Research and Clinical Trials News

Research and Clinical Trials News

  • PDF
  • Print

Inflammatory protein converts glioblastoma cells into most aggressive version

  • Friday, 30 August 2013 21:18

Conditions in brain Tumor environment trigger previously unexplained cellular transition and radiation resistance

HOUSTON -- A prominent protein activated by inflammation is the key instigator that converts Glioblastoma Multiforme cells to their most aggressive, untreatable form and promotes resistance to radiation therapy, an international team led by researchers at The University of Texas MD Anderson Cancer Center reported online today in the journal Cancer Cell.

The discovery by scientists and physicians points to new ways to increase radiation effectiveness and potentially block or reverse progression of glioblastoma multiforme, the most common and lethal form of brain tumor.

"We know that the mesenchymal (MES) subgroup of glioblastoma cells is the most aggressive subgroup clinically," said co-senior author Ken Aldape, M.D., chair and professor of Pathology and Kenneth D. Muller Professor in Tumor Genetics. "This paper shows that the NF-kB pathway causes cells to change to that MES subgroup."

This conversion leads to radiation resistance.

"The pathway we identified serves as an escape mechanism for tumors," said lead author Krishna Bhat, Ph.D., assistant professor of Pathology. "In newly diagnosed patients, even before treatment, these cells already are poised to meet radiation therapy challenges."

NF-κB-driven cell change starts outside the tumor

NF-κB activation is stimulated by inflammation, which occurs in the tumor cell's microenvironment.

"The shift of tumor cells to a MES type, characterized gene expression associated with invasion and new blood vessel formation, leads to radiation resistance," said co-senior author Erik Sulman, M.D., Ph.D., assistant professor of Radiation Oncology. "This suggests blocking the inflammatory response to make tumors more sensitive to standard radiation treatment may improve outcomes for patients."

Standard care for glioblastoma is surgery, followed by radiation and Chemotherapy and then treatment with Temozolomide. An estimated 23,270 people will receive a glioblastoma diagnosis in 2013 and about 14,000 people will die of the disease. Median survival is about one year.

Cell line, mouse model show something missing

"No one really knows how glioblastoma progresses from its early stages because 90-95 percent of cases are diagnosed without prior history of a lower grade Glioma," Bhat said. Of these about 50 percent belong to the MES subgroup. A previous study had shown that glioblastomas with a proneural (PN) type, have a much better Prognosis. But these less-aggressive tumors tend to recur as the aggressive MES subtype after treatment."

Research at MD Anderson and other institutions identified the two distinct cell types based on genes expressed by each. "We haven't known what makes a cell evolve into the MES subtype," Bhat said.

Bhat took cells from 41 human glioblastoma samples and placed them in cell cultures. Of these, 33 developed into neurospheres, cells that take on stem-cell like characteristics.

Microarray analysis of gene expression in the 17 fastest -expanding cell cultures divided them into two distinct groups: one cluster similar to the MES subtype and the other the PN subtype.

They analyzed expression of four genes commonly expressed by each subtype to see how the cultured cells matched up to their parental tumors.

Cue the surprise

All but two of the cell lines (70 percent) that originated from MES tumors lost their MES characteristics and acquired a PN signature. These results do not match the human experience, Bhat noted. Glioblastoma cells don't retreat from an aggressive to less aggressive state.

Either something in the cell culture system favored enrichment of the PN state, or most glioblastoma neurospheres exist in the less-aggressive PN state, and something in the tumor microenvironment triggers their reversible differentiation into the MES state.

Placing the PN cells cultured from MES tumors in mice did not restore those cells to the parent tumor's more aggressive type.

Different responses to radiation treatment

The researchers implanted glioblastoma sphere culture grafts from MES and PN types in mice and then treated them with radiation.

Those with the PN type had increased survival after treatment compared to controls and had a dramatic accumulation of cells (48 to 78 percent) stuck in a specific phase of the cell cycle caused by irradiation, which lead to massive cell death.

Irradiating MES tumors produced no or minimal survival advantage and the percentages of cells arrested by treatment was reduced to 19-25 percent. The MES cells also showed an enhanced ability to repair damage caused by irradiation.

The Cancer Genome Atlas project for glioblastoma had previously found that genes in the TNFα receptor family and the NF-κB pathway are enriched in MES subclass tumors that also express high levels of the surface receptor CD44.

This team found the exact same pathway had been turned on in the MES cells in their study.

Subsequent experiments found:

  • Treating PN cells with TNFα caused a dramatic increase in CD44 expression. This effect could be reversed by impeding NF-κB.
  • Pretreating PN cells with TNF-alpha before radiation treatment greatly reduced cell damage.
  • NF-κB controls three main transcription factors known to produce the MES cell signature and forces conversion to MES by inducing those factors.

MES cells, CD44 levels, NF-kB activation predict human radiation response

In a cohort of newly diagnosed glioblastoma patients, the team found that those in the MES subgroup, with high levels of CD44 and activated NF-κB had poorer response to radiation and reduced survival.

A separate analysis of PN to MES transition in human tumors showed that regions with higher MES signatures had greater invasion by immune cells called macrophages /microglia – elements of the glioblastoma microenvironment – than did PN areas.

"We know we have to control inflammation in this disease," Bhat said. NF-κB is known to play an important role in promoting inflammation in multiple cell types.

"Surprisingly we found that activation of NF-κB was prevalent in the MES subtype even before surgery and radiation, which in turn can cause inflammation and further activation of NF-κB."

Bhat is investigating downstream targets of NF-κB that promote radiation resistance in glioblastoma.

Inhibitors of NF-κB are in clinical trials for inflammatory and autoimmune diseases, Aldape noted.

"One can imagine a clinical trial in which patients are evaluated for MES status and given an NF-κB inhibitor if they have the MES subtype. You can look at improving radiation response, and also whether you can reverse the MES subtype," Aldape said.

###

Co-authors with Bhat, Aldape and Sulman are Karlijn Hummelink, Faith Hollingsworth, Khalida Wani, Ph.D., Lindsey Heathcock, Johanna James, Lihong Long and Adriana Olar, M.D., all of the Department of Pathology; co-lead author Ravesanker Ezhilarasan, Ph.D., and Lindsey Goodman, of Radiation Oncology; Suzhen Wang of Neuro-Oncology; Joy Gumin, Ganesh Rao, M.D., Amy Heimberger, M.D., and Frederick Lang, M.D., of Neurosurgery; co-lead author Veerakumar Balasubramaniyan, Ph.D., Divya Raj, Ph.D., Hendrikus W.G.M. Boddeke, Ph.D., Siobhan Conroy, and Wilfred Den Dunnen, M.D., Ph.D., of the University Medical Center Groningen, University of Groningen, Netherlands; co-lead author Brian Vaillant, M.D., of Seton Brain and Spine Institute, Austin; Nina Lelic and Daniel Cahill, M.D., Ph.D., Massachusetts General Hospital/Brain Tumor Center, Boston; Yoshinori Kodama, M.D., Osaka National Hospital, National Hospital Organization, Osaka, Japan; Aditya Raghunathan, M.D., Henry Ford Hospital, Detroit; Kaushal Joshi, Christopher Pelloski, M.D., and Ichiro Nakano, M.D., Ph.D., of The Ohio State University, Columbus, Ohio; Se Hoon Kim, M.D., Ph.D., of the Yonsei University College of Medicine, Seoul; Heidi Phillips, Ph.D., of Genentech, South San Francisco, CA; and Howard Colman, M.D., Ph.D., of Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.

This research was funded by the Caroline Ross Endowed Fellowship in Brain Cancer Research, the American Brain Tumor Association Basic Research Fellowship, MD Anderson's Odyssey Special Fellowship, the Brain Tumor Funders' Collaborative, the Dr. Marnie Rose Foundation, the National Brain Tumor Society; the V Foundation, grants from the National Cancer Institute of the National Institutes of Health including MD Anderson's Brain Tumor SPORE grant (P50CA127001 and R01-CA1208113), MD Anderson's NCI Cancer Center Support Grant (P30 CA016672), the Huntsman Cancer Foundation, the Ben and Catherine Ivy Foundation and the Dutch Cancer Society.

  • PDF
  • Print

When things are at their worst, Christianity is intensely enacted

  • Friday, 30 August 2013 21:14

IMAGE: This is a photo of Christine Tind Johannessen-Henry, University of Copenhagen.

Click here for more information.

A new University of Copenhagen PhD thesis has taken a look at faith as practiced in the daily lives of Danish Cancer survivors. The thesis shows that Christian beliefs play a significant role in the lives of people suffering from cancer, and that their faith is often displayed in ways that challenge common perceptions of what Christianity is.

"My results show that people's individual Christian faith becomes present during times of personal crisis. Faith and hope manifest themselves very intensely, but it is rare that they show in the classical forms we normally associate with Christianity. Rather than a single and static set of beliefs, everyday Christianity constantly unfolds in multiple ways and in relation to others," says Christine Tind Johannessen-Henry, a PhD fellow at the University of Copenhagen's Department of Theology.

Connections between faith and cancer

Christine Tind Johannessen-Henry carried out her research in collaboration with the Danish Cancer Society Research Center, as part of a cross-disciplinary project involving theology and health sciences. The research involved a questionnaire study of 1,043 people who have survived cancer; 20 of these survivors were also involved in an interview study with participant observation.

"The results of the study show that the deeper the crisis people find themselves in, the higher the level of validation of their various forms of faith and beliefs in God, while they also experience a greater will to live and more vibrant sense of being. The diverse forms of beliefs and hopes are enacted tightly interweaved with situations of confusion, anxiety and joy, all of which emerge as individual pass through diagnosis, Chemotherapy, surgery and sequelae. These types of situations manifest in the bodies of the survivors, and continue to affect the individual for long periods of time," says Christine Tind Johannessen-Henry.

Faith is belief in action

The research, Johannessen-Henry says, found that those participating in the study perform their faith in multiple ways. Denmark is often characterised as a very secular society, which builds on Christian values. The study results show that participants believe in Christian doctrine such as 'God' (59%), 'A loving God' (55%), 'A forgiving God' (49%), 'Christ' (51%) and 'life after death', in the sense that "the impact someone has had on the lives of others will continue to live on in their hearts after they die" (87%). People's individual faith, however, shows through more than just utterances which can be determined by "yes" and "no", but shows through the survivors' different practices.

"Faith is how we 'enact' our beliefs – what we do when we find ourselves in any given situation and must deal with it. One example is when a cancer survivor gives a gift to a relative with the intention that will keep them related after the survivor passes away. Another is when we tell our children that God, angels or deceased family members will take care of them – or even speak to those who we believe will watch over our loved ones – we are, in effect, creating, sharing, giving and receiving faith as a part of a congregation. The images and metaphors we use and use to cope with difficult situations elucidate that Christianity always unfolds in relations and through the life situation of the believer. In this sense Christianity constantly develops, moves and renews and new spaces of faith is created" Johannessen-Henry says.

The relation between dogmatic and everyday Christianity

In her PhD thesis, Johannessen-Henry emphasises the difference between Christianity that is dogmatically practice in theology and Church rituals, and Christianity that people live in their daily lives. These different "Christianities" repeatedly connect and link together, however. The project's research shows that an individual's faith constantly moves between ideas from Christian tradition and all sorts of non-Christian elements. According to Johannessen-Henry, these network of faith practises offer an understanding of how a doctrine such as "resurrection" is enacted in everyday life.

"Even though people suffering from cancer hold beliefs that might not be specifically Christian – for example 'rebirth' in other and very different versions – the mosaic of the Danish participants faith does incorporate pieces of Christianity – 'God as loving father', 'omnipotence', 'sacrifice', 'crucifixion', 'guiding stars', 'angels' – that it is impossible to claim that it isn't Christian either. The different elements are so tightly woven together that it is impossible to distil perceptions of a 'real' Christianity from the 'manyfolded' and diverse Christianity," Johannessen-Henry says.

Christine Tind Johannessen-Henry defended her dissertation, "The Polydoxy of Everyday Christianity. An Empirical-Theological Study of Faith in the Context of Cancer", Friday 23 August 2013.

###

Facts:

Christianity in Denmark

The official religion in the country of Denmark is Evangelical Lutheran, as stated in the Danish Constitution. About 80 percent of the Danish population belongs to the Evangelical Lutheran religion, while 3 percent are Roman Catholics, and less than 2 percent are Muslim. Read more: http://denmark.dk/en/society/religion/

Contact

PhD Christine Tind Johannessen-Henry
Department for Systematic Theology
Faculty of Theology, University of Copenhagen
Tel.:  + 45 29 72 38 88 
Mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Communications Officer Anne Rahbek
Faculty of Theology, The University of Copenhagen
Tel.:  +45 2329 7146 
E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

  • PDF
  • Print

New technique to help brain cancer patients

  • Monday, 26 August 2013 10:13

A new scanning technique developed by Danish and US researchers reveals how susceptible patients with aggressive brain Cancer are to the drugs they receive. The research behind the ground-breaking technique has just been published in Nature Medicine.

Each year sees 260 new cases of the most aggressive type of brain cancer in Denmark. Some patients survive only a few months, while others survive for 18 months. Only very few, 3.5%, are alive five years after their diagnosis. A new scanning technique can now reveal how the Brain Tumour responds to the drug administered:

"We have developed an MRI technique which reveals how a patient will respond to the treatment that inhibits the growth of new blood vessels to the tumour. The technique allows us to only select the patients who will actually benefit from the treatment and to quickly initiate or intensify other treatments for non-responding patients," says Kim Mouridsen, Associate Professor at Aarhus University and head of the research group Neuroimaging Methods at MINDLab, Aarhus University.

He has developed the new technique together with researchers from Harvard Medical School.

Brain architecture providing important knowledge

Aggressive brain cancer is usually treated with drugs that inhibit the growth of new blood vessels, as the most aggressive brain tumours are constantly trying to produce new blood vessels to get oxygen. The treatment alleviates the symptoms, but it also increases the efficacy of radiation therapy because it improves oxygenation.

According to Kim Mouridsen, the new technique – Vessel Architectural Imaging – is an important step towards better treatment:

"Getting more knowledge about what the blood vessels in the tumour look like will also give us a better understanding of the mechanisms which are decisive for the efficacy of the treatment. And understanding these mechanisms is precisely what we need to be able to develop and improve the treatment of brain tumours in general."

###

Read more

Read the scientific article 'Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy' here

The study receives funding from the Danish Research Foundation and the Ministry of Science, Technology and Innovation.

  • PDF
  • Print

Brain cancer survival improved following FDA approval of bevacizumab, Mayo study finds

  • Monday, 19 August 2013 16:27

ROCHESTER, Minn. -- A new population-based study has found that patients with glioblastoma who died in 2010, after the Food and Drug Administration (FDA) approval of bevacizumab, had lived significantly longer than patients who died of the disease in 2008, prior to the conditional approval of the drug for the treatment of the deadly brain Cancer. Bevacizumab is used to treat patients with certain cancers whose cancer has spread. The study appears in the journal Cancer.

"There has been a great deal of debate about the effectiveness of bevacizumab in treating patients with glioblastoma," says lead author Derek Johnson, M.D., a neuro-oncologist at Mayo Clinic Cancer Center. "Our study found that, at the population level, treatment strategies involving bevacizumab prolonged survival in patients with progressive glioblastoma."

Researchers analyzed data on 5,607 adult patients from the National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database before and after the conditional approval of bevacizumab for the treatment of glioblastoma in 2009. The SEER database covers 18 geographic areas of the U.S., which collectively represent 28 percent of the U.S. population.

Researchers studied survival in 1,715 patients with glioblastoma who died in 2006, 1,924 who died in 2008 and 1,968 who died in 2010. "The difference in survival between 2008 and 2010 was highly significant and likely unrelated to any advancements in supportive care," Dr. Johnson says. "This study provides the strongest evidence to date that bevacizumab therapy improves survival in patients with glioblastoma."

Glioblastoma, is an aggressive cancer in which tumors grow rapidly and spread rapidly to new sites. It is the most common Malignant brain Tumor in adults and accounts for about 22 percent of all brain cancers. About 3,000 people develop a glioblastoma each year in the U.S.

###

Co-authors include Heather Leeper, M.D., and Joon Uhm, M.D. both of Mayo Clinic.

About Mayo Clinic Cancer Center

As a leading institution funded by the National Cancer Institute, Mayo Clinic Cancer Center conducts basic, clinical and population science research, translating discoveries into improved methods for prevention, diagnosis, Prognosis and therapy. For information on cancer clinical trials, call  507-538-7623 

About Mayo Clinic

Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit http://www.mayoclinic.org/about and http://www.mayoclinic.org/news.

Journalists can become a member of the Mayo Clinic News Network for the latest health, science and research news and access to video, audio, text and graphic elements that can be downloaded or embedded.

  • PDF
  • Print

New MR analysis technique reveals brain tumor response to anti-angiogenesis therapy

  • Monday, 19 August 2013 13:22

Rapid identification of changes in Tumor blood vessels could help avoid ineffective therapies

A new way of analyzing data acquired in MR imaging appears to be able to identify whether or not tumors are responding to anti-angiogenesis therapy, information that can help physicians determine the most appropriate treatments and discontinue ones that are ineffective. In their report receiving online publication in Nature Medicine, investigators from the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH), describe how their technique, called vessel architectural imaging (VAI), was able to identify changes in brain tumor blood vessels within days of the initiation of anti-angiogenesis therapy.

"Until now the only ways of obtaining similar data on the blood vessels in patients' tumors were either taking a biopsy, which is a surgical procedure that can harm the patients and often cannot be repeated, or PET scanning, which provides limited information and exposes patients to a dose of radiation," says Kyrre Emblem, PhD, of the Martinos Center, lead and corresponding author of the report. "VAI can acquire all of this information in a single MR exam that takes less than two minutes and can be safely repeated many times."

Previous studies in animals and in human patients have shown that the ability of anti-angiogenesis drugs to improve survival in Cancer therapy stems from their ability to "normalize" the abnormal, leaky blood vessels that usually develop in a tumor, improving the perfusion of blood throughout a tumor and the effectiveness of Chemotherapy and radiation. In the deadly brain tumor glioblastoma, MGH investigators found that anti-angiogenesis treatment alone significantly extends the survival of some patients by reducing Edema, the swelling of brain tissue. In the current report, the MGH team uses VAI to investigate how these drugs produce their effects and which patients benefit.

Advanced MR techniques developed in recent years can determine factors like the size, radius and capacity of blood vessels. VAI combines information from two types of advanced MR images and analyzes them in a way that distinguishes among small arteries, veins and capillaries; determines the radius of these vessels and shows how much oxygen is being delivered to tissues. The MGH team used VAI to analyze MR data acquired in a phase 2 clinical trial – led by Tracy Batchelor, MD, director of Pappas Center for Neuro-Oncology at MGH and a co-author of the current paper – of the anti-angiogenesis drug cediranib in patients with recurrent glioblastoma. The images had been taken before treatment started and then 1, 28, 56, and 112 days after it was initiated.

In some patients, VAI identified changes reflecting vascular normalization within the tumors – particularly changes in the shape of blood vessels – after 28 days of cediranib therapy and sometimes as early as the next day. Of the 30 patients whose data was analyzed, VAI indicated that 10 were true responders to cediranib, whereas 12 who had a worsening of disease were characterized as non-responders. Data from the remaining 8 patients suggested stabilization of their tumors. Responding patients ended up surviving six months longer than non-responders, a significant difference for patients with an expected survival of less than two years, Emblem notes. He adds that quickly identifying those whose tumors don't respond would allow discontinuation of the ineffective therapy and exploration of other options.

Gregory Sorensen, MD, senior author of the Nature Medicine report, explains, "One of the biggest problems in cancer today is that we do not know who will benefit from a particular drug. Since only about half the patients who receive a typical anti-cancer drug benefit and the others just suffer side effects, knowing whether or not a patient's tumor is responding to a drug can bring us one step closer to truly personalized medicine – tailoring therapies to the patients who will benefit and not wasting time and resources on treatments that will be ineffective." Formerly with the Martinos Center, Sorensen is now with Siemens Healthcare.

Study co-author Rakesh Jain, PhD, director of the Steele Laboratory in the MGH Department of Radiation Oncology, adds, "This is the most compelling evidence yet of vascular normalization with anti-angiogenic therapy in cancer patients and how this concept can be used to select patients likely to benefit from these therapies."

Lead author Emblem notes that VAI may help further improve understanding of how abnormal tumor blood vessels change during anti-angiogenesis treatment and could be useful in the treatment of other types of cancer and in vascular conditions like stroke. He and his colleagues are also exploring whether VAI can identify which glioblastoma patients are likely to respond to anti-angiogenesis drugs even before therapy is initiated, potentially eliminating treatment destined to be ineffective. A postdoctoral research fellow at the Martinos Center at the time of the study, Emblem is now a principal investigator at Oslo University Hospital in Norway and maintains an affiliation with the Martinos Center.

###

Additional co-authors of the Nature Medicine paper are Kim Mouridsen, PhD, Christian Farrar, PhD, Dominique Jennings, Ronald Borra, PhD, and Bruce Rosen, MD, PhD, Martinos Center at MGH; Rakesh Jain, PhD, Steele Laboratory of Tumor Biology, MGH Radiation Oncology; Atle Bjornerud, PhD, University of Oslo, Norway; Patrick Wen, MD, Dana-Farber Cancer Institute; and Percy Ivy, MD, National Cancer Institute. Support for the study includes numerous grants from the U.S. Public Health Service, the National Cancer Institute and other funders.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Read more...

Page 2 of 227

 


SAPE ERROR: Нет доступа на запись к файлу: /home/btbuddies/public_html/templates/68portal_orig/images/cache/3f9e7ffccc6995af0bc4886a484f1db1/links.db! Выставите права 777 на папку.