Scientists unlock potential of frog skin to treat cancer

ScienceDaily (June 7, 2011) — Scientists at Queen's University Belfast have discovered proteins in frog skins which could be used to treat cancer, diabetes, stroke and transplant patients by regulating the growth of blood vessels.

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The award-winning research, led by Professor Chris Shaw at Queen's School of Pharmacy, has identified two proteins, or 'peptides', which can be used in a controlled and targeted way to regulate 'angiogenesis' -- the process by which blood vessels grow in the body. The discovery holds the potential to develop new treatments for more than seventy major diseases and conditions that affect more than one billion people worldwide.

The proteins are found in secretions on the skins of the Waxy Monkey Frog and the Giant Firebellied Toad. Scientists capture the frogs and gently extract the secretions, before releasing them back in to the wild. The frogs are not harmed in any way during this process.

Professor Shaw said: "The proteins that we have discovered have the ability to either stimulate or inhibit the growth of blood vessels. By 'switching off' angiogenesis and inhibiting blood vessel growth, a protein from the Waxy Monkey Frog has the potential to kill cancer tumours. Most cancer tumours can only grow to a certain size before they need blood vessels to grow into the tumour to supply it with vital oxygen and nutrients. Stopping the blood vessels from growing will make the tumour less likely to spread and may eventually kill it. This has the potential to transform cancer from a terminal illness into a chronic condition.

"On the other hand, a protein from the Giant Firebellied Toad has been found to 'switch on' angiogenesis and stimulate blood vessel growth. This has the potential to treat an array of diseases and conditions that require blood vessels to repair quickly, such as wound healing, organ transplants, diabetic ulcers, and damage caused by strokes or heart conditions."

Explaining how his research team looks to the natural world to solve problems where other methods of drug discovery have failed, Professor Shaw said: "Because of its huge potential, angiogenesis has been a prime target for drugs development research over the past forty years. But despite an investment of around $4-5 billion by scientists and drugs companies around the world, they have yet to develop a drug that can effectively target, control and regulate the growth of blood vessels.

"The aim of our work at Queen's is to unlock the potential of the natural world -- in this case the secretions found on frog and toad skins -- to alleviate human suffering. We are absolutely convinced that the natural world holds the solutions to many of our problems, we just need to pose the right questions to find them.

"It would be a great shame to have something in nature that is potentially the wonder drug to treat cancer and not aim to do everything in our power to make it work."

The Queen's researchers will receive the Commendation in the Cardiovasular Innovation Award at the Medical Futures Innovation Awards in London June 6, 2011. The Awards are one of Europe's most prestigious healthcare and business awards, rewarding innovative ideas from front line clinicians, scientists and entrepreneurs. Professor Shaw's team are the only entry from Northern Ireland to be successful at this year's awards.

Congratulating Professor Shaw and his colleagues, Professor Brian Walker and Dr Tianbao Chen, on their commendation award, Queen's Vice-Chancellor Professor Peter Gregson said: "This award is not only an honour for Professor Shaw and his team, it is recognition of the world-class research taking place at Queen's School of Pharmacy, and the life-changing potential of the University's work in drug discovery."

For more information on the Medical Futures Innovation Awards 2011 visit: www.medicalfutures.co.uk

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Scientists create humanized mouse model for hepatitis C

ScienceDaily (June 8, 2011) — Scientists at Rockefeller University and The Scripps Research Institute have developed the first genetically humanized mouse model for hepatitis C, an achievement that will enable researchers to test molecules that block entry of the hepatitis C virus into cells as well as potential vaccine candidates.

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The finding is reported in the June 9 issue of the journal Nature.

While the hepatitis C virus can infect chimpanzees and humans, scientists have been unable to study the progression of the virus' life cycle or possible treatments in small animal models. The new mouse model is the first to be developed with a fully functioning immune system.

"Our genetically humanized mouse model for hepatitis C will allow us to gain deeper insights in the biology of this important pathogen," says senior author Alexander Ploss, a research assistant professor at Rockefeller. "This robust small animal model also has the potential to serve a critical role in testing and prioritizing drug and vaccine candidates. Results from these tests can potentially guide more expensive pre-clinical and clinical studies in higher order organisms, including humans."

The development of this mouse model is the culmination of several years of research by scientists in the laboratory of Charles M. Rice and other research groups. In 2006, Rice and his colleagues were the first to successfully create a strain of hepatitis C in the laboratory, which can efficiently be grown in the laboratory, and is also infectious in animals. More recently, Rice, Ploss and their colleagues discovered that hepatitis C virus infection requires previously identified CD81 and scavenger receptor type B class I, as well as two tight junction molecules, claudin 1 and occludin. The Rockefeller researchers showed that human CD81 and occludin were required for hepatitis C virus to enter mouse cells.

In the new study, the Rockefeller researchers and colleagues at The Scripps Research Institute tested whether introducing some of these previously identified human genes into mice would allow them to infect the animals with the hepatitis C virus. The researchers compared two groups of mice: one group expressed two genes, CD81 and occludin, while mice in the second group were normal. They found that expression of human CD81 and human occludin in the mouse liver rendered the animals susceptible to HCV infection. Ploss and his colleagues also developed a novel reporter system, which allowed them to sensitively detect HCV infection in living animals.

"We have established a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class 1, a molecule that is being considered as a novel antiviral drug target, for HCV uptake in a living animal," says Charles M. Rice, Maurice R. and Corinne P. Greenberg Professor and head of the Laboratory of Virology and Infectious Disease at Rockefeller. Rice also is executive and scientific director of the Center for the Study of Hepatitis C, an interdisciplinary center established jointly by The Rockefeller University, NewYork-Presbyterian Hospital and Weill Cornell Medical College.

Worldwide at least 130 million people are chronically infected with HCV, which poses a risk of severe liver injury and liver cancer. Current treatments are only partially effective and have considerable side effects, and a vaccine against hepatitis C does not exist.

"The global HCV epidemic mandates the development of more effective therapeutics including a vaccine," says Ploss. "This mouse model is a first step toward a platform that effectively serves this purpose."

This research was supported in part by the National Institutes of Health.

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Multitasking meds: Scientists discover how drug for leukemia, psoriasis, may tackle vascular disease

ScienceDaily (May 26, 2011) — A drug that has been on the market for decades to treat leukemia and skin disorders such as acne and psoriasis may be a possible therapy for vascular diseases, including atherosclerosis and hypertension, which can lead to heart attack or stroke.

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Previously, researchers discovered that retinoids -- commonly used natural or human-made drugs related to vitamin A -- blunted experimental vascular disease by spurring into action a very particular segment of a gene known for its ability to curb cancer cell growth.

The gene, usually shut off or silenced in cancer cells, enabling tumors to form, could be an attractive treatment target not only for vascular diseases, which involve the detrimental growth, spread and accumulation of cells in blood vessels, but for a wide range of cancers, which involve unchecked cell growth, as well.

In the journal PLoS One, a team of researchers led by Joseph M. Miano, Ph.D., associate director of the Aab Cardiovascular Research Institute at the University of Rochester Medical Center, found that a specific section of the complex AKAP12 gene, called AKAP12 beta, is extremely responsive to treatment with retinoids, and that ramping up its activity reduces vascular cell growth.

"Several studies have shown that when this gene is turned on, it decreases the growth of cancer cells, but this is the first time anyone's shown its ability to inhibit growth in non-cancer cells," said Miano, the study's lead author. "In addition to the vascular angle, we hope this work inspires researchers in different disciplines to see if our findings apply in other disease contexts."

A vascular biologist, Miano became interested in retinoids after people close to him battled cancer. When he learned that retinoids, which have several actions, including regulating cell growth, were a treatment option for some cancer patients, he wondered if they might have any use in treating diseases of blood vessels. Like cancer, vascular diseases such as atherosclerosis -- the narrowing of the arteries -- involve excessive cell growth and invasion. Such activities can lead to blocked arteries that obstruct blood flow.

Miano decided to give the idea a try, and in the late 1990's he showed in tissue and in an animal model of vascular disease that retinoids inhibited the growth of smooth muscle cells, which are found within the walls of vessels and contribute to atherosclerosis, which can lead to heart attack or stroke.

In the early 2000's, his team identified a number of genes that were activated or turned on by retinoids, one of which was AKAP12. Because research in the cancer field suggested it was a tumor suppressor gene, named for its ability to hinder cancer cell growth, Miano honed in on AKAP12 to see if it might be a target of retinoids in the context of vascular disease.

The team discovered that AKAP12 is a very complex gene, with three distinct DNA segments, named AKAP12 alpha, beta and gamma. Miano noted, "It is essentially like having three genes in one." Gene expression analyses revealed that the treatment of damaged vessels with retinoids immediately stimulated AKAP12 beta into action, while the alpha and gamma segments showed no response to the therapy.

"There are lots of tumor suppressor genes out there, and a few are mildly responsive to retinoids, but this is the first time we've seen a gene -- AKAP12 beta -- respond so early and so profoundly to retinoid stimulation," said Miano. "Without AKAP12 beta up and running, it is as if there are no brakes and the smooth muscle cells are free to grow. But when AKAP12 beta is amplified, the opposite is true, and we see major decreases in smooth muscle cell growth."

Once AKAP12 beta is switched into "go" mode by retinoids, the team believes it helps deter cell growth by reigning in and directing the action of specific signaling proteins that influence cell growth and migration. More research is needed to pin down the exact processes involved, and Miano hopes to pursue this work in the future by exploring animal models in which AKAP12 is eliminated or turned on with drugs.

According to Irwin H. Gelman, Ph.D., who was the first to identify the AKAP12 gene and has been studying its role in cancer for many years, "This study makes sense and is very consistent with what we've found in cancer cells, which is that AKAP12 is a prime driver to stop the proliferation of cells." Gelman, a study author who has worked with Miano for more than ten years, is the Palisano Chair of Cancer Genetics at Roswell Park Cancer Institute in Buffalo, New York.

"It may be possible that other diseases marked by inappropriate cell proliferation due to AKAP12 turn-off could also be reversed by retinoid treatment," added Gelman.

In addition to Miano, Jeffrey W. Streb, Xiaochun Long, Ting-Hein Lee, Qiang Sun, Chad M. Kitchen, Mary A. Georger, and Orazio J. Slivano from the Aab Cardiovascular Research Institute contributed to the research. Gelman, William S. Blaner, Columbia University, and Daniel W. Carr, Portland Veterans Affairs Medical Center participated in the research as well. The study was funded by the National Heart, Lung and Blood Institute at the National Institutes of Health and the Department of Veterans Affairs at the Veterans Health Administration.

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Stem cell treatment to prevent leukemia returning is a step closer, say scientists

ScienceDaily (June 3, 2011) — Researchers at King's College London have identified a way of eliminating leukemic stem cells, which could lead to new treatments that may enable complete remission for leukemia patients. An early study in mice has shown that leukemic stem cells can be abolished by suppressing two proteins found in the body.

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Leukemic stem cells sustain the disease and are likely to be responsible for relapse, so elimination of these cells is believed to be key for achieving complete remission. These encouraging findings highlight the two proteins as potential therapeutic targets to prevent the most aggressive forms of leukemia returning. The study, funded by Cancer Research UK and leukemia Lymphoma Research, is to be published in the journal Cell Stem Cell.

King's scientists looked at leukemic stem cells found in a type of leukemia that involves mutations of the MLL gene. This accounts for around 70 per cent of infant leukemias and 10 per cent of adult acute leukemias. The prognosis for MLL in children is not good -- only 50 per cent survive past two years after receiving standard treatment.

The protein Bmi1 was already known to play a key role in the survival and proliferation of various cancer stem cells. But this study has for the first time shown that, although the protein is needed for survival of various Acute Myeloid leukemia (AML) cells, in MLL leukemia the cancer stem cells actually survive independently of Bmi1. This shows that for these MLL patients, targeting Bmi1 alone would not have a major impact on eradicating leukemic stem cells, as was previously thought.

However, the team also found high levels of another protein called Hoxa9 in the MLL mice and human patients. Similar to Bmi1, a major role of this protein is to ensure leukemia cells divide and grow by allowing their escape from the inherent surveillance system, which will otherwise cause cell death. They found that in mice with MLL leukemic stem cells (that can proliferate without Bmi1), suppression of both Bmi1 and Hoxa9 completely abolishes the ability of MLL mutation to induce leukemia.

These findings provide evidence for the different pathways involved in the development of different types of leukemic stem cells, and highlight the importance of targeting Bmi1 and Hoxa9 together to abolish MLL leukemic stem cells in particular.

Professor Eric So, Head of the leukemia and Stem Cell Biology group at King's, said: 'These findings take us a step forward in our understanding of how this devastating disease can return in patients after they have received the standard treatment.

'Now we know that leukemic stem cells in certain types of leukemia, such as MLL, can survive and proliferate independently of the Bmi1 protein, we need to consider more carefully the future of stem cell therapy to treat the disease. It's not as easy as people originally thought it might be.

'But these findings provide us with vital information that will help us look at alternative ways of combating different forms of the disease, which will ultimately allow patients to achieve long-term complete remission.

'What we need to do now is to find out exactly how Bmi1 and Hoxa9 proteins sustains the growth of cancer cells in order to develop an effective treatment to stop the disease returning.'

Professor Peter Johnson, Cancer Research UK's chief clinician, said: 'This study builds on previous Cancer Research UK-funded work trying to pinpoint the molecules responsible for driving the development of MLL-related leukemia stem cells.

'Cancer stem cells appear to be more resistant to radiotherapy and chemotherapy than the other leukemia cells, so understanding how they originate -- and how we can kill them -- will be a major step in being able to help even more people survive leukemia in future.'

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Cancer scientists discover new way breast cancer cells adapt to environmental stress

ScienceDaily (May 14, 2011) — An international research team led by Dr. Tak Mak, Director, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital (PMH), has discovered a new aspect of "metabolic transformation," the process whereby tumour cells adapt and survive under conditions that would kill normal cells.

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The findings, published May 15 in Genes and Development, show how breast cancer cells can thrive when deprived of their usual diet of glucose (sugar) and oxygen by turning to fatty acids for energy generation.

"Our results demonstrate that a protein not previously associated with breast cancer is involved in helping these cells to adapt to starvation conditions and to continue their uncontrolled growth," says Dr. Mak, principal investigator and Weekend to End Breast Cancer Chair in Breast Cancer Research at PMH. Dr. Mak is also a Professor at the University of Toronto in the Departments of Medical Biophysics and Immunology.

In the lab, researchers used an anticancer drug called rapamycin to block a molecular signalling pathway within breast cancer cells that stimulates sugar metabolism. However, instead of dying of starvation, the cells continued to multiply. The team also observed an increase in these cells of carnitine palmitoyltransferase 1C (CPT1C), a protein usually found only in the brains of healthy individuals. Moreover, cells engineered to produce high levels of CPT1C were also able to adapt their metabolism as a survival technique.

"In other words," says Dr. Mak, "The cancer cells acted like cheaters on a diet and found a new food source in fatty acids.

"The fact that CPT1C becomes expressed under conditions of metabolic stress highlights the resilience of cancer cells. They are able to adapt to environmental challenges and find alternative sources of food in order to flourish where healthy cells would not survive."

"Our discovery that deprivation of either sugar or oxygen spurs CPT1C expression in tumour cells marks this protein as a potential target for new drug development," says Dr. Mak.

"We also demonstrated that cells that were prevented from using CPT1C to cope with a disruption in sugar metabolism became more sensitive to environmental stress. These findings represent an important stepping stone to developing targeted therapies that can block cancer cells from adapting to environmental challenges and surviving efforts to kill them."

This most recent discovery builds on Dr. Mak's impressive body of work, which has led to important breakthroughs in immunology and our understanding of cancer at the molecular level. Dr. Mak is known for his 1984 landmark scientific paper on the cloning of the genes for the T cell receptor, a key component of the human immune system.

The research published May 15 was financially supported by grants from the Canadian Institutes of Health Research, The Princess Margaret Hospital Foundation, The Canadian Cancer Society, the Forschungskredit of the University of Zurich and Oncosuisse.

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Scientists find new drug target in breast cancer

ScienceDaily (May 22, 2011) — Researchers have identified a new protein involved in the development of drug resistance in breast cancer which could be a target for new treatments, they report May 22 in the journal Nature Medicine.

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In a mouse model of breast cancer, blocking production of the protein using genetic techniques caused tumours to shrink. The scientists are now looking for new drugs which could achieve a similar effect.

Breast cancer is the most common cancer in the UK, affecting about 46,000 women each year. More than two thirds of breast tumours contain oestrogen receptors, meaning that they require the hormone oestrogen to grow and they can be treated with anti-oestrogen drugs such as tamoxifen. However, many patients develop resistance to these treatments so that the drugs eventually cease to be effective.

In the study, researchers from Imperial College London found that blocking a protein called LMTK3 in human cancer cells that were resistant to tamoxifen made the cells more responsive to the drug. In a mouse model of the disease, using genetic techniques to block the production of LMTK3 led to a significant decrease in the size of breast tumours.

The researchers also measured levels of LMTK3 in tissue samples taken from women with breast cancer. They found that women who had higher levels of LMTK3 in their tumours tended to live less long and were less likely to respond to hormone therapy. In addition, they found that particular mutations in the gene coding for LMTK3 also correlated with how long a patient would survive.

"Anti-oestrogen drugs have been very successful at allowing women with breast cancer to live longer, but resistance to these drugs is a common problem," said Professor Justin Stebbing, from the Department of Surgery and Cancer at Imperial College London, the study's senior author. "Our results suggest that the action of LMTK3 on the oestrogen receptor has a crucial role in the development of drug resistance.

"We're now looking for drugs that can block the effect of LMTK3, which we could hopefully give to patients to prevent them from becoming resistant to hormone therapy. It will probably take at least five to ten years to develop new treatments that are safe to be used in humans."

Evidence from the laboratory suggests that resistance to hormone therapy might occur when the oestrogen receptor is modified by enzymes called kinases. The team identified LMTK3 as a potential treatment target by screening for kinases that affect how cancer cells respond to oestrogen.

The researchers also compared DNA sequences in the gene coding for LMTK3 in humans and chimpanzees, because chimpanzees are not susceptible to oestrogen receptor positive breast cancer. They found that substantial differences have evolved in these sequences between the two species.

"It's quite intriguing that humans and chimps have evolved these differences in the LMTK3 gene, since related genes are very similar between the two species," said Dr Georgios Giamas, who designed and led the study, from the Department of Surgery and Cancer at Imperial College London.

"We could speculate that evolutionary changes in this gene might have given humans some unknown advantage, but also have made us more susceptible to breast cancer."

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