days of the AIDS pandemic, Kaposi sarcoma — a rarely seen cancer until then — was one of a trio of cancers known as AIDS-defining malignancies. It, non-Hodgkin lymphoma and, in women, cervical cancer, often signaled that a person’s HIV infection had progressed to full-blown AIDS. People did not die of AIDS, per se. They died of one of these cancers or of infections like pneumocystis pneumonia and toxoplasmosis that took advantage of a weakened immune system.

Since the advent of antiretroviral therapy for HIV in 1996, full-blown AIDS and AIDS deaths have dropped dramatically. But the association between HIV and cancer remains, and not just with the traditional AIDS-defining malignancies. A large study published in the journal Annals of Internal Medicine in 2015 found higher cancer incidence across the board in HIV patients, including lung cancer and Hodgkin lymphoma.

“Globally, more than 35 million people are infected with HIV, and cancer is the number one reason they are dying,” Uldrick said. “Establishing proven effective regimens to manage cancer in people with HIV is critically important.”

The ongoing study will enroll up to 36 patients, and there are plans to include more patients with Kaposi sarcoma, a cancer for which checkpoint inhibitors have not been studied. It is one of the leading causes of cancer deaths in sub-Saharan Africa — where HIV rates are high — and new treatments are sorely needed.

Further study in Kaposi sarcoma

Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus (also known as human herpesvirus 8, or HHV-8) and most commonly appears as lesions on the skin. KSHV can also cause two other B-cell tumors, primary effusion lymphoma and a form of multicentric Castleman disease. Additionally, it can infect blood cells and spread through the bloodstream to infect other cells in the body, Uldrick said.

Also to be presented Friday is the death of one patient later in the study who had Kaposi sarcoma. The death is still being evaluated but was likely due to dissemination of KSHV. Uldrick and Cheever said review of the case suggests the patient had a history of symptomatic KSHV viremia, and the study has been changed to exclude such patients in the future and provide specific guidelines for management should new symptomatic KSHV viremia be observed.

Six other study participants with Kaposi sarcoma or primary effusion lymphoma have been treated on this study. None has experienced similar problems, and some have benefitted from therapy, Uldrick said.

“We do not believe that this takes away from the safety message in patients with HIV and other, better studied cancers,” Uldrick said. “However, more experience is clearly needed in treating KSHV-associated diseases with checkpoint inhibitors.”

A passion to ‘change the culture’

Although the NCI has recommended including people with HIV in immunotherapy clinical trials for a decade, virtually every industry-sponsored study over the last five years excluded them, according to a review by Uldrick and others published in the Journal of Clinical Oncology. Uldrick believes that reluctance to include people with HIV in cancer immunotherapy studies dates back to a time when patients were still dying of opportunistic infections and antiretroviral therapies were more toxic than they are today.

As a physician-scientist who focuses on immunology, virology and cancer, Uldrick became frustrated with the lack of data.

“The culture was slow to change,” he said. “It was preventing the advance of appropriate clinical therapies.”

Dr. Holbrook Kohrt, a Stanford oncologist and researcher, shared that frustration. Kohrt instigated the current clinical trial, according to Cheever, driven by his boyhood experience being one of only two hemophiliacs in a special summer camp who did not die of AIDS. (The genetic disorder impairs the blood’s clotting ability and requires infusions of lifesaving clotting factor, which at that time was made from the pooled blood of tens of thousands of donors. Before a test was developed to detect HIV in blood, about half the hemophiliacs in the United States died of AIDS from infected clotting factor.)

“Holbrook had three patients early on with malignancies that he thought would benefit from [checkpoint inhibitors] and could not get access to the drug because they had HIV,” Cheever said. “He was passionate about this study because he was a passionate individual and physician. But he was also influenced by his experience as someone with hemophilia who lost so many peers to HIV.”

Kohrt died in 2016 from complications of hemophilia. He is named as an author of the study.

“He would have predicted these results,” Cheever said.

Getting out the message

The ongoing study is now being conducted at eight sites, each of which includes physician-researchers with expertise in both cancer and HIV. A majority of the early patients were enrolled on the trial through Uldrick’s group at the NCI Intramural Research Program in Bethesda, Maryland.

Uldrick will continue to lead the study after he leaves the NCI to become deputy head of Fred Hutch Global Oncology on Dec. 1.

He and Cheever are hoping that these early results lead to additional studies of checkpoint inhibitors in people with HIV and malignancies, especially those cancers that are more prevalent in people with HIV such as Kaposi sarcoma and cancers caused by another virus, human papillomavirus, such as cervical cancer.

In the meantime, the researchers intend to talk about their findings at multiple scientific communities so that people with HIV and their physicians become aware of the data.

“We’d recommend that patients with HIV and malignancy be considered for this therapy if it’s approved for their particular cancer,” Uldrick said.

Targeting a microRNA shows potential to enhance effectiveness of diabetes drugs

Over the past 15 years, University of Alabama at Birmingham endocrinologist Anath Shalev, M.D., has unraveled a crucial biological pathway that malfunctions in diabetes.

Her latest discovery in this beta-cell pathway, published in the journal Diabetes, shows the potential to enhance the effectiveness of existing diabetes drugs, as well as reduce some of the unwelcome side effects of those drugs.

The need for improved treatment is great. Diabetes is a disorder characterized by elevated blood sugar that afflicts one of every 10 U.S. adults and doubles the risk of early death. More than 30 million people in the United States have diabetes, which is the seventh-leading cause of death and also leads to blindness and lower-limb amputations.

In 2013, the UAB researchers found that either diabetes or elevated production of the protein TXNIP induced beta-cell expression of microRNA-204, or miR-204, and this microRNA, in turn, blocked insulin production. The Shalev group has now found another vital role for miR-204 — regulating the cell surface receptor that is the target of many of the newer type 2 diabetes drugs, such as Byetta, Victoza, Trulicity, Januvia, Onglyza and Tradjenta. This drug target is the glucagon-like peptide 1 receptor, or GLP1R. Activation of GLP1R with these drugs helps the beta cell produce and secrete more insulin.

Shalev’s new work was performed in rat beta cells, genetically modified mice, mouse pancreatic islets and human pancreatic islets. Healthy beta cells, which are found in the pancreatic islets, produce insulin to control blood sugar levels; in diabetes the beta cells are impaired and dysfunctional, and have lower GLP1R levels.

In the Diabetes study, Shalev and colleagues found that overexpression of miR-204 decreased expression of GLP1R in rat beta cells and in mouse and human pancreatic islets. Conversely, knock-down of miR-204 increased expression of GLP1R in those cells and pancreatic islets.

Greater GLP1R expression is beneficial because it helps transfer a signal to the beta cell to secrete more insulin, such as after a meal. Also, many of the newer diabetes drugs act as agonists to activate GLP1R. Higher expression can allow use of a lower-drug dose to treat diabetes, thus reducing dose-dependent side effects.

In mice, the UAB researchers found that a deletion of miR-204 caused enhanced GLP1R expression, and also better insulin secretion and glucose control. Furthermore, the knockout mice were more responsive to a GLP1R agonist in glucose tolerance tests. When the GLP1R knockout mice were used in a model of diabetes, where beta cells are damaged by low doses of the toxin streptozotocin, the diabetic mice showed improved glucose control and increased serum insulin levels.

These results suggest that downregulating miR-204, now revealed as an upstream regulator of GLP1R, could lead to better treatment of diabetes.

One key fact about miR-204 may further aid improved treatment. This microRNA is highly expressed in beta cells, but it is not highly expressed in the rest of the pancreas or in cells of the gastrointestinal tract that also express GLP1R and therefore respond to GLP1R agonists. Thus, an inhibitor of miR-204 would be relatively selective for beta cells.

“This novel concept of inhibiting a microRNA in a non-targeted manner, but taking advantage of its restricted tissue distribution and thereby selectively upregulating its target genes in that tissue, may have far reaching implications for microRNA biology and tissue-specific gene targeting in general,” Shalev said.

“Since miR-204 is expressed primarily in pancreatic beta cells, manipulating its levels allows for preferential upregulation of GLP1R in the beta cell, where it helps secrete insulin, rather than in the gastrointestinal system, where it can cause nausea and impaired gastric emptying, or in the pancreas, where it can increase the risk for pancreatitis,” Shalev said. “So by inhibiting miR-204, one could increase the effects of GLP1R agonist drugs on insulin secretion, thereby lowering the necessary dose and avoiding some of the dose-dependent adverse effects.”

The mechanism by which miR-204 downregulates expression of GLP1R is binding of the microRNA to the 3-prime-untranslated region of GLP1R messenger RNA. Such binding is a known method to control gene expression by microRNAs. The UAB researchers discovered this specific binding using microRNA target prediction software. They found two binding sites for miR-204 in the messenger RNA for human GLP1R and one binding site in the messenger RNA for mouse GLP1R. When they mutated those binding sites, it eliminated the regulatory effect of miR-204.

Additionally, the Shalev group showed a novel link between TXNIP and GLP1R signaling. Mice with a beta cell-specific knockout of the protein TXNIP had lower miR-204 levels and higher GLP1R expression, and the mice showed enhanced insulin secretion and glucose control in response to an agonist of GLP1R. Thus, through both control of insulin production and regulation of GLP1R, as well as regulation of the unfolded protein response and beta cell apoptosis, miR-204 appears to play a linchpin role to control the function of beta cells in the pancreas.

Study Finds a New Way to Shut Down Cancer Cells’ Ability to Consume Glucose

Cancer cells consume exorbitant amounts of glucose, a key source of energy, and shutting down this glucose consumption has long been considered a logical therapeutic strategy. However, good pharmacological targets to stop cancers’ ability to uptake and metabolize glucose are missing. In a new study published in Cell Reports, a team of University of Colorado Cancer Center researchers, led by Matthew Galbraith, PhD, and Joaquin Espinosa, PhD, finally identifies a way to restrict the ability of cancer to use glucose for energy.

Over-expression of the gene CDK8 is linked to the development of many cancers including colorectal cancer, melanoma, and breast cancer, where it regulates pathways that drive the growth and survival of cancer cells. Although a number of drugs aimed at blocking CDK8 activity are currently being developed, it is not yet clear how effective they are at treating various cancers. Galbraith and Espinosa have been working to better understand the role of CDK8 in cancer biology in the hopes of aiding the introduction of CDK8-based therapies as cancer treatments.

Their most recent study, which was funded in part by the Cancer League of Colorado and the Mary Miller and Charlie Fonfara-Larose Leukemia in Down Syndrome Fund, demonstrates that CDK8 plays a critical role in allowing cancer cells to use glucose as an energy source.

The finding takes place against the backdrop of the tissue conditions in which tumors grow – as cancer cells rapidly multiply, their growth often outstrips their blood supply, leading to depletion of oxygen (i.e. hypoxia) and other nutrients such as glucose. In 2013, the group published a paper showing that CDK8 is important for activation of many genes switched on in hypoxic conditions. During adaptation to these conditions, cancer cells must alter their metabolism to consume more glucose through a process called glycolysis. In fact, many cancer cells have permanent increases in glycolysis, maintained even in conditions of plentiful oxygen, a phenomenon known as the Warburg effect, which was described as far back as 1924. Consequently, many cancers are heavily dependent on glucose metabolism for their growth and survival. This is true to the point that doctors use glucose isotopes and PET scans to pinpoint the exact location of a tumor and its metastases within the human body – where there are abnormally high levels of glucose being used, chances are there is a cancerous growth.

When Galbraith used a sophisticated chemical genetics approach to specifically switch off CDK8 activity in colorectal cancer cells, he saw that the cells failed to activate glycolysis genes and took up much less glucose. He confirmed this in experiments showing that blocking CDK8 activity leads to a lower rate of glucose use.

“Because of this role of CDK8 in glycolysis, I reasoned that the cells with impaired CDK8 activity should be more susceptible to drugs that block glycolysis,” Galbraith says. Sure enough, treating cancer cells with drugs that block both CDK8 and glycolysis slowed their growth more effectively than either approach alone.

“These are very exciting discoveries. The Warburg effect and consequent addiction to glucose is a hallmark of cancerous tissues, something that distinguishes cancer cells from most normal tissues. Therefore, combining drugs that block CDK8 activity with those that block glycolysis may enable specific targeting of cancer cells without harmful effects on normal cells,” says Espinosa, the paper’s senior author.

The team was recently awarded a grant from the Denver chapter of Golfers Against Cancer to advance their findings through pre-clinical research in mouse models, a necessary step to test the clinical value of this new strategy targeting CDK8 and glucose metabolism.

Immune Cells Mistake Heart Attacks for Viral Infections

A study led by Kevin King, a bioengineer and physician at the University of California San Diego, has found that the immune system plays a surprising role in the aftermath of heart attacks.  The research could lead to new therapeutic strategies for heart disease.

The team, which also includes researchers from the Center for Systems Biology at Massachusetts General Hospital (MGH), Brigham and Women’s Hospital, Harvard Medical School, and the University of Massachusetts, presents the findings in the Nov. 6 issue of Nature Medicine.

Ischemic heart disease is the most common cause of death in the world and it begins with a heart attack. During this process, heart cells die, prompting immune cells to enter the dead tissue, clear debris and orchestrate stabilization of the heart wall.

But what is it about dying cells in the heart that stimulates the immune system? To answer this, researchers looked deep inside thousands of individual cardiac immune cells and mapped their individual transcriptomes using a method called single cell RNA-Seq. This led to the discovery that after a heart attack, DNA from dying cells masquerades as a virus and activates an ancient antiviral program called the type I interferon response in specialized immune cells. The researchers named these “interferon inducible cells (IFNICs).”

When investigators blocked the interferon response, either genetically or with a neutralizing antibody given after the heart attack, there was less inflammation, less heart dysfunction, and improved survival. Specifically, blocking antiviral responses in mice improved survival from 60 percent to over 95 percent. These findings reveal a new potential therapeutic opportunity to prevent heart attacks from progressing to heart failure in patients.

“We are interested to learn whether interferons contribute to adverse cardiovascular outcomes after heart attacks in humans,” said King, who did most of the work on the study while he was a cardiology fellow at Brigham and Women’s Hospital and at the Center for Systems Biology at MGH in Boston.

The immune system has evolved innate antiviral programs to defend against a diverse range of invading pathogens. Immune cells do this by detecting molecular fingerprints of pathogens, activating a protein called IRF3, and secreting interferons, which orchestrate a defense program mediated by hundreds of interferon-stimulated genes. Investigators found that surprisingly, the antiviral interferon response is also turned on after a heart attack despite the absence of any infection. Their results point to dying cell DNA as the cause of this confusion because the immune system interprets it as the molecular signature of a virus.

Surprisingly, the immune cells participating in the interferon response were a previously unrecognized subset of cardiac macrophages. These cells could not be identified by conventional flow sorting because unique markers on the cell surface were not known. By using single cell RNA Seq, an emerging technique that combines microfluidic nanoliter droplet reactors with single cell barcoding and next generation sequencing, the researchers were able to examine expression of every gene in over 4,000 cardiac immune cells and found the specialized IFNIC population of responsible cells.

Future studies will aim to better understand the interferon response and the IFNIC cell type and explore their roles in the infarcted and remodeling heart. The team is also working to understand the interferon response in other tissues and diseases where cell death occurs.

Trained T-Cells to Target Toxic Viruses in Pediatric Patients New Cellular Therapy Approach for Children with Compromised Immune Systems

Michael Pulsipher, MD, of the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles, along with Michael Keller, MD from Children’s National Health System in Washington, DC, have been awarded $4.8 million by the California Institute for Regenerative Medicine (CIRM) to study the use of a new T-cell therapy to help fight active viral infections in children with severe immune deficiencies. In what will be the largest multi-center pediatric clinical trial of this kind to date, investigators will test the feasibility of using “viral specific” T-cells that are engineered to target three common and potentially toxic viruses: Epstein-Bar virus (EBV), cytomegalovirus (CMV) and adenovirus.

In healthy individuals infections with EBV, CMV and adenovirus cause fatigue, sore muscles, sore throat and swollen glands, but after a short period they recover. For children with weakened immune systems, however, infection with these viruses can lead to severe organ damage or death.

“When patients have severe inherited immune deficiencies or are intensely immune suppressed after a bone marrow transplant, standard antiviral medications are sometimes not enough and patients can die from common viral infections,” explained Pulsipher. “Patients often need at least some function of their own immune systems in addition to antiviral medications in order to clear these infections, but sometimes the patient’s own T-cells are not up to the task.”

Previous studies have demonstrated success in restoring immunity against a particular virus by using donor T-cells that are engineered to target a specific virus for therapy following BMT.

For the new clinical trial, Pulsipher, Keller and their collaborators will use T-cells from healthy donors that have been trained and expanded to target the viruses, then preserved in a donor “bank” for use in the trial. The cells are then individually matched to specific patients based upon their genetic make-up and the viral infection they are experiencing, and shipped to individual centers for infusion. After infusion, the virus-specific targeted T-cells can not only control the active infection, but can help prevent other infections.

“It is our hope that with these trained T-cells, we can help the most vulnerable patients fight off life-threatening viral infections,” said Keller. “By offering a ‘donor’ bank, we are significantly expanding the reach of this therapy and increasing access to even more children, which is extremely exciting.”

“Our study design is to use a multi-virus T-cell therapy to reconstitute immunity against all three of these viruses,” said Pulsipher. “Restoring immunity against multiple viruses simultaneously provides patients with protection from severe viral infections and reduces the need for continued prophylaxis with pharmacotherapy drugs after transplant which can have adverse effects.”

The study, which is expected to include up to 30 centers, will be run through the Pediatric Blood and Marrow Transplant Consortium (PBMTC) Operations Center at CHLA and was developed and is being performed in collaboration with the Primary Immune Deficiency Treatment Consortium (PIDTC). Cell manufacturing for use in the clinical trial will be conducted by the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) of the Children’s National Health System.

FDA Announces First Approval of Targeted Therapy Based on Basket Study

Precision medicine clinical trial leads to approval of first treatment for Erdheim-Chester disease

The US Food and Drug Administration (FDA) has announced that it has approved the drug vemurafenib for the treatment of patients with BRAF V600-mutant Erdheim-Chester disease (ECD). This is the first approval of a targeted therapy based on a basket study and the first-ever drug approved for ECD, a rare blood disorder.

This landmark approval came as a direct result of research at Memorial Sloan Kettering Cancer Center (MSK). MSK researchers, led by Physician-in-Chief José Baselga, MD, PhD, pioneered the concept of a basket study, which harnesses the power of precision medicine by assigning treatments to patients based on the genetic alterations driving their cancers rather than where their tumors originated in the body. This approval is based off of the data of 22 ECD patients enrolled in the phase II VE-BASKET study. 

ECD is one of an extremely rare form of blood cancers known collectively as histiocytoses that can lead to life-threatening complications, including damage to the heart, lungs, and kidneys. It’s estimated that there are fewer than 300 cases of ECD in the United States. More than 50 percent of people with ECD have BRAF V600-mutant disease, indicating that they would benefit from this drug. Previous treatments for ECD have included off-label use of chemotherapy, radiation, steroids, and the immunotherapy drug interferon, but all of these have limited efficacy based on anecdotal reports and potentially severe side effects.

Based on the work of MSK medical oncologist Paul Chapman, MD, vemurafenib was previously approved for the treatment of advanced melanoma that carries the BRAF V600E mutation. Dr. Chapman led the phase III trial for vemurafenib that led to the drug’s approval for that disease in 2011. In August 2017, vemurafenib was granted FDA Priority Review and Breakthrough Therapy Designation for the treatment of BRAF V600-mutant ECD.

About the Study

This approval is based on data from the phase II VE-BASKET study, a nonrandomized, histology-independent evaluation of the efficacy of vemurafenib, an inhibitor of BRAF V600 kinase, in non-melanoma cancers, including ECD. This first-in-kind study enrolled participants across multiple diseases, based predominantly on genetic profile rather than where the cancer originated. Initial study results were published in the New England Journal of Medicine in August 2015.

Final results for the 22 people with ECD showed a best overall response rate of 54.4 percent by RECIST v1.1. Importantly, responses and disease control were extremely durable. The median duration of response was not estimable at a median follow-up time of 26.6 months. At two years, 83 percent of patients remained progression free. The safety of vemurafenib in ECD patients was similar to that previously reported in patients with melanoma. The most common adverse events were joint pain, rash, hair loss, fatigue, change in heart rhythm and skin tags. 

Precision Medicine at MSK

Experts at MSK have taken the lead in developing clinical trials for a number of promising treatments that are based on tumors’ mutational profiles. Since August 2015, when MSK experts published initial results of the first basket study, histology-agnostic clinical trials have emerged as one important means of systematically testing a targeted therapy across a variety of tumor types. This innovative clinical trial design helps collect data faster and may accelerate the development of medicines for diseases with high unmet need. Basket studies can include many more people than disease-specific trials, allowing researchers to evaluate multiple diseases simultaneously. This is particularly important for diseases such as ECD that are extremely rare, making it difficult to fully enroll a disease or tumor-specific trial.

MSK leadership saw the promise of precision oncology early on and committed to realizing its ability to create better treatment options for all people with cancer. In 2014, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO) was established to improve cancer care and research through genomic analysis and MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets) was launched. This powerful diagnostic test provides detailed genetic information about a patient’s cancer that can guide treatment and identify clinical trial opportunities. To date, more than 20,000 MSK patients with advanced cancer have had their tumors sequenced through MSK-IMPACT. Most recently, Dr. Baselga and colleagues published a roadmap to precision oncology in the form of a seminal review paper in Cell.  

FDA Approves the Roll-Over Combination Study with Checkpoint Inhibitor Immunotherapies to Allow Continued Access to BriaVax™ in Patients with Advanced Breast Cancer

The FDA has approved the roll-over combination study of the investigational breast cancer vaccine, BriaVax™ with pembrolizumab {Keytruda; manufactured by Merck & Co., Inc. or ipilimumab {Yervoy; manufactured by Bristol-Myers Squibb Company for patients previously treated with BriaVax™ from the ongoing Phase I/IIa Clinical Trial in Advanced Breast Cancer.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system by allowing the body to recognize and eliminate cancerous cells by inducing tumor-directed T cell and potentially antibody responses.

This roll-over combination study allows the patients who did not respond to BriaVax™ (monotherapy) treatment to be treated and continue to receive the potential clinical benefits of the vaccine in combination with either pembrolizumab or ipilimumab. This approach is based on the hypothesis that both pembrolizumab and ipilimumab may improve the anti-tumor activity of vaccine in patients with advanced breast cancer. Safety and efficacy data will be evaluated.

“We are very excited to evaluate the effects of BriaVax™ with other approved anti-tumor immunotherapeutic agents. We expect this study to extend and potentiate the clinical benefits of BriaVax™ in advanced breast cancer patients,” stated Dr. Williams, BriaCell’s President & CEO in a press release. “We look forward to expanding our clinical study and exploring potential immunotherapy partnerships with leading pharmaceutical companies in the future, and we are pleased with the FDA decision,” Dr. Williams added.

The clinical investigators will work closely with Cancer Insight, LLC, BriaCell’s contract research organization, to manage the clinical and regulatory aspects of the clinical trial for the roll-over combination study of BriaVax™ on behalf of BriaCell. More information on the roll-over combination study of BriaVax™ with either ipilimumab or pembrolizumab will be available on ClinicalTrials.gov (Study identifier: BRI-ROL-001).

Manufactured by Merck & Co., Inc., KEYTRUDA® (pembrolizumab) is a prescription medicine that may treat certain cancers by working with the immune system. It has been approved for the treatment of a number of cancer indications excluding breast cancer.

Manufactured by Bristol-Myers Squibb Company, YERVOY® (ipilimumab) is a prescription medicine used in adults and children 12 years and older to treat melanoma (a kind of skin cancer) that has spread (metastatic) or cannot be removed by surgery (unresectable). It is a monoclonal antibody that works to activate the immune system and enabling them to recognize and destroy cancer cells.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system. Previously, a small Phase I study documented very prompt and near complete regression of metastatic breast cancer deposits in the breast, lung, soft tissue, and even the brain.

The ongoing open-label Phase I/IIa study will evaluate BriaVax™ in up to 40 advanced breast cancer patients. This trial is listed in ClinicalTrials.gov as NCT03066947. The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

BriaCell is an immuno-oncology focused biotechnology company developing a targeted and safe approach to the management of cancer. BriaCell’s mission is to serve late-stage cancer patients with no available treatment options.

Immunotherapy has come to the forefront of the fight against cancer, harnessing the body’s own immune system in recognizing and selectively destroying the cancer cells while sparing normal ones. Immunotherapy, in addition to generally being more targeted and less toxic than commonly used types of chemotherapy, is also thought to be a strong type of approach aimed at preventing cancer recurrence.

The results of two previous Phase I clinical trials (one with the precursor cell line not genetically engineered to produce GM-CSF and one with BriaVax™) have been encouraging in patients with advanced breast cancer. Most notably, one patient with metastatic breast cancer responded to BriaVax™ with substantial reduction in tumor burden including lung and brain metastases. The company is currently conducting a Phase I/IIa clinical trial for BriaVax™ in patients with advanced breast cancer whose disease has progressed following at least one prior treatment course.

This trial is listed in ClinicalTrials.gov as NCT03066947.  The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

In a previous Phase I setting, a patient with metastatic breast cancer responded to BriaVax™ with objective reduction in tumor burden. To expand on this finding, after updating the clinical protocol of the original investigational new drug (IND) application, an open-label Phase I/IIa clinical trial enrolling up to 40 late stage breast cancer patients with recurrent and/or metastatic disease has been launched. Patients will be administered BriaVax™ every two weeks for the first month of treatment, then monthly up to one year.

The primary objective of the Phase I/IIa clinical trial is to evaluate the safety of BriaVax™ in study subjects, and the principal secondary objective is an evaluation of the tumor size reduction. Tumor response will be monitored every three months during the study. The trial will also evaluate progression-free survival (PFS) and overall survival (OS).

For additional details regarding the clinical trial, please visit:
https://www.clinicaltrials.gov/ct2/show/NCT03066947

Breast cancer researchers track changes in normal mammary duct cells leading to disease

Breast cancer researchers have mapped early genetic alterations in normal-looking cells at various distances from primary tumours to show how changes along the lining of mammary ducts can lead to disease.

The findings of the multidisciplinary team of surgeons, pathologists and scientists led by principal investigator Dr. Susan Done are published online today in Nature Communications. Dr. Done, a pathologist affiliated with The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, is also an associate professor in the Department of Laboratory Medicine and Pathobiology, University of Toronto.

“We have found another piece in the cancer puzzle – knowledge that could one day be used for more precision in screening and breast cancer prevention, and also help with therapeutic approaches to block some of the earliest alterations before cancer develops and starts to spread.”

Lead author Moustafa Abdalla writes: “Almost all genomic studies of breast cancer have focused on well-established tumours because it is technically challenging to study the earliest mutational events occurring in human breast epithelial cells.” Instead, this study found a way to identify early changes that preceded the tumour, enabling better understanding of cancer biology and disease development.

“Normal breast epithelium from the duct giving rise to a breast cancer has not been previously studied in this way.”

Dr. Done explains: “Most breast cancer starts in the epithelial cells lining the mammary ducts. But the breast ducts are complex structures, like the branches of a tree. Guesstimating which duct is close to the tumour is not very accurate. Thanks to our surgeons, we were able to obtain samples along normal-looking ducts close to the nipple and close to the tumour, as well as samples on the opposite side of the same breast to study and compare.”

In the operating room, surgeons inserted a fibre-optic scope through the nipple into the ducts below, and then injected dye into cancerous breasts being removed. This ductoscopy technique enabled the pathologists to identify the exact duct leading to the tumour and subsequently classify genetic alterations either increasing or decreasing as they moved nearer to the cancer.

“Cancer is not a switch that happens overnight. Once a patient notices a lump the tumour has been present for some time accumulating genetic changes. It is difficult at that point to identify the first changes that may have had a role in initiating or starting the cancer,” says Dr. Done.

The research further identified genes that seem to be acting together in groups or pathways. “Some of these genes were either increased or decreased in the area of the tumour, no matter the type of breast cancer, and this is important because within the patterns we identified were predictable alterations. This meant we could determine from the sample where it came from in the breast,” says Dr. Done.

“Our research demonstrated and supports earlier research from elsewhere that changes in cells occur before you can see them. The fact that changes are already present in different regions of the breast could be important in the delivery of radiation therapy or surgical margin assessment. We’re a long way from bringing this into clinic, but it is something we will think about as we continue our research.”

Topical gel made from oral blood pressure drugs shown effective in healing chronic wounds

An international team of researchers led by Johns Hopkins has shown that a topical gel made from a class of common blood pressure pills that block inflammation pathways speeds the healing of chronic skin wounds in mice and pigs.

A report of the findings, published Oct. 16 in the Journal of Investigative Dermatology, marks efforts to seek approval from the U.S. Food and Drug Administration (FDA) to use the gel application in treatment-resistant skin wounds among diabetics and others, particularly older adults.

“The FDA has not issued any new drug approval for wound healing in the past 10 years,” says Peter Abadir, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine and the paper’s first author. “Using medicines that have been available for more than two decades, we think we have shown that this class of medicines holds great promise in effectively healing chronic wounds that are prevalent in diabetic and aged patients.”

Chronic wounds, defined as skin injuries that fail to heal in a timely manner and increase the risk of infection and tissue breakdown, accounted for more than 100 million hospital visits in United States hospitals in 2008, according to Abadir.

In recent years, attention has turned to the skin’s renin-angiotensin system (RAS), which is involved in the skin’s inflammatory response, collagen deposition and signaling necessary for wound healing. Studies show that the RAS system is abnormally regulated in diabetic and older adults.

Abadir and colleagues experimented with gel formulations of angiotensin II receptor antagonists, or blockers, a long-standing class of drugs that includes losartan and valsartan, prescribed to treat hypertension. The drugs block RAS and increase wound blood flow, and the goal was to apply the gels directly to wounds, increasing wound tissue level of the drugs that promote faster healing.

Abadir and colleagues first tested 5 percent topical losartan on mice in three different phases of wound healing: group 1 treatment, for up to three days post-wound infliction to target the inflammatory phase; group 2 treatment, starting on day seven after wound infliction to target the proliferative/remodeling (later) phase of tissue healing; and group 3 treatment, starting the first day of wound infliction until closure to treat all wound healing phases. A fourth group was kept back as a control and given standard care and a placebo. Mice in group 2 experienced the most accelerated wound healing rate.

Next, Abadir and colleagues compared the effects of different concentrations of losartan and valsartan on young diabetic and aged mice during the proliferation/remodeling phase of wound healing, which involves the regrowth of normal tissue.

The results showed that valsartan was more effective in accelerating wound healing than losartan, without any significant difference in healing time between valsartan doses. Overall, 1 percent valsartan had the greatest impact on total closure compared with the other agents, and 10 percent losartan led to the worst wound healing, which Abadir says may be attributed to toxicity.

Final results showed that half of all mice that received 1 percent valsartan achieved complete wound healing, while only 10 percent of the mice given the placebo did.

Driven by 1 percent valsartan’s promising results in mice, the researchers tested its effects on wounds among aged, diabetic pigs, as pig skin has more similar properties to human skin.

Compared with pigs in the placebo group, wounds that received 1 percent valsartan healed much more quickly, and all 12 wounds were closed by day 50, compared with none of the placebo-treated wounds, the researchers say.

Of note, Abadir says, a low concentration (1 to 50 nanomoles) of valsartan was detected in the pigs’ blood near the beginning of treatment, and none was detected later in the treatment course, suggesting that the drug acts locally on the tissues where it’s absorbed, rather than affecting the entire body.

For comparison, oral ingestion of valsartan generally yields 4,000 to 5,000 nanomoles in the blood level for a human. This suggests that topical application of valsartan will not be absorbed into the bloodstream and could have unintended physiological effects, such as those that affected blood pressure, body weight or kidney function.

Finally, to determine the quality of 1 percent valsartan’s biological effects on wound repair–not just rate of repair–Abadir and colleagues examined collagen content and tensile strength in the pigs’ skin. Pigs treated with valsartan had a thicker epidermal layer (the outermost layer of the skin) and dermal collagen layer, as well as a more organized collagen fiber arrangement, all of which indicate 1 percent valsartan application leads to stronger healing skin, Abadir says.

“Our strategy for specifically targeting the biology that underlies chronic wounds in diabetics and older adults differs greatly from other approaches to wound care thus far. The topical gel likely enables a cascade of positive biological effects that facilitates and accelerates chronic wound healing,” says Jeremy Walston, M.D., professor of medicine and the paper’s senior author.

“Now that we’ve proven efficacy in animals, we’re moving on to the next stage of FDA-required testing in humans. Hopefully, this medication will be available for public use in a few years, if further research bears out our results,” adds Walston. Walston and colleagues envision that the medication could one day also be used to treat scars, wrinkles and other skin problems.

Twenty-nine million Americans have diabetes and 1.7 million are newly diagnosed each year. Of this group, approximately 900,000 will develop diabetic foot ulcers annually. With an aging population and incidence of diabetes increasing rapidly across the globe. Abadir estimates the total number of diabetic foot ulcers to be more than 20 million per year, with an estimated total cost of $25 billion annually in the U.S. alone.

New Treatment Shows Promise for Patients with Rare Dermatologic Disease

A new treatment for a rare and often incurable condition called dermatomyositis (DM) reduced the severity of the disease in patients whose DM was resistant to other therapies. As part of a randomized, double-blind study conducted at the Perelman School of Medicine at the University of Pennsylvania, 22 patients were given either a drug called anabasum or a placebo. The 11 patients who got the drug improved during the trial, with less severe skin disease and better patient-reported quality of life and symptom assessments. Researchers will present their findings at the American College of Rheumatology Annual Meeting in San Diego next week.

Dermatomyositis is an inflammatory disease that causes a rash on the skin and is frequently associated with muscle weakness. Some patients are only affected on the skin. Other symptoms can include fevers, shortness of breath due to lung disease, weight loss, and sensitivity to light. While there are fewer than 100,000 cases of DM overall in the United States, treatment is often ineffective and frequently requires drugs that suppress the immune system, which can leave patients susceptible to other illnesses.

“Not only are current treatments limited, but this disease itself is very understudied, so we’ve had to build our understanding of DM from the ground up just to be in a position to run a trial like this,” said the study’s principal investigator Victoria P. Werth, MD, a professor of Dermatology at Penn and the Chief of Dermatology at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia.

One of the first challenges was developing a way to measure the severity of a patient’s DM. In other dermatologic conditions, such as psoriasis or eczema, doctors can measure the percentage of the skin that is affected – a measurement known as body surface area.

“In DM, body surface area is less informative, because even though you may only have DM on a small percentage of your skin, it can still have severe effects,” Werth said. “We needed a way to look for the amount of disease in a given area.”

Werth and her team developed a metric called the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). It measures the amount of skin severity as separate activity and damage scores, with a higher score representing more severe disease. The median activity score among Penn’s clinical population is 13, but this trial involved patients with more severe disease, so scores ranged from 33 to 35.

Penn researchers have spent the last decade developing and validating the CDASI, and though it has become standard practice for use in DM research, this is the first placebo-controlled randomized clinical trial to report the score to evaluate the results of a new treatment.

Patients in this trial all had skin-predominant DM and had not responded to standard treatments such as antimalarial or immunosuppressive therapies. Patients received a single 20mg dose of anabasum for a month and then went to two doses per day for two months, or they were assigned to the placebo. All patients were followed for one month post-treatment. The 11 patients who received the drug had a mean decrease of more than six points relative to the placebo during dosing with the higher dose of drug. The most common side effects seen in the study were diarrhea, dizziness, fatigue, and dry mouth, but these were mild and did not cause anyone to stop taking the drug.

Twenty of the 22 patients on this trial have entered a one-year, long-term extension study. Werth says that will be critical to understanding the efficacy and safety of anabasum, but she also says a larger study is warranted based on these results.

This trial was supported by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR066286) and Corbus Pharmaceuticals, which is developing anabasum for a number of rare inflammatory diseases including DM.

New molecule shows promise in HIV vaccine design

Researchers at the University of Maryland and Duke University have designed a novel protein-sugar vaccine candidate that, in an animal model, stimulated an immune response against sugars that form a protective shield around HIV. The molecule could one day become part of a successful HIV vaccine.

“An obstacle to creating an effective HIV vaccine is the difficulty of getting the immune system to generate antibodies against the sugar shield of multiple HIV strains,” said Lai-Xi Wang, a professor of chemistry and biochemistry at UMD. “Our method addresses this problem by designing a vaccine component that mimics a protein-sugar part of this shield.”

Wang and collaborators designed a vaccine candidate using an HIV protein fragment linked to a sugar group. When injected into rabbits, the vaccine candidate stimulated antibody responses against the sugar shield in four different HIV strains. The results were published in the journal Cell Chemical Biology on October 26, 2017.

The protein fragment of the vaccine candidate comes from gp120, a protein that covers HIV like a protective envelope. A sugar shield covers the gp120 envelope, bolstering HIV’s defenses. The rare HIV-infected individuals who can keep the virus at bay without medication typically have antibodies that attack gp120.

Researchers have tried to create an HIV vaccine targeting gp120, but had little success for two reasons. First, the sugar shield on HIV resembles sugars found in the human body and therefore does not stimulate a strong immune response. Second, more than 60 strains of HIV exist and the virus mutates frequently. As a result, antibodies against gp120 from one HIV strain will not protect against other strains or a mutant strain.

To overcome these challenges, Wang and his collaborators focused on a small fragment of gp120 protein that is common among HIV strains. The researchers used a synthetic chemistry method they previously developed to combine the gp120 fragment with a sugar molecule, also shared among HIV strains, to mimic the sugar shield on the HIV envelope.

Next, the researchers injected the protein-sugar vaccine candidate into rabbits and found that the rabbits’ immune systems produced antibodies that physically bound to gp120 found in four dominant strains of HIV in circulation today. Injecting rabbits with a vaccine candidate that contained the protein fragment without the sugar group resulted in antibodies that primarily bound to gp120 from only one HIV strain.

“This result was significant because producing antibodies that directly target the defensive sugar shield is an important step in developing immunity against the target and therefore the first step in developing a truly effective vaccine,” Wang said.

Although the rabbits’ antibodies bound to gp120, they did not prevent live HIV from infecting cells. This result did not surprise Wang, who noted that it usually takes humans up to two years to build immunity against HIV and the animal study only lasted two months.

“We have not hit a home run yet,” Wang noted. “But the ability of the vaccine candidate to raise substantial antibodies against the sugar shield in only two months is encouraging; other studies took up to four years to achieve similar results. This means that our molecule is a relatively strong inducer of the immune response.”

The researchers’ next steps will be to conduct longer-term studies in combination with other vaccine candidates, hone in on what areas of gp120 the antibodies are binding to and determine how they can increase the antibodies’ effectiveness at neutralizing HIV.

Cancer trial led by University of Minnesota Medical School’s Dr. Clark Chen shows promise

New data from a Phase I clinical trial led by Clark Chen, M.D., Ph.D., Lyle French Chair in Neurosurgery and Head of the University of Minnesota Medical School Department of Neurosurgery shows more than a quarter of patients with recurrent high-grade glioma, a form of brain cancer, were alive more than three years after treatment.

“Given the deadly nature of this disease, three-year survival is rarely reported in the recurrent setting. It is notable that the survival benefit was seen across a range of patients and not just limited to patients with specific genetic mutations,” said Chen. “This finding indicates that many patients could benefit from this treatment.”

As Chen explained at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics two steps were involved in the treatment of the 56 patients who participated in this clinical trial. First, patients were injected with Toca 511, which is a replicating virus that only infects actively dividing tumor cells. Once inside the cancer cell, the virus delivered a gene for an enzyme, cytosine deaminase (CD). As the virus began to replicate and spread to other cancer cells, it programmed them to make CD. Next, patients received a pill, Toca FC, which is an inert compound. Once inside the cancer cell, CD converted Toca FC into the anticancer drug 5-fluorouracil, which killed the cancer cell. In addition to destroying the cancer cells, 5-fluorouracil killed certain immune suppressive myeloid cells, thus boosting the patient’s immune system to recognize and attack the cancer cells.

“The treatment we tested in this trial delivers local chemotherapy specifically to the brain tumor. Toca 511 and Toca FC work together to turn the brain tumor into a factory that produces an anticancer drug while also activating the immune system through a combination of mechanisms, which together work to attack the cancer,” Chen said.

Dr. Chen also noted that five patients are experiencing a durable complete response with a median of at least 35.7 months. Within a subgroup of 23 patients, there were an additional five patients who achieved stable disease, bringing the number of patients who derived benefit from Toca 511 to 10 (or 43.4 percent of the patients who underwent Toca 511 therapy).

According to Chen, the median survival in this trial is nearly double that of historical data. In the subgroup, median survival was 14.4 months, compared to approximately eight months for historical controls.

“Brain cancer is one of the deadliest cancers, giving urgency to finding an effective treatment,” Chen said. “The 160,000 people diagnosed with high-grade gliomas worldwide each year–and high-profile cases including U.S. Senator John McCain, Senator Edward Kennedy, and Beau Biden–demonstrate the high unmet need of this disease. The data generated in the Toca 511 research provides hope for patients with brain cancer and their families.”

This study was a single arm trial without a control group which acted as a limitation. “The ongoing randomized phase II/III trial will be important to confirm the promising safety and efficacy results reported in this Phase I study,” Chen noted.