Press Room
August 2010
Contact:
Ben Norman
+44 (0) 1243 770375
Lifesciencenews@wiley.com
Gene Therapy Breakthrough Heralds Treatment for β-thalassemia
Italian scientists pioneering a new gene transfer treatment for the blood disorder β-thalassemia have successfully completed preclinical trials, claiming they can correct the lack of beta-globin (ß-globin) in patients’ blood cells which causes the disease. The research, published in EMBO Molecular Medicine, reveals how gene therapy may represent a safe alternative to current cures that are limited to a minority of patients.
The disorder β-thalassemia, also known as Cooley’s anemia, is caused when a patient cannot produce enough of the ß-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. The lack of ß-globin causes life threatening anemia, leading to severe damage of the body’s major organs. The condition is most commonly found in Mediterranean, Middle Eastern and Asian populations.
“Currently treatments are limited to lifelong regular blood transfusions, and iron chelation to prevent fatal iron overload. The alternative is bone marrow transplantation, an option open to less than 25% of patients,” said Dr Giuliana Ferrari from the San Raffaele Telethon Institute for Gene Therapy in Milan. “Our research has focused on gene therapy: by transplanting genetically corrected stem cells we can restore haemoglobin production and overcome the disorder.”
Diseases of the blood are good targets for gene therapy because it is possible to harvest stem cells from the patient’s bone marrow. The team developed a tool to deliver the correct gene for ß-globin into these harvested cells, a viral vector they called GLOBE.
The cells can then be genetically modified with GLOBE to restore hemoglobin production before being re-administered back into the patient via intravenous injections. The important focus of this work was not only to show that GLOBE can restore haemoglobin production in human cells, but that this genetic transfer-based approach does not impair the biological features of the cells and is not associated with any intrinsic risk for the human genome.
This research is not only crucial for developing a cure for one disease, but as Dr David Williams from the Harvard Medical School says, it may advance the entire discipline of gene therapy research
“This work represents the kind of translational studies that are required to move human investigations forward but are often difficult to fund and publish,” said Williams. “Considering the inherent difficulties accompanying human research, studies like those reported in EMBO Molecular Medicine are extremely important for moving the field forward.” As the Milan based team can now correct the defective production of beta-globin in patients’ blood cells the next step will be to place the corrected cells back into the patient, a step which has already proven successful in mice.
Successful gene therapies are the results of very long studies and our research represents the most comprehensive pre-clinical analysis ever performed on cells derived from thalassemic patients” concluded Ferrari. “We believe this study paves the way forward for the clinical use of stem cells genetically corrected using the GLOBE vector.”
This study is published in EMBO Molecular Medicine . Media wishing to receive a PDF of this article may contact Lifesciencenews@wiley.com
Full citation:
Roselli E.A., Mezzadra. R, Frittoli M.C., Maruggi. G, Biral. E, Mavilio. F, Mastropietro. F, Amato. A, Tonon. G, Refaldi. C, Cappellini M.D., Andreani M., Lucarelli G. , Roncarolo M.G., Marktel S. and Ferrari G. “Correction of ß-thalassemia major by gene transfer in hematopoietic progenitors of pediatric patients.” EMBO Molecular Medicine, Wiley-Blackwell, July 2010.
DOI: 10.1002/emmm.201000083
Closeup paper citation:
Milsom M.D., Williams D.A., Gaining the hard yard: pre-clinical evaluation of lentiviral-mediated gene therapy for the treatment of β-thalassemia, EMBO Molecular Medicine, Wiley-Blackwell, July 2010, DOI :10.1002/emmm.201000086
About the Author: The corresponding author for this paper is Dr Giuliana Ferrari, who conducts research from San Raffaele Telethon institute for Gene Therapy (HSR-TIGET) at the San Raffaele Scientific institute in Milan, Italy. To contact the author please do so via Lifesciencenews@wiley.com
March 2010
Targeting leukemia cell's gene 'addiction' presents new strategy for treatment
An international team of scientists studying acute forms of Leukaemia have identified a new drug target to inhibit the genes which are vital for the growth of diseased cells. The research, reported in EMBO Molecular Medicine, reveals how leukaemia cells become 'addicted' to genes, which if targeted could prevent diseased cells from developing.
The team, led by Dr Veronika Sexl from the University of Vienna, carried out their research on acute lymphoid leukaemia (ALL) and chronic myelogenous leukaemia (CML), which can both be caused by fusion protein, Bcr-Abl, created through the joining of two or more genes originally coded for separate proteins.
This joining of genes results in a complex tumor supporting 'network' which supports the growth and survival of the leukaemic cells. Inhibitor drugs such as 'Imatinib' can block vital signals and lead to leukemia cell death, but there are several mutations which can resist these inhibitors, making them ineffective.
As an alternative strategy the team investigated transcription factors Stat3 and Stat5 which are linked to bcr/abl-induced transformation. The team tested whether Stat3 and Stat5, acting downstream of Bcr-Abl are critical for leukaemia maintenance and if they could be a alternative target for treatment.
"We developed a tumour-specific gene-deletion approach to analyse the roles of Stat5 and Stat3 in Bcr/Abl-induced leukaemia growth," said Sexl. "We discovered that both factors are required for the development of Bcr-Abl, but once established only Stat5 is crucial for the survival and growth of leukemic Cells."
Even mutated forms of bcr-abl, Leukaemia cells, which are resistant to inhibiting drugs such as Imatinib, are still dependent on Stat5.
"Cancer cells undergo extensive adaptations in their signalling and metabolic pathways, thereby becoming dependent on certain genes," said Sexl. "In fact the activity of these genes can become limiting for a cancer cell."
The term 'Non-oncogene addication' (NOA) has been coined to describe this phenomenon of gene dependency and inhibiting these critical genes within the signalling network is predicted to cause system failure and halt the growth of leukaemia cells.
"In this study we demonstrated that bcr-abl, Leukaemia cells are addicted to Stat5 to maintain the leukameic state, concluded Sexl. "We've identified Stat5 as an Achilles' heel in the signalling network downstream of Bcr-Abl. Thus, inhibition of Stat5 may provide a novel therapeutic approach for treatment of leukaemia."
Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia
Andrea Hoelbl, Christian Schuster, Boris Kovacic, Bingmei Zhu, Mark Wickre, Maria A. Hoelzl, Sabine Fajmann, Florian Grebien, Wolfgang Warsch, Gabriele Stengl, Lothar Hennighausen, Valeria Poli, Hartmut Beug, Richard Moriggl, Veronika Sexl
EMBO Mol Med Vol 2(3)
# DOI: 10.1002/emmm.201000062
Scientists discover clues to what makes human muscle age
A study led by researchers at the University of California, Berkeley, has identified critical biochemical pathways linked to the aging of human muscle. By manipulating these pathways, the researchers were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.
"Our study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals," said Professor Irina Conboy, a faculty member in the graduate bioengineering program that is run jointly by UC Berkeley and UC San Francisco, and head of the research team conducting the study. "This provides promising new targets for forestalling the debilitating muscle atrophy that accompanies aging and perhaps other tissue degenerative disorders as well."
Previous research in animal models led by Conboy, who is also an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), revealed that the ability of adult stem cells to do their job of repairing and replacing damaged tissue is governed by the molecular signals they get from surrounding muscle tissue, and that those signals change with age in ways that preclude productive tissue repair.
Those studies have also shown that the regenerative function in old stem cells can be revived given the appropriate biochemical signals. What was not clear until this new study was whether similar rules applied for humans. Unlike humans, laboratory animals are bred to have identical genes and are raised in similar environments, noted Conboy, who received a New Faculty Award from the California Institute of Regenerative Medicine (CIRM) that helped fund this research. Moreover, the typical human lifespan lasts seven to eight decades, while lab mice are reaching the end of their lives by age 2.
Working in collaboration with Dr. Michael Kjaer and his research group at the Institute of Sports Medicine and Centre of Healthy Aging at the University of Copenhagen in Denmark, the UC Berkeley researchers compared samples of muscle tissue from nearly 30 healthy men who participated in an exercise physiology study. The young subjects ranged from age 21 to 24 and averaged 22.6 years of age, while the old study participants averaged 71.3 years, with a span of 68 to 74 years of age.
In experiments conducted by Dr. Charlotte Suetta, a post-doctoral researcher in Kjaer's lab, muscle biopsies were taken from the quadriceps of all the subjects at the beginning of the study. The men then had the leg from which the muscle tissue was taken immobilized in a cast for two weeks to simulate muscle atrophy. After the cast was removed, the study participants exercised with weights to regain muscle mass in their newly freed legs. Additional samples of muscle tissue for each subject were taken at three days and again at four weeks after cast removal, and then sent to UC Berkeley for analysis.
Morgan Carlson and Michael Conboy, researchers at UC Berkeley, found that before the legs were immobilized, the adult stem cells responsible for muscle repair and regeneration were only half as numerous in the old muscle as they were in young tissue. That difference increased even more during the exercise phase, with younger tissue having four times more regenerative cells that were actively repairing worn tissue compared with the old muscle, in which muscle stem cells remained inactive. The researchers also observed that old muscle showed signs of inflammatory response and scar formation during immobility and again four weeks after the cast was removed.
"Two weeks of immobilization only mildly affected young muscle, in terms of tissue maintenance and functionality, whereas old muscle began to atrophy and manifest signs of rapid tissue deterioration," said Carlson, the study's first author and a UC Berkeley post-doctoral scholar funded in part by CIRM. "The old muscle also didn't recover as well with exercise. This emphasizes the importance of older populations staying active because the evidence is that for their muscle, long periods of disuse may irrevocably worsen the stem cells' regenerative environment."
At the same time, the researchers warned that in the elderly, too rigorous an exercise program after immobility may also cause replacement of functional muscle by scarring and inflammation. "It's like a Catch-22," said Conboy.
The researchers further examined the response of the human muscle to biochemical signals. They learned from previous studies that adult muscle stem cells have a receptor called Notch, which triggers growth when activated. Those stem cells also have a receptor for the protein TGF-beta that, when excessively activated, sets off a chain reaction that ultimately inhibits a cell's ability to divide.
The researchers said that aging in mice is associated in part with the progressive decline of Notch and increased levels of TGF-beta, ultimately blocking the stem cells' capacity to effectively rebuild the body.
This study revealed that the same pathways are at play in human muscle, but also showed for the first time that mitogen-activated protein (MAP) kinase was an important positive regulator of Notch activity essential for human muscle repair, and that it was rendered inactive in old tissue. MAP kinase (MAPK) is familiar to developmental biologists since it is an important enzyme for organ formation in such diverse species as nematodes, fruit flies and mice.
For old human muscle, MAPK levels are low, so the Notch pathway is not activated and the stem cells no longer perform their muscle regeneration jobs properly, the researchers said.
When levels of MAPK were experimentally inhibited, young human muscle was no longer able to regenerate. The reverse was true when the researchers cultured old human muscle in a solution where activation of MAPK had been forced. In that case, the regenerative ability of the old muscle was significantly enhanced.
"The fact that this MAPK pathway has been conserved throughout evolution, from worms to flies to humans, shows that it is important," said Conboy. "Now we know that it plays a key role in regulation and aging of human tissue regeneration. In practical terms, we now know that to enhance regeneration of old human muscle and restore tissue health, we can either target the MAPK or the Notch pathways. The ultimate goal, of course, is to move this research toward clinical trials."
Other co-authors of the EMBO Molecular Medicine paper include Abigail Mackey at the University of Copenhagen in Denmark, and Per Aagaard at the University of Southern Denmark.
Carlson.M, Suetta.C, Conboy.M, Aagaard.P, Mackey.A, Kjaer.M, Conboy.I, ‘Molecular aging and rejuvenation of human muscle stem cells’, EMBO, Wiley-Blackwell, 2009,
DOI 10.1002/emmm.200900045
Breakthrough Breast Cancer scientists discover that a new targeted treatment could treat tens of thousands of cancer patients in the UK each year
Breakthrough Breast Cancer scientists have discovered that a new treatment could treat many more types of cancer than previously thought, potentially helping tens of thousands of cancer patients in the UK each year.
Scientists from the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research (ICR) showed that PARP inhibitors can kill cancer cells with a faulty PTEN gene while leaving healthy cells relatively unharmed. They showed that cells with faulty PTEN genes were up to 25 times more sensitive to PARP inhibitors than cells with normal PTEN, according to results published today (16 September) in the journal EMBO Molecular Medicine.
Faults in the PTEN gene are common in a range of cancers, accounting for between 30 and 80% of breast, prostate, melanoma (skin), endometrial (womb) and colon cancers. Nearly 46,000 women are diagnosed with breast cancer in the UK each year, with just under 12,000 women dying of the disease.
PARP inhibitors, including Olaparib which was developed from Breakthrough Breast Cancer research and used in this study, are currently in clinical trials for breast and ovarian cancers. They are showing considerable promise in certain subtypes such as those with BRCA mutations.
Professor Alan Ashworth, Director of the Breakthrough Breast Cancer Research Centre at the ICR, said: “These results are exciting because they show that PARP inhibitors are potentially a targeted treatment with few side effects for a broad range of cancer patients.
“Clinical trials have already shown the potential of PARP inhibitors for patients with tumours caused by faulty BRCA genes. We now need to test whether these very promising results can be matched in the much larger group of patients with PTEN-related tumours.”
The use of PARP inhibitors is part of a novel approach to cancer therapy called synthetic lethality. A cell with a PTEN fault relies on a protein called PARP to keep its DNA undamaged. PARP inhibitors work by blocking PARP, and when combined with defective PTEN, causes the cancer cell to die. This means the tumour should either stop growing or get smaller. Due to the drug working in a targeted way, it kills cancer cells while leaving healthy cells relatively unaffected, which means fewer side effects for patients.
Patients with inherited forms of advanced breast, ovarian and prostate cancers - caused by faulty BRCA1 and BRCA2 genes – have already benefited from PARP inhibitors in a recently published Phase I clinical trial. Despite having previously received many standard therapies, more than half of the patients’ tumours shrank or stabilised, with one of the first patients to be given the treatment still in remission after two years. BRCA-related tumours make up about 5% of breast cancer cases.
Dr Julia Wilson, Head of Research Management at Breakthrough Breast Cancer, said: “This new class of drugs could potentially make a big difference for many thousands of cancer patients, including some with very limited treatment options. It shows Breakthrough’s focus on turning lab research into patient benefit as quickly as possible is having an impact.
Full Citation: Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors, Ana M. Mendes-Pereira, Sarah A. Martin, Rachel Brough, Afshan McCarthy, Jessica R. Taylor, Jung-Sik Kim, Todd Waldman, Christopher J. Lord, Alan Ashworth, EMBO Mol Med 1(6-7) 2009 DOI: 10.1002/emmm.200900041
August, 2009
60-Year-Old Drug Shows New Promise For Inherited Cancer
CANCER RESEARCH UK-funded scientists have shown that an early chemotherapy drug invented in the 1940s has the potential to work against a genetic fault called HNPCC* which is linked to bowel and other cancers. The results are published in EMBO Molecular Medicine** today, (Thursday).
HNPCC is a hereditary condition involved in around five per cent of all bowel cancer cases. As well as bowel cancer, it puts people at increased risk of developing stomach, womb, ovarian, kidney and other cancers. Almost 40 per cent of people with HNPCC have a faulty MSH2 gene.
Scientists at the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research (ICR) in London sought to improve treatments for people with cancer caused by HNPCC by finding drugs which selectively kill cells containing the damaged MSH2 gene. In this study, the scientists tested a range of drugs on cells with the faulty MSH2 gene. They found that a drug called methotrexate*** worked particularly well in destroying these cells.
This study suggests that methotrexate could help to treat people whose cancer is driven by the MSH2 genetic fault, potentially opening the door to a more targeted treatment option. A new clinical trial has begun at The Royal Marsden NHS Foundation Trust to see how well methotrexate treats patents with advanced bowel cancer following this study****.
Methotrexate is similar to a normal molecule called folinic acid, which is required for copying DNA. The drug prevents cells from making and repairing DNA – a process needed for cancer growth. It was one of the first chemotherapy drugs to be invented in the 1940s and is still used to treat a number of cancers today. But until now, it has not commonly been used to treat people with HNPCC.
Professor Alan Ashworth, who led this Cancer Research UK-funded study at the ICR, said: “The MSH2 gene plays a vital role in repairing DNA damage but if it is faulty, mistakes accumulate in cells and increase the risk of cancer developing.
“What’s exciting about methotrexate is that it selectively destroys the cells lacking the MSH2 function. This indicates that it may make an excellent treatment for patients with the genetic alteration. With our colleagues at The Royal Marsden Hospital, we have set up clinical trials to test this.”
Dr Lesley Walker, director of cancer information at Cancer Research UK said: “In the past, many treatments were developed which indiscriminately kill dividing cells. With improved scientific understanding, we are starting to be able to offer targeted therapies that are selective for the genetic faults in cancer. It’s really fascinating that our scientists have discovered that an old-fashioned drug of this type shows new promise for this very specific group of patients.
“This is the first time scientists have identified a drug that targets cells lacking functional MSH2 genes. The chemotherapy drug methotrexate has already shown benefit for patients with breast, bladder and bone cancer as well as some types of leukaemia. We now need to find out if it is effective in patients with MSH2 gene defects.”
Notes:
*Hereditary non-polyposis colorectal cancer (HNPCC) is a hereditary condition which gives people a predisposition to developing some forms of cancer. It is also known as Lynch syndrome.
** Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Molecular Medicine. Martin et al. August 2009.
***You can find our more about the drug methotrexate on Cancer Research UK’s patient information website CancerHelp UK www.cancerhelp.org.uk
**** You can find out more about this trial on Cancer Research UK’s clinical trials database CancerHelp UK http://www.cancerhelp.org.uk/trials/trials/trial.asp?=&trialno=20942
Contact:
Ben Norman/Wiley-Blackwell PR Team
Lifesciencenews@wiley.com
‘Hedgehog’ Pathway May Hold Key to Anti-Cancer Therapy
Research into the role of pathway gene could provide novel method to treat cancer metastases
Scientists in Switzerland have discovered a way to block the growth of human colon cancer cells, preventing the disease from reaching advanced stages and the development of liver metastases. The research, published today in EMBO Molecular Medicine, shows that blocking the so-called Hedgehog-GLI pathway can prevent the growth of tumours, metastatic lesions and cancer stem cells, the cells thought to lie at the root of cancer growth.
Colon cancer often begins in a treatable form when it is confined to the bowel wall, but in frequent cases it can develop to an incurable metastatic stage. A Geneva-based research team has discovered the essential role played by HH-GLI in the progression of colon cancer to these late and incurable stages. HH-GLI is a signalling pathway used by cells to communicate with each other, often used to determine position, growth and survival.
“Previous works hinted at the possible role of HH-GLI in colon cancer, but this was denied by other studies, so its involvement was never entirely clear,” said lead researcher Professor Ariel Ruiz i Altaba of Geneva University. “In this study we have proven that HH-GLI is essential for the development and growth of colon cancers. The research demonstrates the active presence of HH-GLI signalling in epithelial cells of colon cancers. Moreover, we find that metastatic tumours rely on this pathway for sustained growth. This identifies HH-GLI as a target for novel anti-cancer therapies against so far incurable forms of colon cancer in distant organs, such as the liver.”
This research opens the possibility of new anti-cancer therapies, specifically the use of RNA interference and of Cyclopamine, a plant product known to block Hedgehog pathway activity. This and other similar molecules can now be considered for future research as a treatment for terminal patients with metastatic disease and to fight resurgent forms of the disease.
“Recurrence is a major problem in cancer treatment. Even after a patient has displayed an apparent complete recovery from a primary tumour, recurrence at nearby or distal locations has a poor prognosis,” said Ruiz i Altaba. “While monitoring recovering mice we noted that tumours began to recur in all cases except for those treated with Cyclopamine for a short period of time after tumour disappearance. The treated mice were kept for up to one year after the treatment and remained healthy and tumour free.”
Using these genetic or pharmacologic methods to block HH-GLI activity also prevents cancer stem cell self-renewal. Using a new in vivo assay to test the participation of cancer stem cells in a growing tumour, the research team demonstrated the essential role of this pathway for the maintenance and survival of cancer stem cells.
“This work firmly establishes the critical action of HH-GLI in human colon cancer cells, providing the platform for preclinical and future clinical work.” concluded Ruiz i Altaba. “The finding that a blockade of HH-GLI for a relatively short period was sufficient to eliminate the tumour and prevent recurrence, without negatively affecting the health of the mice, opens the possibility for the use of a therapeutic window to eradicate the tumour without major side effects.”
This paper is published in EMBO Molecular Medicine. To request this paper or for other media enquires contact Ben Norman at Lifesciencenews@wiley.com or +44 (0) 1243 775 375
Full Citation
Varnat.F, Duquet.A, Malerba,M, Zbinden,M, Mas.C, Gervaz.P, Ruiz i Altaba.A, ‘Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion’ EMBO Molecular Medicine, July 2009.
About the Author
Dr Ariel Ruiz I Altaba received his PhD from Harvard University and conducts research and teaches in the University of Geneva in Switzerland. The aim of his team’s research is to understand how form develops in the embryo, how it is maintained in the adult and how it is deregulated in disease.
To arrange an interview or for other media questions please contact Dr Ruiz i Altaba through the Geneva University Press Office. Charles-Antoine Courcoux (Charles-Antoine.Courcoux@unige.ch)
Contact: Michael David
midavid@ucsd.edu
University of California - San Diego
Anti-inflammatory drugs may defeat a treatment-resistant type of cancer
Effective drugs for treating a chemotherapy-resistant form of lymphoma might already be on the market according to a study that has pieced together a chemical pathway involved in the disease.
By following the trail of several molecular flags that mark this type of cancer, a team from the University of California, San Diego, the Burnham Institute for Medical Research and the University of Copenhagen Hospital have discovered that anti-inflammatory drugs used to treat arthritis will shrink lymphoma tumors in mice.
Their report, published in the July issue of the journal EMBO Molecular Medicine, also strengthens evidence for a link between inflammation and cancer.
"If this shows promise with early clinical experiments, the treatment would be immediately available," said Michael David, a professor of biology who leads the group at UC San Diego.
The research focused on a type of non-Hodgkin lymphoma called diffuse large B-cell lymphoma. In some patients with the disease, chemotherapy works well. In a recent study of 40 patients more than 75 percent of patients with one form of this type of lymphoma survived five years or longer.
But that study also identified a group of patients whose cancer proved difficult to treat. Their tumors failed to respond to chemotherapy, and only 16 percent of patients with this form of lymphoma survived more than five years after they were diagnosed.
Several molecular flags mark this treatment-resistant lymphoma, but the links between them were unknown until now. The new paper reports that tumor cells isolated from these patients have depressed levels of a protein called SHIP1, which was known to suppress tumors. In fact, patients with the lowest levels of SHIP1 are the least likely to survive.
The resistant type of lymphoma cells also have elevated levels of miR-155, a specific example of a type of genetic material called microRNA, the team found. They demonstrated that miR-155 suppresses SHIP1 by sticking to the template for the protein, preventing its manufacture.
This raised the possibility that these patients might respond favorably to a treatment that interrupted that pathway. "It makes sense to block that loop," said Irene Pedersen, a research scientist in the Division of Biological Sciences at UC San Diego and lead author of the paper.
The final clue came from earlier reports that an inflammatory molecule called TNFα could boost levels of miR-155. Additional laboratory work confirmed the observation for this type of lymphoma cell.
"Our study strengthens the scientific link between inflammation and tumor progression," David said. "The prevailing thought is that you need two mutations to get cancer. But it might take just one mutation plus inflammation."
The anti-inflammatory drugs etanercept and infliximab, which are currently used to treat arthritis and inflammatory bowel disease, work by suppressing TNFα, suggesting a new way to curb the malignancy of this type of lymphoma.
The team tested the idea in mice that had been injected with aggressive lymphoma cells and found that nascent tumors shrank in six days.
"It's a promising result of this whole translational path," said Pedersen, whose initial training was in cancers of the blood. "To get somewhere we had to study the mouse models and the molecular profiles. I hope it will be beneficial to patients."
Patients with lymphoma that has not responded to chemotherapy and who are ineligible for a bone-marrow transplant will be the first to receive the new treatment. The team in Copenhagen has begun recruiting patients for an initial clinical study.
Grants from the National Cancer Institute and the Novo Nordisk Foundation supported this research program.
This study is published in EMBO Molecular Medicine.
Full citation:
Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, Ralfkiaer E, Rickert RC, Gronbaek K & David M: Onco-miR-155 targets SHIP1 to promote TNF -dependent growth of B cell lymphomas. EMBO Mol. Med. 2009 1(5), 10.1002/emmm.200900028
June 2009
Contact:
Ben Norman/Wiley-Blackwell PR Team
+44 (0) 1243 770375
wbnewseurope@wiley.com
Alzheimer's Disease: Newly Found Peptide Offers Hope of Early Test and Better Treatment
Researchers in Japan have detected a peptide in cerebrospinal fluid (CSF) that can show whether a person is developing Alzheimer's disease. Measuring the level of this peptide could show that the disease process has started, long before any serious damage is done to the brain.
This research, published in the journal EMBO Molecular Medicine, raises new opportunities for combating Alzheimer's disease. Currently treatments can only be started after considerable structural damage has occurred in the person's brain. However, if this finding is broadly used as a clinical test, treatment may be possible before too much damage is present, offering the hope of much better outcomes.
"This novel peptide is the long-sought surrogate marker for Alzheimer's disease," says lead researcher Masayasu Okochi, who works in the Department of Neuropsychiatry at Osaka University Graduate School of Medicine, Japan.
Treating Alzheimer's disease is complex for a number of reasons. First, there are few or no signs that a person has the disease until the destructive process has been active in the person's brain for many months or years. Second, once the damage is done in the brain, it is difficult to restore lost function.
Consequently, many people are trying to find ways of detecting the onset of Alzheimer's disease long before any symptoms appear. In addition, they want to use a sampling method that does not involve costly scanning equipment.
The multi-centre Japanese team analysed CSF and brain tissue samples from people with and without diagnosis of Alzheimer's disease. They discovered that increases in levels of their newly identified peptide (APL1beta28) reflected increased production of Abeta42 in the brain. While Abeta42 is always produced in the brain, this peptide is one of the key constituents of the senile plaques that play a critical role in Alzheimer's disease, and increased production is associated with plaque formation.
"Many pharmaceutical companies are developing Abeta-targeting compounds that could prevent some of the brain damage associated with Alzheimer's disease, but their use will be limited if given after symptoms appear. Our new test allows early diagnosis, giving patients the chance of getting maximum benefit from these new drugs," says Okochi.
_______________________________________________________________
This study is published in EMBO Molecular Medicine. Media wishing to receive a PDF of this article may contact wbnewseurope@wiley.com
Full citation:
Yanagida.K, Okochi.M, et al. The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42production in the central nervous system. EMBO Mol. Med. 2009 1(4), 10.1002/emmm.200900026
About the Author:
Masayasu Okochi (MD) is based at the Osaka University Graduate School of Medicine in Japan. For further information on this paper Dr Okochi can be contacted on: mokochi@psy.med.osaka-u.ac.jp
Japanese speakers may also phone Osaka University on: +81-6-6879-3053
April 2009
Contact:
Jennifer Beal / Wiley-Blackwell PR Team
+44 (0) 1243 770633
+44 (0) 7802 468863
wbnewseurope@wiley.com
Bio-engineered Proteins: Trial Confirms New Way to Tackle Cancer
Re-engineering a protein that helps prevent tumours spreading and growing has created a potentially powerful therapy for people with many different types of cancer. In a study published in the first issue of EMBO Molecular Medicine, Canadian researchers modified the tumour inhibiting protein, von Hippel-Lindau (VHL), and demonstrated that it could suppress tumour growth in mice.
When solid tumours grow they often have relatively poor and disorganised blood supplies. As a result, various regions including the centre of the tumour have low levels of oxygen and are said to be hypoxic. Cells in these hypoxic areas produce hypoxia-inducible factor (HIF) that helps them carry on growing. Consequently HIF is associated with aggressiveness in some of the most common types of cancer, including prostate, breast, colon and lung cancer. Under normal conditions VHL degrades HIF, but VHL is deactivated when oxygen levels are low. So, in hypoxic regions of a tumour, just where VHL is needed to inhibit cancer, it is ineffective.
The researchers, therefore, created a new version of VHL that does not stop working when oxygen is scarce. Introducing this newly engineered version of VHL into mice that had kidney tumours dramatically reduced levels of HIF, caused tumours to regress and limited the formation of new blood vessels within the tumours.
“We have genetically removed the Achilles’ heel of VHL to permit unrestricted destruction of HIF,” says lead researcher Professor Michael Ohh, who works in the Faculty of Medicine at the University of Toronto. “The level of HIF is usually very high under conditions of low oxygen, but when we put in our bioengineered VHL its levels go right down to a level that would be comparable to that in normal oxygen levels.”
Their findings could have implications for any type of cancer in which HIF plays a role. “We used kidney cancer as a model because it is one of the most resistant tumours to conventional radiation and chemotherapy, but our findings provide a novel concept that could potentially serve as a foundation for smarter anti-cancer strategy for a wide variety of cancers,” says Ohh.
_________________________________________________________________
This study is published in the first issue (April 2009) of EMBO Molecular Medicine. Media wishing to receive a PDF of this article may contact wbnewseurope@wiley.com
Full citation:
Sufan R.I., Moriyama E.H., Mariampillai A., Roche O., Evans A.J., Alajez N.M., Vitkin I.A., Yang V.X.D., Liu F., Wilson B.C., Ohh M.; OXYGEN-INDEPENDENT DEGRADATION OF HIF VIA BIOENGINEERED VHL TUMOUR SUPPRESSOR COMPLEX; EMBO Mol Med 2009 1(1); DOI: emmm.200900004
About the Author:
Michael Ohh, Ph.D., is based at the University of Toronto, Canada. To arrange an interview, please contact Paul Cantin, Associate Director, Strategic Communications & Public Relations at the University of Toronto, on +001-416-978-2890 or email: paul.cantin@utoronto.com.
2008
A new journal where molecular biology meets clinical research
Click here to read this Press Release
Heidelberg, 9 October 2008
Journal Menu
-
Authors & Referees
