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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY


Quarta-feira, 19.08.15

special brain mechanism that can retrieve unconscious memories

 

Scientists discover special brain mechanism that can retrieve unconscious memories

Published on August 18, 2015 at 8:46 AM ·

Some stressful experiences - such as chronic childhood abuse - are so overwhelming and traumatic, the memories hide like a shadow in the brain.

At first, hidden memories that can't be consciously accessed may protect the individual from the emotional pain of recalling the event. But eventually those suppressed memories can cause debilitating psychological problems, such as anxiety, depression, post-traumatic stress disorder or dissociative disorders.

A process known as state-dependent learning is believed to contribute to the formation of memories that are inaccessible to normal consciousness. Thus, memories formed in a particular mood, arousal or drug-induced state can best be retrieved when the brain is back in that state.

In a new study with mice, Northwestern Medicine scientists have discovered for the first time the mechanism by which state-dependent learning renders stressful fear-related memories consciously inaccessible.

"The findings show there are multiple pathways to storage of fear-inducing memories, and we identified an important one for fear-related memories," said principal investigator Dr. Jelena Radulovic, the Dunbar Professor in Bipolar Disease at Northwestern University Feinberg School of Medicine. "This could eventually lead to new treatments for patients with psychiatric disorders for whom conscious access to their traumatic memories is needed if they are to recover."

It's difficult for therapists to help these patients, Radulovic said, because the patients themselves can't remember their traumatic experiences that are the root cause of their symptoms.

The best way to access the memories in this system is to return the brain to the same state of consciousness as when the memory was encoded, the study showed.

The study will be published August 17 in Nature Neuroscience.

Changing the Brain's Radio Frequencies

Two amino acids, glutamate and GABA, are the yin and yang of the brain, directing its emotional tides and controlling whether nerve cells are excited or inhibited (calm). Under normal conditions the system is balanced. But when we are hyper-aroused and vigilant, glutamate surges. Glutamate is also the primary chemical that helps store memories in our neuronal networks in a way that they are easy to remember.

GABA, on the other hand, calms us and helps us sleep, blocking the action of the excitable glutamate. The most commonly used tranquilizing drug, benzodiazepine, activates GABA receptors in our brains.

There are two kinds of GABA receptors. One kind, synaptic GABA receptors, works in tandem with glutamate receptors to balance the excitation of the brain in response to external events such as stress.

The other population, extra-synaptic GABA receptors, are independent agents. They ignore the peppy glutamate. Instead, their job is internally focused, adjusting brain waves and mental states according to the levels of internal chemicals, such as GABA, sex hormones and micro RNAs. Extra-synaptic GABA receptors change the brain's state to make us aroused, sleepy, alert, sedated, inebriated or even psychotic. However, Northwestern scientists discovered another critical role; these receptors also help encode memories of a fear-inducing event and then store them away, hidden from consciousness.

"The brain functions in different states, much like a radio operates at AM and FM frequency bands," Radulovic said. "It's as if the brain is normally tuned to FM stations to access memories, but needs to be tuned to AM stations to access subconscious memories. If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again, essentially tuning the brain into the AM stations."

Retrieving Stressful Memories in Mice

In the experiment, scientists infused the hippocampus of mice with gaboxadol, a drug that stimulates extra-synaptic GABA receptors. "It's like we got them a little inebriated, just enough to change their brain state," Radulovic said.

Then the mice were put in a box and given a brief, mild electric shock. When the mice were returned to the same box the next day, they moved about freely and weren't afraid, indicating they didn't recall the earlier shock in the space. However, when scientists put the mice back on the drug and returned them to the box, they froze, fearfully anticipating another shock.

"This establishes when the mice were returned to the same brain state created by the drug, they remembered the stressful experience of the shock," Radulovic said.

The experiment showed when the extra-synaptic GABA receptors were activated with the drug, they changed the way the stressful event was encoded. In the drug-induced state, the brain used completely different molecular pathways and neuronal circuits to store the memory.

"It's an entirely different system even at the genetic and molecular level than the one that encodes normal memories," said lead study author Vladimir Jovasevic, who worked on the study when he was a postdoctoral fellow in Radulovic's lab.

This different system is regulated by a small microRNA, miR-33, and may be the brain's protective mechanism when an experience is overwhelmingly stressful.

The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.

Traumatic Memories Rerouted and Hidden Away

Memories are usually stored in distributed brain networks including the cortex, and can thus be readily accessed to consciously remember an event. But when the mice were in a different brain state induced by gaboxadol, the stressful event primarily activated subcortical memory regions of the brain. The drug rerouted the processing of stress-related memories within the brain circuits so that they couldn't be consciously accessed.

Source:

Northwestern University

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por cyto às 11:42

Terça-feira, 21.07.15

Study stresses importance of investigating telomeres to improve diagnoses, develop treatments for many diseases

 

Study stresses importance of investigating telomeres to improve diagnoses, develop treatments for many diseases

Published on July 16, 2015 at 3:04 AM 

Studying telomeres, the structures that protect the ends of chromosomes, has become a key issue in biology. In recent years, not only has their relation to ageing been confirmed; defective telomeres seem to be linked to more and more illnesses, including many types of cancer. The review published by Paula Martínez and María Blasco from the CNIO in Trends in Biochemical Sciences, stresses the importance of investigating these structures to improve diagnoses and develop possible treatments for many diseases. Telomeres, in the opinion of these researchers, will become increasingly important in clinical studies.

The chromosomes in every single cell are made up of DNA and shaped like strands, with a kind of protective cap at the end of each strand of DNA. Without this end protective cap, the DNA strands would chemically bond to other strands, i.e. the chromosomes would merge and that would be lethal for the cell. The structures that prevent this catastrophe are the telomeres. They were discovered in the 1930s but decades elapsed before someone decided to study them in any depth and since the late 1990s they have always been on the cutting edge of biology research. Biologists are often surprised by their amazing and unexpected complexity, and their health-related significance.

"The biology of telomeres is extremely complex and the more we discover the more we realise what remains to be discovered", says Paula Martínez from CNIO's Telomere and Telomerase Group. "What surprises me most is the high number of factors we are finding that are essential to the preservation of telomeres and, above all, the precise coordination that is required between them all".

The fact that telomeres have been tightly preserved throughout the evolutionary tree -in most eukaryotes: vertebrates, plants and even unicellular organisms such as yeast- indicates their importance. In addition to preventing the merger of chromosomes, telomeres are needed to prevent the loss of genetic information each time a cell divides.

PREVENTING INFORMATION LOSS

When a cell replicates, the molecular machinery in charge of duplicating the chromosomes - so that each daughter cell has a copy -cannot reach the tip. This is inherently impossible due to the way the DNA replication machinery works, and it implies that any genetic material at the end of a chromosome with significant information for the cell would be lost. Telomeres prevent this from happening: they consist of a DNA sequence that does not contain genes and that is repeated numerous times- in humans and other species the sequence is TTAGGG; the letters correspond to three of the building blocks that make up the DNA: thymine, adenine and guanine.

Consequently, the shortening of the DNA with every division is not significant. At least not until a certain limit is reached. When the telomeres become too short, we see the problems associated with ageing: cells reach a point where they interpret critically short telomeres as irreparable damage and react by no longer dividing, which prevents tissue from regenerating.

This happens in healthy cells but not in cancer cells. There is an enzyme, telomerase, which is capable of lengthening the telomeres de novo. This enzyme is not present in most cells of an adult organism but it is active in tumour cells. By repairing the telomeres, the telomerase enables cancer cells to proliferate and become virtually immortal.

This link to ageing and cancer, has led to the intense study of telomere-based strategies to combat cancer and diseases associated with ageing. Blasco's group has recently shown that it is possible to make cancer cells mortal by acting on the telomeres.

ZOOMING IN TO THE TIP OF THE BUFFER

The above-mentioned description of telomeres however is a simplified version of the story. We now know that there is a protective structure enveloping telomeric DNA consisting of six proteins known as shelterins, which are crucial. Another more recent discovery is that there are proteins that, although not in the telomeres themselves, interact with them at specific times to enable them to perform their functions.

These proteins enable the telomeres to unwind, for example; because, the sequence repeated in telomeres, TTAGGG, ends in a single strand of DNA that curves forming a loop and connects to the original strand of the double chain forming a triple chain. "Yes, it is very complicated", admits Martínez. "Structures of up to four chains of DNA can form".

When a cell divides, the telomeres are also replicated. This implies that the end loop must unwind first and then form again. This process also contributes to the shortening of telomeres and we now know that some of the shelterins as well as other associated proteins that interact with telomeres are key elements in this process.

TELOMERE SYNDROMES

According to Martínez, "there is now more evidence about relationship between telomere maintenance and several illnesses".

Telomere syndromes, or telomeropathies, have been identified in patients with mutations of the telomerase enzyme. This group includes, for example, pulmonary fibrosis and problems related to the malfunction of the bone marrow. A direct relationship between telomere dysfunctions and many types of cancer has also been found. More recently, we have also discovered that mutations of the proteins that protect telomeric DNA, the shelterins, and those that interact with the telomeres, are linked to various diseases, such as dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome or Revesz syndrome.

"These discoveries underline the plethora of components and pathways that control telomere functions", write the authors in the paper. "In the future, research will bring to light more unknown factors that will improve our understanding of the mechanisms governing cancer and syndromes linked to the shortening of telomeres. We hope that this knowledge will be transferred to the clinic in order to improve the diagnosis and treatment of diseases".

Source:

Centro Nacional de Investigaciones Oncologicas (CNIO)

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por cyto às 18:18

Terça-feira, 21.07.15

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

 

Ludwig, CRI launch clinical trials to evaluate immunotherapies for treatment of GBM and solid tumors

Published on July 8, 2015 at 11:50 PM 

Ludwig Cancer Research (Ludwig) and the Cancer Research Institute (CRI) have launched clinical trials evaluating an immunotherapy for the treatment of the brain cancer glioblastoma multiforme (GBM), and a combination of immunotherapies for a variety of solid tumors.

The trials are being conducted through the CVC Clinical Trials Network in collaboration with MedImmune, the global biologics research and development arm of AstraZeneca. The CVC Clinical Trials Network -- jointly managed by Ludwig and CRI -- is a coordinated global network of basic and clinical immunologists with expertise in devising and developing immunotherapies for the treatment of cancer. The CVC Clinical Trials Network is led by Jedd Wolchok, Ludwig member and director of the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center, as well as associate director of the CRI Scientific Advisory Council.

The GBM trial is a nonrandomized, multicenter Phase 2 trial testing the effects of MedImmune's checkpoint blockade antibody durvalumab (MEDI4736) in patients with GBM, which is the most aggressive and deadly type of adult brain cancer. The study will be conducted using three cohorts of patients - newly diagnosed, recurrent patients and those with tumors which have become unresponsive to standard treatment of care.

"GBM is an inevitably lethal cancer that has so far eluded every therapy in the pharmaceutical arsenal," said Jonathan Skipper, Ludwig's executive director of technology development. "We are hopeful that adding a promising immunotherapy to the treatment regimen for this brain cancer will yield significant benefits for patients who today have a median life expectancy of roughly 15 months, even with the best treatment available."

Durvalumab is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor's immune-evading tactics. The antibody belongs to an emerging class of immunotherapies commonly referred to as checkpoint inhibitors because they remove checks the body places on immune activation.

"Checkpoint inhibitors have deservedly stirred considerable excitement in the oncology community as their application yields notable results against a growing variety of cancers," said Adam Kolom, managing director of CRI's venture fund and Clinical Accelerator, which organizes and provides philanthropic funding and clinical resources for this and other promising immunotherapy trials. "This will be the first time the immunotherapeutic agent will be tested against this difficult-to-treat cancer, and its outcomes are eagerly anticipated by the GBM patient community."

The other trial, which Ludwig and CRI launched in 2013, is a Phase 1 nonrandomized multicenter trial evaluating the combination of durvalumab with another checkpoint blockade therapy (tremelimumab, anti-CTLA-4) for the treatment of a variety of advanced solid tumors including ovarian cancer, non-small cell lung cancer, colorectal cancer, head and neck cancer, cervical cancer and kidney cancer.

Both clinical trials, which are now under way, are part of a larger clinical research program supported by Ludwig and CRI to speed the evaluation of novel cancer immunotherapies, alone or in combination with other cancer drugs. All of the studies will include collection of genetic and immunologic data derived from clinical samples obtained from patients. Such information will provide clues to the impact of the evaluated therapies and suggest refined or new strategies for treating cancer.

Source:

Ludwig Institute for Cancer Research

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por cyto às 18:12

Sábado, 04.07.15

gene mutation linked to anaplastic oligodendroglioma

Scientists identify gene mutation linked to anaplastic oligodendroglioma

Published on June 12, 2015 at 9:23 AM · 

Scientists have identified a gene mutation linked to the development of an aggressive form of brain cancer.

Researchers found that errors in a gene known as TCF12 - which plays a key role in the formation of the embryonic brain are associated with more aggressive forms of a disease called anaplastic oligodendroglioma.

The new research is the largest ever genetic study of oligodendrogliomas, and provides important insights into their causes - and how they might be treated.

Oligodendrogliomas are fast-growing cancers that account for around 5-10 per cent of all tumours of the brain and central nervous system, and typically have a very poor prognosis.

Researchers at The Institute of Cancer Research, London, in collaboration with laboratories in France and Canada, compared the genetic sequence of 134 of these brain tumours with the DNA of healthy cells.

The study was largely funded by Investissements d'avenir and Génome Québec, with support from Cancer Research UK, and was published in the journal Nature Communications.

Researchers identified mutations in the TCF12 gene in 7.5 per cent of anaplastic oligodendrogliomas. They found that this subset of cancers grew more rapidly, and in other ways seemed more aggressive, than those where the gene was intact.

TCF12 is the genetic code for a protein that binds to DNA and controls the activity of other genes. The researchers found that mutations in TCF12 rendered the protein less able to bind to DNA, and this in turn led to a reduction in activity of other key genes - including one already associated with cancer spread, known as CHD1.

The researchers initially read the DNA sequence of 51 tumours and went on to look for TCF12 mutations in an additional group of 83.

The researchers also discovered errors in the gene IDH1 in 78 per cent of the tumours, confirming the findings of an initial scan of the data.

Finding out more about what genetic faults cause anaplastic oligodendrogliomas will allow scientists and clinicians to develop new personalised therapies that target a range of the mutations driving the disease.

Professor Richard Houlston, Professor of Molecular and Population Genetics at The Institute of Cancer Research, London, said:

"Our in-depth study has set out many of the genetic defects that cause this rare but highly aggressive form of brain cancer - including identifying a gene mutation that appears in particularly fast-growing forms.

"Anaplastic oligodendrogliomas are difficult to remove by surgery and don't respond well to other forms of treatment. We hope this new information might be used to discover new targeted therapies, offering patients a better chance at survival from this aggressive cancer."

Source:

Institute of Cancer Research

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por cyto às 11:46

Sábado, 04.07.15

Harvard Medical School scientists reveal structure of vesicular stomatitis virus protein

Harvard Medical School scientists reveal structure of vesicular stomatitis virus protein

Published on July 3, 2015 at 5:17 AM 

Viruses need us. In order to multiply, viruses have to invade a host cell and copy their genetic information. To do so, viruses encode their own replication machinery or components that subvert the host replication machinery to their advantage.

Ebola virus and rabies virus, two of the most lethal pathogens known to humans, belong to an order of RNA viruses that share a common strategy for copying their genomes inside their hosts. Other relatives include Marburg virus, measles, mumps, respiratory syncytial virus and vesicular stomatitis virus (VSV). Scientists study VSV, which causes acute disease in livestock but typically does not lead to illness in people, as a model for viruses that are harmful to humans.

Now a team from Harvard Medical School, using electron cryomicroscopy (imaging frozen specimens to reduce damage from electron radiation), has for the first time revealed the structure of a VSV protein at the atomic level. Called polymerase protein L, it is required for viral replication in this group of RNA viruses. The findings are published in Cell.

"We now have a better understanding of how RNA synthesis works for these viruses," said Sean Whelan, HMS professor of microbiology and immunobiology and senior author of the paper. "I think if you were trying to develop a viral-specific target to block the replication of one of these viruses, having the structure of the polymerase protein would help."

Scientists already know how these RNA viruses infect cells. They start by delivering a large protein RNA complex, which is viral RNA enclosed in a protein coat. The protein that copies viral RNA is polymerase protein L, which conducts all the enzymatic activities needed to synthesize RNA and then add a cap structure to its end to ensure it doesn't get destroyed by the cell--and to ensure that it can be translated into protein.

While researchers have known the atomic structures of the protein that coats the viral RNA, there are no data on protein L's atomic structure.

Antiviral drugs that target polymerase molecules are based in part on knowing their structure. That approach has been successful against HIV and herpes and hepatitis C viruses. But for the class of viruses known as nonsegmented negative-strand RNA viruses, finding the structure of polymerase protein L has been challenging.

The "L" stands for large. Larger proteins are often difficult to produce and to purify, Whelan said. Protein L is also flexible, with many functional fragments that are hard to isolate. The viruses evolved to make only small quantities of this protein.

Five years ago, using a lower-resolution form of electron microscopy in which the protein is visualized in the presence of negative stain, Whelan's team was able to detect at low resolution a structure that looked like a doughnut with three globular domains. Those earlier studies were informative, but the approach could not provide the atomic level of resolution the team ultimately needed.

Advances in electron cryomicroscopy encouraged them to try again. A team from Whelan's lab, working with a group led by Stephen Harrison, Giovanni Armenise - Harvard Professor of Basic Biomedical Science at HMS and a Howard Hughes Medical Institute (HHMI) investigator, was able to collect data from their viral samples that gave them much greater resolution. They also were able to align the images they collected into a three-dimensional model of polymerase protein L.

Into the density map obtained from these studies, members of the team built an atomic model of the polypeptide chain of VSV L protein. Solving this puzzle was a significant challenge and also involved the team of Nikolaus Grigorieff at HHMI's Janelia campus.

The result? An atomic level model of polymerase protein L's structure for VSV, which will form the basis for understanding the L protein of the other viruses in the order.

"The Ebola protein will look the same, the rabies protein will look the same, the other L proteins will look the same," Whelan said. "There will be some subtle differences reflecting the precise nature of amino acids, but we know that they're functionally and structurally the same."

Knowing the structure means scientists can explore how RNA synthesis is working in these viruses.

"It begins to suggest ways that we can perhaps pull apart other proteins that have not been so easy to express, such as the L protein in Ebola," Whelan said. "It doesn't mean we're going to have inhibitors immediately, but this is an important step, I think, towards that longer-term goal."

Source:

Harvard Medical School

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por cyto às 11:37

Sábado, 04.07.15

new protein that affects growth of secondary breast tumours in the brain

Scientists identify new protein that affects growth of secondary breast tumours in the brain

Published on July 1, 2015 at 7:19 AM 

Scientists from the University of Leeds and The Institute of Cancer Research, London, have discovered a new protein which triggers the growth of blood vessels in breast cancer tumours which have spread to the brain, a common location which breast cancer can spread to.

Dr Georgia Mavria's team in the School of Medicine at Leeds found that by withholding the DOCK4 protein in mouse models, a particular part of the blood vessel did not form as quickly, meaning tumours grew at a slower rate.

Dr Mavria said: "We want to understand how these tumours form and grow, but we still need to do more research to stop these tumours growing altogether.

"The finding gives an important indicator of how the protein affects the growth of secondary breast tumours in the brain. The discovery could also enable experts to predict which patients might be at risk of their breast cancer spreading, and develop drugs to prevent the growth of secondary tumours."

Working with Professor Chris Marshall, Professor of Cell Biology at The Institute of Cancer Research, London and the late Dr Tony Pawson at the Lunenfeld-Tanenbaum Research Institute in Toronto, researchers found that a complex of two related proteins, DOCK4 and DOCK9, is critical in the formation of the lumen, the interior space of a vessel through which blood flows.

By impeding the speed at which the lumen forms, tumours are not fed as effectively by blood vessels.

Normally, when breast cancer spreads to other parts of the body, it forces new blood vessels to form to supply it with nutrients and oxygen to help it to grow, resulting in tumours that are very difficult to treat.

Professor Marshall said: "Our study reveals new insights into how the complex process of forming blood vessels is controlled. This knowledge could lead to new approaches to preventing the blood supply to tumours and metastases. If we can find new ways to reduce the blood supply to tumours, we might be able to find new ways to slow cancer growth in future."

The research, which has been published in Nature Communications, was funded by Breast Cancer Now, Yorkshire Cancer Research and Cancer Research UK.

Dr Matthew Lam, Senior Research Communications Officer at Breast Cancer Now, said: "These findings could one day help us better identify and treat patients that might be at risk of their breast cancer spreading to the brain, a particularly common site for metastasis.

"12,000 women have their lives cut short by breast cancer in the UK each year. An understanding of what is happening on a molecular level - such as the role played by DOCK proteins - will be essential if we are to find ways to prevent secondary tumours and finally stop women dying from the disease."

Kathryn Scott, Head of Research and Innovation at Yorkshire Cancer Research, said: "Tumours need blood vessels to grow, but these blood vessels could be the cancer's weakest link because it is believed that they are less able to become resistant to drugs than the cancer cells themselves. Targeting drugs to the blood vessels that are serving the tumour rather than the tumour itself is an exciting new area of research and we are supporting a number of projects in Yorkshire which are investigating this approach."

Dr Aine McCarthy, Science Information Officer at Cancer Research UK, said: "This research shows for the first time that a molecule called DOCK4 is a key player in tumour blood vessel development and blocking it could slow tumour growth by starving the cancer cells. But the study was carried out in mice, so more research is needed to see if drugs can be developed that target the molecule and whether this approach would be safe and effective in people with cancer."

Source:

University of Leeds

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por cyto às 11:34

Sábado, 04.07.15

way to stop growth of cancer cells by targeting the Warburg Effect

SLU researchers find way to stop growth of cancer cells by targeting the Warburg Effect

Published on June 26, 2015 at 10:55 PM 

In research published in Cancer Cell, Thomas Burris, Ph.D., chair of pharmacology and physiology at Saint Louis University, has, for the first time, found a way to stop cancer cell growth by targeting the Warburg Effect, a trait of cancer cell metabolism that scientists have been eager to exploit.

Unlike recent advances in personalized medicine that focus on specific genetic mutations associated with different types of cancer, this research targets a broad principle that applies to almost every kind of cancer: its energy source.

The Saint Louis University study, which was conducted in animal models and in human tumor cells in the lab, showed that a drug developed by Burris and colleagues at Scripps Research Institute can stop cancer cells without causing damage to healthy cells or leading to other severe side effects.

The Warburg Effect

Metabolism -- the ability to use energy -- is a feature of all living things. Cancer cells aggressively ramp up this process, allowing mutated cells to grow unchecked at the expense of surrounding tissue.

"Targeting cancer metabolism has become a hot area over the past few years, though the idea is not new," Burris said.

Since the early 1900s, scientists have known that cancer cells prefer to use glucose as fuel even if they have plenty of other resources available. In fact, this is how doctors use PET (positron emission tomography) scan images to spot tumors. PET scans highlight the glucose that cancer cells have accumulated.

This preference for using glucose as fuel is called the Warburg effect, or glycolysis.

In his paper, Burris reports that the Warburg effect is the metabolic foundation of oncogenic (cancer gene) growth, tumor progression and metastasis as well as tumor resistance to treatment.

Cancer's goal: to grow and divide

Cancer cells have one goal: to grow and divide as quickly as possible. And, while there are a number of possible molecular pathways a cell could use to find food, cancer cells have a set of preferred pathways.

"In fact, they are addicted to certain pathways," Burris said. "They need tools to grow fast and that means they need to have all of the parts for new cells and they need new energy."

"Cancer cells look for metabolic pathways to find the parts to grow and divide. If they don't have the parts, they just die," said Burris. "The Warburg effect ramps up energy use in the form of glucose to make chemicals required for rapid growth and cancer cells also ramp up another process, lipogenesis, that lets them make their own fats that they need to rapidly grow."

If the Warburg effect and lipogenesis are key metabolic pathways that drive cancer progression, growth, survival, immune evasion, resistance to treatment and disease recurrence, then, Burris hypothesizes, targeting glycolysis and lipogenesis could offer a way to stop a broad range of cancers.

Cutting off the energy supply

Burris and his colleagues created a class of compounds that affect a receptor that regulates fat synthesis. The new compound, SR9243, which started as an anti-cholesterol drug candidate, turns down fat synthesis so that cells can't produce their own fat. This also impacts the Warburg pathway, turning cancer cells into more normal cells. SR9243 suppresses abnormal glucose consumption and cuts off cancer cells' energy supply.

When cancer cells don't get the parts they need to reproduce through glucose or fat, they simply die.

Because the Warburg effect is not a feature of normal cells and because most normal cells can acquire fat from outside, SR9243 only kills cancer cells and remains non-toxic to healthy cells.

The drug also has a good safety profile; it is effective without causing weight loss, liver toxicity, or inflammation.

Promising Results So far, SR9243 has been tested in cultured cancer cells and in human tumor cells grown in animal models. Because the Warburg pathway is a feature of almost every kind of cancer, researchers are testing it on a number of different cancer models.

"It works in a wide range of cancers both in culture and in human tumors developing in animal models," Burris said. "Some are more sensitive to it than others. In several of these pathways, cells had been reprogramed by cancer to support cancer cell growth. This returns the metabolism to that of more normal cells."

In human tumors grown in animal models, Burris said, "It worked very well on lung, prostate, and colorectal cancers, and it worked to a lesser degree in ovarian and pancreatic cancers."

It also seems to work on glioblastoma, an extremely difficult to treat form of brain cancer, though it isn't able to cross the brain/blood barrier very effectively. The challenge for researchers in this scenario will be to find a way to allow the drug to cross this barrier, the body's natural protection for the brain, which can make it difficult for drug treatments to reach their target.

And, in even more promising news, it appears that when SR9243 is used in combination with existing chemotherapy drugs, it increases their effectiveness, in a mechanism apart from SR9243's own cancer fighting ability.

Source:

Saint Louis University

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por cyto às 11:25

Quinta-feira, 25.06.15

Acute Lymphoblastic Leukemia, Blood, Blood Cancer, Blood Disorder, Bone, Bone Marrow, Cancer, Cardiology, Cell, DNA, Education, Gene, Genetic, Genetics, Hematology, Hospital, Leukemia, Neurology, Neurosurgery, Oncology, Pediatrics, Platelets, Thrombocytop

Researchers track down key gene mutation responsible for causing acute lymphoblastic leukemia

Published on June 18, 2015 at 8:52 AM ·

After collecting data on a leukemia-affected family for nearly a decade, Children's Hospital of Michigan, Detroit Medical Center (DMC), Hematologist and Wayne State University School of Medicine Professor of Pediatrics Madhvi Rajpurkar, M.D., joined an international team of genetic researchers in an effort to track down a mutation partly responsible for causing the disease. Their findings, recently published in one of the world's leading science journals, have "major implications" for better understanding the genetic basis of several types of cancer, including leukemia.

Says Children's Hospital of Michigan Hematology/Oncology Researcher and Wayne State University Assistant Professor of Pediatrics Michael Callaghan, M.D., an investigator who co-authored the recently published study in Nature Genetics: "This is a very exciting new finding in cancer research - and I think a lot of the credit has to go to Dr. Rajpurkar for identifying the family (with the genetic mutation). This is a great example of how an astute clinician can help accomplish a breakthrough in research by paying careful attention to patients and then thinking long and hard about what she is seeing in the treatment room."

Two medical researchers from the Children's Hospital of Michigan and the Wayne State University School of Medicine have published the results of a nearly 10-year investigation that identified a key gene mutation that can trigger acute lymphoblastic leukemia, or ALL, and several other types of cancer.

Recently published in Nature Genetics, the findings assembled by the Children's Hospital of Michigan and Wayne State University School of Medicine duo and a team of international investigators have for the first time pinpointed a mutation that allows a lymphoblastic leukemia "precursor" to set the biochemical stage for the blood disorder.

ALL is a blood cancer that attacks an early version of white blood cells manufactured in bone marrow. Investigators have long suspected that it is caused in part by a mutation in a gene that is supposed to "turn off" excessive blood-cell growth. When the mutation suppresses the controlling mechanism that regulates the runaway growth, leukemia is often the result.

The study, "Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia," began nearly a decade ago when Dr. Rajpurkar treated a child at the Children's Hospital of Michigan for low blood platelets, known medically as "congenital thrombocytopenia." When both the child and an aunt later developed ALL - even as several other family members were diagnosed with thrombocytopenia - Dr. Rajpurkar began to suspect that there might be a genetic mutation at work in the family.

What followed was a 10-year journey through the labyrinth of the Human Genome, as the researchers worked with a growing number of genetic investigators to isolate and identify the mutation in a gene (ETV6) that regulates growth rates in bone marrow.

A key breakthrough in the quest for the genetic culprit took place when a nationally recognized expert in gene mutation - University of Colorado physician-researcher Jorge DiPaola, M.D. - joined Drs. Rajpurkar and Callaghan, and other investigators from Italy and Canada, in the effort to solve the DNA puzzle by uncovering the flaw in ETV6. The mutation discovery occurred in a core facility where the gene-sequencing took place.

While noting that "our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition," the study's authors concluded that the mutation occurs through "aberrant cellular localization" of the gene, which can result in "decreased transcriptional repression" during white blood cell formation.

"What we think that means," Dr. Callaghan said, "is that ETV6's job is to 'turn off' growth, but when you have this mutation, it can't turn it off because it's in the wrong place. It's usually supposed to sit on the DNA and keep things (including cancer) from getting made, but when you have this mutation, instead of sitting on the DNA it's sitting in a different part of the cell.... And that predisposes you to getting a (blood) cancer."

Dr. Rajpurkar, who is also the division chief of Hematology at the Children's Hospital of Michigan and an associate professor of Pediatrics at the Wayne State University School of Medicine, said she was "greatly pleased" that her decade of treating the Detroit family with the mutation eventually led to the breakthrough. "I told them that I didn't know what the family had," she said, "but that I would do my best to find out. Sometimes one has to accept uncertainty in the field of medicine, but (persistence in clinical research) pays off!"

The Children's Hospital of Michigan Pediatrician-in-Chief and chair of the Wayne State University School of Medicine Department of Pediatrics Steven E. Lipshultz, M.D., said the breakthrough was "hugely important" because it resulted in "a new association (between a genetic mutation and leukemia) that can now be scanned for.

"Because of this finding," he added, "families will eventually be counseled regarding their risk for some kinds of cancer and targeted interventions will be devised and tested."

Dr. Lipshultz also noted that the new findings in "what many physicians and researchers regard as the leading journal in the world on the molecular genetic basis of human disease" also provide "an exciting and extremely encouraging example of how research that takes place in the clinical setting can greatly improve care for patients.

"Our goal at the Children's Hospital of Michigan is to do everything we can to help achieve better outcomes for the patients we serve. This latest publication by two CHM physician-researchers and their colleagues underlines the vitally important links between treatment and research, and to see them demonstrated so compellingly inNature Genetics is quite thrilling for all of us who spend our days trying to help kids at the Children's Hospital of Michigan!"

Source:

Wayne State University - Office of the Vice President for Research

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por cyto às 11:49

Segunda-feira, 18.05.15

new strategy to combat cancer

CNIO researchers identify new strategy to combat cancer

Published on May 14, 2015 at 4:23 AM · 

Scientists from the Spanish National Cancer Research Centre (CNIO) have discovered a new strategy to fight cancer, which is very different from those described to date. Their work shows for the first time that telomeres -- the structures protecting the ends of the chromosomes -- may represent an effective anti-cancer target: by blocking the TRF1 gene, which is essential for the telomeres, they have shown dramatic improvements in mice with lung cancer.

"Telomere uncapping is emerging as a potential mechanism to develop new therapeutic targets for lung cancer," mention the authors with equal contribution in EMBO Molecular Medicine; Maria Garcia-Beccaria, Paula Martinez and Marinela Mendez, from the CNIO Telomeres and Telomerase Group led by Maria Blasco, who is also an author in the article. The research was also carried out in collaboration with the Experimental Therapeutics Programme, the Experimental Oncology Group and the Histopathology, Molecular Imaging and Microscopy Units at the CNIO, as well as with the Animal Medicine and Surgery Department at the Universidad Complutense de Madrid.

Every time a cell divides, it must duplicate its genetic material, the DNA, which is packed inside the chromosomes. However, given how the mechanism of DNA replication works, the end of each chromosome cannot be replicated completely, and, as a result, telomeres shorten with each cell division. Excessively short telomeres are toxic to cells, which stop replicating, and eventually, the cells are eliminated by senescence or apoptosis.

This phenomenon has been known for decades, as well as the fact that it usually does not occur in tumour cells. Cancer cells proliferate without any apparent limits, and therefore, they are constantly dividing, but their telomeres do not gradually become shorter; the key behind this mechanism is that the telomerase enzyme in cancer cells remains active, while in most healthy cells telomerase is turned off. The constant repair of telomeres by telomerase is, in fact, one of the mechanisms that allows tumour cells to be immortal and divide endlessly.

Hence, an obvious strategy to fight cancer is to inhibit the telomerase enzyme in tumour cells. This approach has been tested before, but with worrisome results: telomeres do shorten, but this shortening is lethal to tumour cells only after a variable number of cell divisions necessary for telomeres to become completely eroded-- thus the effects are not instantly seen.

In the study now published, the researchers also target telomeres, but their approach is completely different from the telomerase one.

A NEW APPROACH FOR THE ACUTE TELOMERE UNCAPPING

Telomeres are made up of repeating patterns of DNA sequences that are repeated hundreds of times -- this is the structure that shortens with each cellular division. Telomere DNA is bound by a six-protein complex, called shelterin (from the term shelter or protection), which forms a protective covering. The CNIO team strategy consisted of blocking one of the shelterins, namely TRF1, so that that the telomere shield was destroyed.

The idea of targeting one of the shelterins has not been tried so far, due to the fear of encountering many toxic effects caused by acting on these proteins that are present in both healthy and tumour cells.

"Nobody had explored the idea of using one of the shelterins as an anti-cancer target," explains Blasco. "It is difficult to find drugs that interfere with protein binding to DNA, and the possibility exists that drugs targeting telomere caps could be very toxic. For these reasons, no one had explored this option before, although it makes a lot of sense."

FEWER THAN EXPECTED SIDE-EFFECTS

The present work subtitled 'Shelterin as a novel target in cancer,' shows that blocking TRF1 only causes minor toxicities that are well tolerated by mice. "It does however prevent the growth of lung carcinomas already developed in mice," write the authors inEMBO Molecular Medicine.

"TRF1 removal induces an acute telomere uncapping, which results in cellular senescence or cell death. We have seen that this strategy kills cancer cells efficiently, stops tumour growth and has bearable toxic effects," explains Blasco.

TRF1 has been inhibited both genetically -- in mice where the gene has been removed -- and chemically using selected compounds from CNIO's proprietary collection of active compounds. These compounds, including the inhibitor ETP-470037 developed by the CNIO Experimental Therapeutics Programme, may provide a starting point for the development of new drugs for cancer therapy.

"We've shown that we can find potential drugs able to inhibit TRF1 that have therapeutic effects when administered orally to mice," says Blasco.

A CANCER WITH NO CURRENTLY AVAILABLE THERAPEUTIC TARGETS

The scientists worked with mouse models for lung cancer, the cancer type that has the highest death rates worldwide. Specifically, they used a mouse with a very aggressive type of lung cancer for which no drug targets have been found to date: the tumours have an active K-Ras oncogene and the p53 tumor suppressor is missing. TRF1 is the first target that is able to inhibit the growth of these highly aggressive tumours.

The work process has been long. The researchers first selected TRF1 among the shelterin family. TRF1 is one of the most studied shelterins that is present exclusively at the telomeres and has potential as a good anti-cancer target -- its inhibition also affects the so-called cancer stem cells that might be responsible for tumour recurrence over time.

The next aim was to demonstrate that TRF1 is really an anti-cancer target. To do so, the researchers genetically blocked its activity in mice with lung cancer as well as in healthy mice, in order to test the toxicity of the procedure.

Having established the effectiveness and low toxicity of the new target, the researchers searched for chemical compounds that could have activity against TRF1. Two types of compounds have been found. "We are now looking for partners in the pharmaceutical industry to bring this research into more advanced stages of drug development," says Blasco.

Source:

Centro Nacional de Investigaciones Oncologicas (CNIO)

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por cyto às 13:46


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