Virus-derived particles target blood cancer.

WEDNESDAY, 14 AUGUST 2013

 

Ottawa researchers have developed unique virus-derived particles that can kill human blood cancer cells in the laboratory and eradicate the disease in mice with few side effects. The study is published in Blood Cancer Journal by co-senior authors Drs. David Conrad and John Bell of the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa (uOttawa).

While Dr. Bell and his colleagues have been investigating replicating viruses for the treatment of solid cancers for many years, with very promising results, this is the first major success they have had treating blood cancer (leukemia). It is also the first success they have had using a non-replicating virus-derived particle as opposed to a replicating virus.

"Our research indicated that a replicating virus might not be the safest or most effective approach for treating leukemia, so we decided to investigate whether we could make virus-derived particles that no longer replicate but still kill cancer," said Dr. Conrad, a hematologist conducting research in the Blood and Marrow Transplant Program at The Ottawa Hospital, and currently completing his PhD at OHRI and uOttawa in the Department of Cellular and Molecular Medicine. "We were delighted to see that this novel therapy was very safe at high doses, and worked extremely well in our laboratory leukemia models. We hope to test this in patients in the near future."

The researchers used a specific method and dose of UV light to transform regular replicating viruses into unique particles that could no longer replicate and spread, but could still enter cancer cells efficiently, kill them and stimulate a strong immune response against the cancer. These particles were able to kill multiple forms of leukemia in the laboratory, including samples taken from local patients who had failed all other therapies. Normal blood cells were not affected. This novel treatment was also successful in mouse models of leukemia. In fact, 80 per cent of the mice that received the therapy had markedly prolonged survival and 60 per cent were eventually cured, while all of the untreated mice died of their leukemia within 20 days.

"Leukemia is a devastating disease that can be very difficult to treat, and new therapies are urgently needed," said Dr. Conrad. "While we're still at the early stages of this research, I think this therapy holds a lot of promise because it appears to have a potent, long-lasting effect on leukemia without the debilitating side effects of many cancer therapies used in the clinic right now. We will likely see even better results once we optimize the dose in our preparations to advance this research into human clinical trials."

This research was funded by the Ontario Institute for Cancer Research, the Terry Fox Foundation, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, Ottawa's Department of Medicine and The Ottawa Hospital Foundation.

Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunity. Batenchuk C, Le Boeuf F, Stubbert L, Falls T, Atkins HL, Bell JC, and Conrad DP. Blood Cancer J. 2013 Jul 12;3:e123. doi: 10.1038/bcj.2013.23. Corresponding author: Dr. David P Conrad.

 

  Preclinical tests may lead to new approach to treat CNS lymphoma

   TUESDAY, 13 AUGUST 2013

 A drug recently approved for use in multiple myeloma is now being tested for its ability to fight central nervous system (CNS) lymphoma, a deadly cancer of the immune system that can affect the brain, spinal cord and fluid, and eyes. The clinical trial, now open at the three campuses of Mayo Clinic - in Florida, Minnesota and Arizona - follows successful testing of the drug, pomalidomide, in mouse models of CNS lymphoma. Details of the preclinical testing are available in the science journal PLOS ONE.

Approximately 5,000 patients are diagnosed with the disease every year in the United States.

"We believe pomalidomide could be beneficial in patients with this cancer because it does two things that most anti-cancer drugs do not do," says Han Tun, M.D., an oncologist at Mayo Clinic in Florida. "The drug has excellent brain penetration, which is a requirement in treatment of brain tumors. The other interesting thing is that it is not only active directly against lymphoma cells but also alters the tumor microenvironment."

Dr. Tun is the senior investigator of the PLOS ONE study and the principal investigator for the clinical trial, which is accruing patients.

"Our preclinical study suggests pomalidomide is very promising. Treatment with pomalidomide in mouse models for CNS lymphoma significantly improved the survival and suppressed the tumor growth," he says. "The phase I clinical trial was developed based on these preclinical results."

Pomalidomide belongs to a class of drugs called immunomodulatory agents. Thalidomide was the first drug in this class and was approved in 2006 for treatment of multiple myeloma, a bone marrow cancer. Pomalidomide was approved for use in multiple myeloma in February.

 

 Novartis first company accredited with global CEO Cancer Gold Standard

 MONDAY, 12 AUGUST 2013

 

Novartis is the first company to earn global CEO Cancer Gold Standard accreditation by the non-profit organization CEO Roundtable on Cancer, a group of cancer fighting CEOs from a variety of industries, including healthcare. The designation recognizes the company's efforts to provide support to Novartis associates in the prevention, diagnosis and treatment of cancer.

"At Novartis, we believe that everyone should have access to early screening programs and innovative therapies," said Joseph Jimenez, CEO of Novartis. "Our efforts for our associates, which are recognized by this designation, are an extension of our goal to redefine cancer for all patients."

Novartis is passionate about the discovery and development of innovative medicines to help provide a broad range of new therapies and practical solutions to advance care of patients. The company's research is driven by a distinctive scientific and clinical strategy focusing on unmet medical needs and knowledge of disease pathways. The Novartis research strategy leverages biomarkers and targeted drug development focused on individual patients. The company's extensive portfolio of access-to-treatment projects adapts to patients' needs, products, collaborators and countries.

Novartis first achieved CEO Cancer Gold Standard designation in the US, and quickly extended these resources around the world. Since then, the company has offered programs such as:

• adding preventive health services in Portugal
• a yearlong plan on health promotion and its benefits in the Philippines
• regular screenings for colon and breast cancers in Japan and Brazil

The impact has been significant. In fact, through the Novartis cancer screening program alone, the company has already documented cases of early cancer detection among our associates and has been able to offer the kind of support and treatment that helps to change lives. Novartis continues to expand the program to leverage the company's internal expertise and expand our cancer network and resources to support employees and their families with the best medical, emotional and physical support possible.

The CEO Roundtable on Cancer was founded in 2001, when former President George H.W. Bush challenged a group of executives to "do something bold and venturesome about cancer within your own corporate families." The CEOs responded by creating and encouraging the widespread adoption of the CEO Cancer Gold Standard which calls for organizations to evaluate their health benefits and workplace culture and take extensive, concrete actions in five key areas of health and wellness to fight cancer in the workplace.

 

 GSK launches $50 million venture capital fund to invest in pioneering bioelectronic medicines and  technologies

 FRIDAY, 09 AUGUST 2013

 

GlaxoSmithKline has announced the launch of Action Potential Venture Capital (APVC) Limited, a new $50 million strategic venture capital fund that will invest in companies that pioneer bioelectronic medicines and technologies. The fund's first investment will be in SetPoint Medical, a California company considered a trailblazer in creating implantable devices to treat inflammatory diseases.

The fund complements the work of GSK’s Bioelectronics R&D unit, which was established in 2012 after a two-year effort to seek out and engage the most promising researchers in this emerging area of science. The name of the fund comes from electrical signals called action potentials that pass along the nerves in the body. Irregular or altered patterns of these impulses may occur in association with a broad range of diseases.

GSK believes that miniaturised devices, or bioelectronic medicines, can be designed to read these patterns. The devices could be designed to interface between the peripheral nervous system and specific organs to read, change or generate electronic impulses that help treat disorders as diverse as inflammatory bowel disease or rheumatoid arthritis; respiratory diseases such as asthma and COPD and metabolic diseases including Type 2 diabetes.

The field of bioelectronic medicines is in its very early stages. GSK's ambition, through collaboration with scientists globally, is to have the first medicine that speaks the electrical language of our body ready for approval by the end of this decade.

"We want to help create the medicines of the future and be the catalyst for this work," said Moncef Slaoui, chairman of R&D and architect of GSK's early stage investment strategy. "GSK can play the integrating role that is needed to drive this new type of medical treatment all the way from the bench to the patient and this fund is a key part of our efforts."

Action Potential Venture Capital intends to build a portfolio of five to seven companies over the next five years. The fund will focus investments in three areas:

• New start-up companies that aim to pursue the vision of bioelectronic medicines
• Existing companies with technologies that are interacting with the peripheral nervous system through first-generation devices that can stimulate or block electrical impulses
• Companies advancing technology platforms that will underpin these treatment modalities

Action Potential Venture Capital will be based in Cambridge, Massachusetts and managed by a small, dedicated team. The fund has named Imran Eba as its first partner. Imran will move from GSK's Worldwide Business Development organisation and work closely with the Bioelectronics R&D unit.

Taking a three-pronged approach to bioelectronics research
GSK's Bioelectronics R&D unit will be supporting the development of a new bioelectronics research community in three ways over the coming months.

In addition to working with the new venture fund, the unit is in the process of offering up to 20 new exploratory research grants and creating a network of investigators. Discovery work has begun on the relationship between the nerves in the body and a range of diseases; the particular pattern of impulses along these nerves; and new technologies that can interface with individual nerve fibres. The unit is also seeking to integrate a broader research community and is engaging with other major funding and research organisations interested in the field. This broader community will be invited to meet at customised summits, including the first global summit to be announced shortly, where Bioelectronics R&D is committed to launching a million dollar innovation prize.

"The Action Potential Venture Capital fund is the third strand in our approach to galvanising a new research community," Imran said. "Together, these three mechanisms will contribute to bolster an ecosystem in which exploratory research as well as product translation is supported, and from which we expect a major wave of new medicines to emerge and benefit patients in future decades."

First APVC investment in SetPoint Medical
GSK's first investment will be in SetPoint Medical, based in Valencia, CA. SetPoint is developing a highly novel and potentially transformative approach to treat inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, by using implantable devices that stimulate the body's vagus nerve. The treatments have been developed based on new understanding that the immune system can be influenced by the nervous system; inflammatory diseases were previously thought to be accessible only by molecular medicines.

In addition to the novel treatment approach, GSK believes SetPoint's new proprietary miniaturised device has important hallmarks of future bioelectronic medicines. Together, SetPoint's treatment approaches and technology promise to provide alternate, and possibly more precise, ways of treating some major diseases.

GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer.

 THURSDAY, 08 AUGUST 2013

 Drinking two cups of hot chocolate a day may help older people keep their brains healthy and their thinking skills sharp, according to a study published in the August 7, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study involved 60 people with an average age of 73 who did not have dementia. The participants drank two cups of hot cocoa per day for 30 days and did not consume any other chocolate during the study. They were given tests of memory and thinking skills. They also had ultrasounds tests to measure the amount of blood flow to the brain during the tests.

"We're learning more about blood flow in the brain and its effect on thinking skills," said study author Farzaneh A. Sorond, MD, PhD, of Harvard Medical School in Boston and a member of the American Academy of Neurology. "As different areas of the brain need more energy to complete their tasks, they also need greater blood flow. This relationship, called neurovascular coupling, may play an important role in diseases such as Alzheimer's."

Of the 60 participants, 18 had impaired blood flow at the start of the study. Those people had an 8.3-percent improvement in the blood flow to the working areas of the brain by the end of the study, while there was no improvement for those who started out with regular blood flow.

The people with impaired blood flow also improved their times on a test of working memory, with scores dropping from 167 seconds at the beginning of the study to 116 seconds at the end. There was no change in times for people with regular blood flow.

A total of 24 of the participants also had MRI scans of the brain to look for tiny areas of brain damage. The scans found that people with impaired blood flow were also more likely to have these areas of brain damage.

Half of the study participants received hot cocoa that was rich in the antioxidant flavanol, while the other half received flavanol-poor hot cocoa. There were no differences between the two groups in the results.

"More work is needed to prove a link between cocoa, blood flow problems and cognitive decline," said Paul B. Rosenberg, MD, of Johns Hopkins School of Medicine in Baltimore, who wrote an editorial accompanying the study. "But this is an important first step that could guide future studies."

The study was supported by the National Institute on Aging and the National Heart, Lung, and Blood Institute. The cocoa was provided by Mars Inc.

 Targeting aggressive prostate cancer.

A team of researchers from UC Davis, UC San Diego and other institutions has identified a key mechanism behind aggressive prostate cancer. Published on August 14, 2013 in Nature, the study shows that two long non-coding RNAs (PRNCR1 and PCGEM1) activate androgen receptors, circumventing androgen-deprivation therapy. In their active state, these receptors turn on genes that spur growth and metastasis, making these cancers highly treatment-resistant. The study illustrates how prostate cancer can thrive, even when deprived of hormones, and provides tempting targets for new therapies.

"Androgen-deprivation therapy will often put cancer in remission, but tumors come back, even without testosterone," said contributor Christopher Evans, professor and chair of the Department of Urology at the UC Davis School of Medicine. "We found that these long non-coding RNAs were activating the androgen receptor. When we knocked them out, cancer growth decreased in both cell lines and tumors in animals."

Evans' UC Davis group was part of a larger team, led by Michael Geoff Rosenfeld, professor at the Howard Hughes Medical Institute in the School of Medicine at UC San Diego, which has been eager to determine how androgen-dependent cancers become androgen-independent (also called castration-resistant). These prostate cancers are very aggressive and usually fatal, but their continued growth, despite being deprived of hormones, is just now being better understood. It's not unlike removing the key from a car ignition, only to have the vehicle re-start on its own.

In this case, the aberrant starting mechanisms are long non-coding RNAs, a class of genetic material that regulates gene expression but does not code for proteins. Using patient samples from UC Davis, the group determined that both PRNCR1 and PCGEM1 are highly expressed in aggressive tumors. These RNAs bind to androgen receptors and activate them in the absence of testosterone, turning on as many as 617 genes.

Further investigation determined that one of these long non-coding RNAs is turning on androgen receptors by an alternate switching mechanism, like a car with a second ignition. This is critically important because many prostate cancer treatments work by blocking a part of the androgen receptor called the C-terminus. However, PCGEM1 activates another part of the receptor, called the N-terminus, which also turns on genes - with bad results.

"The androgen receptor is unique, if you knock out the C-terminus, that remaining part still has the ability to transcribe genes," said Evans.

In addition, about 25 percent of these cancers have a mutated version of the androgen receptor that has no C-terminus. These receptors are locked in the "on" position, activating genes associated with tumor aggression.

Regardless of the receptor's status, PRNCR1 and PCGEM1 are crucial to prostate cancer growth. In turn, knocking out these RNAs has a profound impact on gene expression, both in cell lines and animal models. The team used complementary genetic material, called antisense, to knock out the RNAs and observe how the tumors and cells responded. In each case, there was a direct relationship between RNA activity, gene expression and cancer growth.

"These long non-coding RNAs are a required component for these castration-resistant cancers to keep growing," said Evans. "Now we have preclinical proof of principle that if we knock them out, we decrease cancer growth."

The research team's next step is developing treatments that specifically target these long non-coding RNAs. That process has already begun.

"Most treatments for castration-resistant prostate cancer will get us around two to three years of survival," said Evans. "We rarely cure these patients. The tumor will continue to evolve resistance mechanisms. But now that we have additional insight into what's activating these receptors, we can begin developing new types of therapies to prevent it."

First pre-clinical gene therapy study to reverse Rett symptoms

The concept behind gene therapy is simple: deliver a healthy gene to compensate for one that is mutated. New research published today in the Journal of Neuroscience suggests this approach may eventually be a feasible option to treat Rett Syndrome, the most disabling of the autism spectrum disorders. Gail Mandel, Ph.D., a Howard Hughes Investigator at Oregon Health and Sciences University, led the study. The Rett Syndrome Research Trust, with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation, funded this work through the MECP2 Consortium.

In 2007, co-author Adrian Bird, Ph.D., at the University of Edinburgh astonished the scientific community with proof-of-concept that Rett is curable, by reversing symptoms in adult mice. His unexpected results catalyzed labs around the world to pursue a multitude of strategies to extend the pre-clinical findings to people.

Today's study is the first to show reversal of symptoms in fully symptomatic mice using techniques of gene therapy that have potential for clinical application.

Rett Syndrome is an X-linked neurological disorder primarily affecting girls; in the US, about 1 in 10,000 children a year are born with Rett. In most cases symptoms begin to manifest between 6 and 18 months of age, as developmental milestones are missed or lost. The regression that follows is characterized by loss of speech, mobility, and functional hand use, which is often replaced by Rett's signature gesture: hand-wringing, sometimes so intense that it is a constant during every waking hour. Other symptoms include seizures, tremors, orthopedic and digestive problems, disordered breathing and other autonomic impairments, sensory issues and anxiety. Most children live into adulthood and require round-the-clock care.

The cause of Rett Syndrome's terrible constellation of symptoms lies in mutations of an X-linked gene called MECP2 (methyl CpG-binding protein). MECP2 is a master gene that regulates the activity of many other genes, switching them on or off.

"Gene therapy is well suited for this disorder," Dr. Mandel explains. "Because MECP2 binds to DNA throughout the genome, there is no single gene currently that we can point to and target with a drug. Therefore the best chance of having a major impact on the disorder is to correct the underlying defect in as many cells throughout the body as possible. Gene therapy allows us to do that."

Healthy genes can be delivered into cells aboard a virus, which acts as a Trojan horse. Many different types of these Trojan horses exist. Dr. Mandel used adeno-associated virus serotype 9 (AAV9), which has the unusual and attractive ability to cross the blood-brain barrier. This allows the virus and its cargo to be administered intravenously, instead of employing more invasive direct brain delivery systems that require drilling burr holes into the skull.

Because the virus has limited cargo space, it cannot carry the entire MECP2 gene. Co-author Brian Kaspar of Nationwide Children's Hospital collaborated with the Mandel lab to package only the gene's most critical segments. After being injected into the Rett mice, the virus made its way to cells throughout the body and brain, distributing the modified gene, which then started to produce the MeCP2 protein.

As in human females with Rett Syndrome, only approximately 50% of the mouse cells have a healthy copy of MECP2. After the gene therapy treatment 65% of cells now had a functioning MECP2 gene.

The treated mice showed profound improvements in motor function, tremors, seizures and hind limb clasping. At the cellular level the smaller body size of neurons seen in mutant cells was restored to normal. Biochemical experiments proved that the gene had found its way into the nuclei of cells and was functioning as expected, binding to DNA.

One Rett symptom that was not ameliorated was abnormal respiration. Researchers hypothesize that correcting this may require targeting a greater number of cells than the 15% that had been achieved in the brainstem.

"We learned a critical and encouraging point with these experiments - that we don't have to correct every cell in order to reverse symptoms. Going from 50% to 65% of the cells having a functioning gene resulted in significant improvements," said co-author Saurabh Garg.

One of the potential challenges of gene therapy in Rett is the possibility of delivering multiple copies of the gene to a cell. We know from the MECP2 Duplication Syndrome that too much of this protein is detrimental. "Our results show that after gene therapy treatment the correct amount of MeCP2 protein was being expressed. At least in our hands, with these methods, overexpression of MeCP2 was not an issue," said co-author Daniel Lioy.

Dr. Mandel cautioned that key steps remain before clinical trials can begin. "Our study is an important first step in highlighting the potential for AAV9 to treating the neurological symptoms in Rett. We are now working on improving the packaging of MeCP2 in the virus to see if we can target a larger percentage of cells and therefore improve symptoms even further," said Mandel. Collaborators Hélène Cheval and Adrian Bird see this as a promising follow up to the 2007 work showing symptom reversal in Rett mice. "That study used genetic tricks that could not be directly applicable to humans, but the AAV9 vector used here could in principle deliver a gene therapeutically. This is an important step forward, but there is a way to go yet."

"Gene therapy has had a tumultuous road in the past few decades but is undergoing a renaissance due to recent technological advances. Europe and Asia have gene therapy treatments already in the clinic and it's likely that the US will follow suit. Our goal now is to prioritize the next key experiments and facilitate their execution as quickly as possible. Gene therapy, especially to the brain, is a tricky undertaking but I'm cautiously optimistic that with the right team we can lay out a plan for clinical development. I congratulate the Mandel and Bird labs on today's publication, which is the third to be generated from the MECP2 Consortium in a short period of time," said Monica Coenraads, Executive Director of the Rett Syndrome Research Trust and mother of a teenaged daughter with the disorder.