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



Sábado, 04.07.15

Fibromyalgia now considered as a lifelong central nervous system disorder

Fibromyalgia now considered as a lifelong central nervous system disorder

Published on May 18, 2015 at 6:10 AM ·

Fibromyalgia is the second most common rheumatic disorder behind osteoarthritis and, though still widely misunderstood, is now considered to be a lifelong central nervous system disorder, which is responsible for amplified pain that shoots through the body in those who suffer from it. Daniel Clauw, M.D., professor of anesthesiology, University of Michigan, analyzed the neurological basis for fibromyalgia in a plenary session address today at the American Pain Society Annual Scientific Meeting.

"Fibromyalgia can be thought of both as a discreet disease and also as a final common pathway of pain centralization and chronification. Most people with this condition have lifelong histories of chronic pain throughout their bodies," said Clauw. "The condition can be hard to diagnose if one isn't familiar with classic symptoms because there isn't a single cause and no outward signs."

Clauw explained that fibromyalgia pain comes more from the brain and spinal cord than from areas of the body in which someone may experience peripheral pain. The condition is believed to be associated with disturbances in how the brain processes pain and other sensory information. He said physicians should suspect fibromyalgia in patients with multifocal (mostly musculoskeletal) pain that is not fully explained by injury or inflammation.

"Because pain pathways throughout the body are amplified in fibromyalgia patients, pain can occur anywhere, so chronic headaches, visceral pain and sensory hyper-responsiveness are common in people with this painful condition," said Clauw.

"This does not imply that peripheral nociceptive input does not contribute to pain experienced by fibromyalgia patients, but they do feel more pain than normally would be expected from the degree of peripheral input. Persons with fibromyalgia and other pain states characterized by sensitization will experience pain from what those without the condition would describe as touch," Clauw added.

Due to the central nervous system origins of fibromyalgia pain, Clauw said treatments with opioids or other narcotic analgesics usually are not effective because they do not reduce the activity of neurotransmitters in the brain. "These drugs have never been shown to be effective in fibromyalgia patients, and there is evidence that opioids might even worsen fibromyalgia and other centralized pain states," he said.

Clauw advises clinicians to integrate pharmacological treatments, such as gabapentinoids, trycyclics and serotonoin reuptake inhibitors, with nonpharmacological approaches like cognitive behavioral therapy, exercise and stress reduction.

"Sometimes the magnitude of treatment response for simple and inexpensive non-drug therapies exceeds that for pharmaceuticals," said Clauw. "The greatest benefit is improved function, which should be the main treatment goal for any chronic pain condition. The majority of patients with fibromyalgia can see improvement in their symptoms and lead normal lives with the right medications and extensive use of non-drug therapies."

Source:

American Pain Society (APS)

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por cyto às 11:40

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

Umeå University researchers capture and describe 'invisible' protein structure

Umeå University researchers capture and describe 'invisible' protein structure

Published on July 3, 2015 at 6:07 AM 

A research group at Umeå University in Sweden has managed to capture and describe a protein structure that, until now, has been impossible to study. The discovery lays the base for developing designed enzymes as catalysts to new chemical reactions for instance in biotechnological applications. The result of the study is published in the journal Nature Communications.

Enzymes are extraordinary biocatalysts able to speed up the cellular, chemical reactions several million times. This increase of speed is completely necessary for all biological life, which would otherwise be limited by the slow nature of vital chemical reactions. Now, a research group at the Department of Chemistry has discovered a new aspect in enzymes that, in part, explains how enzymes manage their tasks with unmatched efficiency and selectivity.

So-called high-energy states in enzymes are regarded as necessary for catalysing of chemical reactions. A high-energy level is a protein structure only occurring temporarily and for a short period of time; and these factors collaborate until its state becomes invisible to traditional spectroscopic techniques. The Umeå researchers have managed to find a way to maintain a high-energy state in the enzyme, adenylate kinase, by mutating the protein.

"Thanks to this enrichment, we have been able to study both structure and dynamics of this state. The study shows that enzymatic high-energy states are necessary for chemical catalysis," says Magnus Wolf-Watz, research group leader at the Department of Chemistry.

The study also indicates a possibility to fine-tune the dynamics of an enzyme and this possibility can be useful for researchers in developing new enzymes for catalysis of new chemical reactions.

"Research on Bioenergy is an active field at Umeå University. An important, practical application of the new knowledge can be enzymatic digestion of useful molecules from wooden raw materials," says Magnus Wolf-Watz.

The discovery has been made possible thanks to a broad scientific approach where numerous advanced biophysical techniques have been used; Nuclear Magnetic Resonance (NMR) and x-ray crystallography being the main techniques.

"One of the strengths of Umeå University is the open cooperative climate with low or no barriers between research groups. It means that exciting research can be conducted in the borderland of differing expertise," says Magnus Wolf-Watz.

The main author of the article is Michael Kovermann who has completed his postdoctoral position at Umeå University and will shortly return to Germany for a professorship at the University of Konstanz.

Source:

Umea University

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por cyto às 11:31

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

Sábado, 04.07.15

Nanoparticles packed with chemotherapy drug and coated with chitosan target cancer stem-like cells

 

Nanoparticles packed with chemotherapy drug and coated with chitosan target cancer stem-like cells

Published on July 1, 2015 at 7:35 AM ·

Nanoparticles packed with a clinically used chemotherapy drug and coated with an oligosaccharide derived from the carapace of crustaceans might effectively target and kill cancer stem-like cells, according to a recent study led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James). Cancer stem-like cells have characteristics of stem cells and are present in very low numbers in tumors. They are highly resistant to chemotherapy and radiation and are believed to play an important role in tumor recurrence. This laboratory and animal study showed that nanoparticles coated with the oligosaccharide called chitosan and encapsulating the chemotherapy drug doxorubicin can target and kill cancer stem-like cells six times more effectively than free doxorubicin.

"Our findings indicate that this nanoparticle delivery system increases the cytotoxicity of doxorubicin with no evidence of systemic toxic side effects in our animal model," says principal investigator Xiaoming (Shawn) He, PhD, associate professor of Biomedical Engineering and a member of the OSUCCC - James Translational Therapeutics Program.

"We believe that chitosan-decorated nanoparticles could also encapsulate other types of chemotherapy and be used to treat many types of cancer."

This study showed that chitosan binds with a receptor on cancer stem-like cells called CD44, enabling the nanoparticles to target the malignant stem-like cells in a tumor.

The nanoparticles were engineered to shrink, break open, and release the anticancer drug under the acidic conditions of the tumor microenvironment and in tumor-cell endosomes and lysosomes, which cells use to digest nutrients acquired from their microenvironment.

He and his colleagues conducted the study using models called 3D mammary tumor spheroids (i.e., mammospheres) and an animal model of human breast cancer.

The study also found that although the drug-carrying nanoparticles could bind to the variant CD44 receptors on cancerous mammosphere cells, they did not bind well to the CD44 receptors that were overexpressed on noncancerous stem cells.

Source:

Ohio State University Wexner Medical Center

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por cyto às 11:21

Sábado, 04.07.15

new immunotherapy treatment for cancer patients

 

CTCA at Western begins Phase Ib/II trial of new immunotherapy treatment for cancer patients

Published on June 27, 2015 at 2:15 AM · 

Cancer Treatment Centers of America® (CTCA) at Western Regional Medical Center (Western) in Goodyear, Arizona, has begun a new Phase Ib/II clinical trial using a new immunotherapy treatment for patients with advanced kidney, non-small cell lung cancer, pancreatic cancer and colorectal carcinoma.

This "NivoPlus" clinical trial combines an immunotherapy drug (nivolumab) with already FDA-approved chemotherapy drugs (temsirolimus, irinotecan, and a combination of irinotecan and capecitabine).

The addition of nivolumab is intended to activate the body's own immune system to improve on the results that otherwise might not be achieved from chemotherapy alone. This combination of chemotherapy and immunotherapy drugs is investigational in this study and is the third such combination clinical trial launched in the past year by CTCA® at Western.

There are anticipated to be up to 49 patients enrolled on the multi-arm NivoPlus study. The first patient received treatment on this study earlier this month.

"Some of these drug combinations are not available elsewhere, giving CTCA patients additional treatment options," said Dr. Glen Weiss, Director of Clinical Research and Medical Oncologist, CTCA at Western. "Our ultimate goal is to evaluate if these combinations yield improved results for our patients."

Nivolumab works by inhibiting a protein called PD-1, which otherwise blocks the body's immune system from attacking cancerous cells.

Nivolumab was approved by the Food and Drug Administration in December 2014 for the treatment of advanced melanoma and on March 4, 2015, for patients with previously treated metastatic squamous non-small cell lung cancer.

"Patients with these types of advanced-stage cancers have tumors that may be challenging to treat," said Dr. Vivek Khemka, Medical Oncologist, CTCA Western and NivoPlus Principal Investigator. "We are investigating whether combining nivolumab with these chemotherapy drugs will be a more powerful approach against their disease."

Recent data reported in the New England Journal of Medicine and Lancet demonstrates promising results with antibody-based immunostimulatory therapy in treating melanoma, renal cell carcinoma, non-small cell lung cancer and colorectal cancer. Data has also shown synergetic effects of utilizing cytotoxic chemotherapy in combination with immunostimulatory therapy. NivoPlus will build upon this data, extending treatment options to additional cancer types.

CTCA investigators have been actively researching the impact of immunotherapy, a topic prominently highlighted this year at the annual conferences of both the American Association for Cancer Research (AACR) and the American Society of Clinical Oncologists (ASCO).

At AACR, physicians described immunotherapy as now being considered an integral part of cancer biology and cancer treatment, and recent clinical successes were described as "stunning" and "unprecedented" in their ability to improve the care of cancer patients.

At ASCO, a full press briefing was devoted to the subject of immunotherapy, which was described by doctors as "one of the most exciting advances in oncology," enabling the body's own immune system to target cancer tumors and key to helping accelerate the pace of progress "and ultimately achieve cures for cancer."

Additionally, in 2013, Science magazine named cancer immunotherapy the scientific breakthrough of the year.

CTCA physicians are committed to bringing the latest technologies and advanced treatment options to their patients as quickly as possible. At the same time, CTCA patients are supported with therapies to reduce side effects, boost energy levels and keep them strong during treatment.

Source:

Cancer Treatment Centers of America

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por cyto às 11:18

Quinta-feira, 02.07.15

CTCA at Western begins Phase Ib/II trial of new immunotherapy treatment for cancer patients

CTCA at Western begins Phase Ib/II trial of new immunotherapy treatment for cancer patients

Published on June 27, 2015 at 2:15 AM · 

Cancer Treatment Centers of America® (CTCA) at Western Regional Medical Center (Western) in Goodyear, Arizona, has begun a new Phase Ib/II clinical trial using a new immunotherapy treatment for patients with advanced kidney, non-small cell lung cancer, pancreatic cancer and colorectal carcinoma.

This "NivoPlus" clinical trial combines an immunotherapy drug (nivolumab) with already FDA-approved chemotherapy drugs (temsirolimus, irinotecan, and a combination of irinotecan and capecitabine).

The addition of nivolumab is intended to activate the body's own immune system to improve on the results that otherwise might not be achieved from chemotherapy alone. This combination of chemotherapy and immunotherapy drugs is investigational in this study and is the third such combination clinical trial launched in the past year by CTCA® at Western.

There are anticipated to be up to 49 patients enrolled on the multi-arm NivoPlus study. The first patient received treatment on this study earlier this month.

"Some of these drug combinations are not available elsewhere, giving CTCA patients additional treatment options," said Dr. Glen Weiss, Director of Clinical Research and Medical Oncologist, CTCA at Western. "Our ultimate goal is to evaluate if these combinations yield improved results for our patients."

Nivolumab works by inhibiting a protein called PD-1, which otherwise blocks the body's immune system from attacking cancerous cells.

Nivolumab was approved by the Food and Drug Administration in December 2014 for the treatment of advanced melanoma and on March 4, 2015, for patients with previously treated metastatic squamous non-small cell lung cancer.

"Patients with these types of advanced-stage cancers have tumors that may be challenging to treat," said Dr. Vivek Khemka, Medical Oncologist, CTCA Western and NivoPlus Principal Investigator. "We are investigating whether combining nivolumab with these chemotherapy drugs will be a more powerful approach against their disease."

Recent data reported in the New England Journal of Medicine and Lancet demonstrates promising results with antibody-based immunostimulatory therapy in treating melanoma, renal cell carcinoma, non-small cell lung cancer and colorectal cancer. Data has also shown synergetic effects of utilizing cytotoxic chemotherapy in combination with immunostimulatory therapy. NivoPlus will build upon this data, extending treatment options to additional cancer types.

CTCA investigators have been actively researching the impact of immunotherapy, a topic prominently highlighted this year at the annual conferences of both the American Association for Cancer Research (AACR) and the American Society of Clinical Oncologists (ASCO).

At AACR, physicians described immunotherapy as now being considered an integral part of cancer biology and cancer treatment, and recent clinical successes were described as "stunning" and "unprecedented" in their ability to improve the care of cancer patients.

At ASCO, a full press briefing was devoted to the subject of immunotherapy, which was described by doctors as "one of the most exciting advances in oncology," enabling the body's own immune system to target cancer tumors and key to helping accelerate the pace of progress "and ultimately achieve cures for cancer."

Additionally, in 2013, Science magazine named cancer immunotherapy the scientific breakthrough of the year.

CTCA physicians are committed to bringing the latest technologies and advanced treatment options to their patients as quickly as possible. At the same time, CTCA patients are supported with therapies to reduce side effects, boost energy levels and keep them strong during treatment.

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por cyto às 11:56

Quinta-feira, 02.07.15

The HDAC6/APOBEC3G complex regulates HIV-1 infectiveness by inducing Vif autophagic degradation

The HDAC6/APOBEC3G complex regulates HIV-1 infectiveness by inducing Vif autophagic degradation

María-Soledad Valera1, Laura de Armas-Rillo1, Jonathan Barroso-González1, Serena Ziglio1, Julien Batisse2, Noé Dubois2, Sara Marrero-Hernández1, Sophie Borel3, Laura García-Expósito1, Martine Biard-Piechaczyk3, Jean-Christophe Paillart2 and Agustín Valenzuela-Fernández1*

  • *Corresponding author: Agustín Valenzuela-Fernández avalenzu@ull.edu.es

  • † Equal contributors

Author Affiliations

For all author emails, please log on.

Retrovirology 2015, 12:53  doi:10.1186/s12977-015-0181-5


María-Soledad Valera and Laura de Armas-Rillo contributed equally to this work

Published: 24 June 2015

Abstract

Background

Human immunodeficiency virus type 1 (HIV-1) has evolved a complex strategy to overcome the immune barriers it encounters throughout an organism thanks to its viral infectivity factor (Vif), a key protein for HIV-1 infectivity and in vivo pathogenesis. Vif interacts with and promotes “apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3G” (A3G) ubiquitination and subsequent degradation by the proteasome, thus eluding A3G restriction activity against HIV-1.

Results

We found that cellular histone deacetylase 6 (HDAC6) directly interacts with A3G through its C-terminal BUZ domain (residues 841–1,215) to undergo a cellular co-distribution along microtubules and cytoplasm. The HDAC6/A3G complex occurs in the absence or presence of Vif, competes for Vif-mediated A3G degradation, and accounts for A3G steady-state expression level. In fact, HDAC6 directly interacts with and promotes Vif autophagic clearance, thanks to its C-terminal BUZ domain, a process requiring the deacetylase activity of HDAC6. HDAC6 degrades Vif without affecting the core binding factor β (CBF-β), a Vif-associated partner reported to be key for Vif- mediated A3G degradation. Thus HDAC6 antagonizes the proviral activity of Vif/CBF-β-associated complex by targeting Vif and stabilizing A3G. Finally, in cells producing virions, we observed a clear-cut correlation between the ability of HDAC6 to degrade Vif and to restore A3G expression, suggesting that HDAC6 controls the amount of Vif incorporated into nascent virions and the ability of HIV-1 particles of being infectious. This effect seems independent on the presence of A3G inside virions and on viral tropism.

Conclusions

Our study identifies for the first time a new cellular complex, HDAC6/A3G, involved in the autophagic degradation of Vif, and suggests that HDAC6 represents a new antiviral factor capable of controlling HIV-1 infectiveness by counteracting Vif and its functions.

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por cyto às 11:55

Quarta-feira, 01.07.15

Immunotherapies Shine at ASCO Annual Meeting

Immunotherapies Shine at ASCO Annual Meeting

 

The number of immunotherapy agents approved by the U.S. Food and Drug Administration for the treatment of patients with cancer has risen rapidly in recent years.

Naked monoclonal antibodies, such as bevacizumab, rituximab, and trastuzumab, are now approved for the treatment of various solid and hematologic cancers.

Chemolabeled antibodies, such as brentuximab vedotin, ado-trastuzumab emtansine, and the prostate cancer vaccine sipuleucel-T, add to the growing number of immunotherapies being used to combat cancer.

Positive results from various studies evaluating the use of  standard immunotherapies for different cancers and novel immunotherapies were announced at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, IL.

The antiangiogenic drug bevacizumab (Avastin), which is already approved for the treatment of six cancer types, was shown to significantly increase progression-free survival (PFS) in combination with carboplatin and paclitaxel in recurrent endometrial cancer compared with carboplatin plus paclitaxel alone.

The phase 2 study showed that the addition of bevacizumab improved median  PFS by more than 4 months.1 A phase 3 trial evaluating the addition of bevacizumab to letrozole as first-line endocrine therapy found that bevacizumab improved PFS by 4 months in patients with hormone receptor-positive advanced breast cancer.2

In addition, BCD-021, a bevacizumab biosimilar candidate was found to be non-inferior to Avastin in patients with non-small cell lung cancer (NSCLC) in a phase 3 trial.3 Biosimilar drugs, unlike generic drugs, do not have identical active ingredients, but are similar.

Ramucirumab (Cyramza), which is now approved for the treatment of patients with gastric, colorectal, and NSCLC, was shown to provide clinical benefit in combination with docetaxel in advanced NSCLC in the phase 3 REVEL trial, but the study had a limited number of East Asian patients who received the docetaxel 75 mg/m2 dose.

A similar phase 2 study in Japanese patients demonstrated improved clinical benefit with ramucirumab plus docetaxel 60 mg/m2 compared with docetaxel plus placebo.4

The addition of obinutuzumab (Gazyva), a CD20-directed cytolytic antibody, to bendamustine was shown to significantly improve PFS compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma (NHL).5

RELATED: Pembrolizumab Immunotherapy Effective in Recurrent, Metastatic Head and Neck Cancer

“Obinutuzumab plus bendamustine followed by obinutuzumab maintenance represents an effective treatment option for patients with relapsed/refractory indolent NHL who are refractory to rituximab,” said Laurie Sehn, MD, MDCM, MPH, of the British Columbia Cancer Agency in Canada.

“The trial results are remarkable as this does represent the first randomized, controlled trial data that demonstrates the utility of a novel anti-CD20 monoclonal antibody in patients with rituximab-refractory lymphoma.”

The results of two trials evaluating combination immunotherapy in patients with advanced melanoma were announced at the conference. One trial included treatment with nivolumab plus ipilimumab and the other with pembrolizumab plus low-dose ipilimumab.

The first study found that nivolumab plus ipilimumab and nivolumab alone had superior clinical activity compared with ipilimumab alone in treatment-naïve patients.6

The second study demonstrated significantly improved PFS and objective response rate (ORR) with nivolumab plus ipilimumab versus ipilimumab alone.7

A small phase 1 study showed an acceptable safety profile with pembrolizumab plus low-dose ipilimumab in patients with advanced melanoma or renal cell carcinoma, as well.8

Immunotherapies for melanoma have multiplied in the last 5 years with the approval of ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo); however, these treatments can cost up to tens of thousands of dollars.

Two new immunotherapies currently under investigation were shown to have encouraging results in patients with relapsed/refractory hematologic cancers.

The first, polatuzumab vedotin, an anti-CD79b antibody-drug conjugate demonstrated high ORRs when used in combination with rituximab in patients with relapsed/refractory follicular lymphoma.9

The other, elotuzumab, was shown to significantly reduce the risk of progression and death when used in combination with lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma.10.

“Elotuzumab now is the first monoclonal antibody demonstrating [PFS] benefit in combination with [lenalidomide/dexamethasone] in a large randomized phase 3 trial of relapsed/refractory multiple myeloma,” said Sagar Lonial, MD, Chief Medical Officer at Winship Cancer Institute of Emory University in Atlanta, GA.

While a number of studies evaluated the use of monoclonal antibodies, there were also various studies presented that tested vaccines and chimeric antigen receptor (CAR) modified T cells.

An autologous tumor-derived heat shock protein peptide vaccine improved survival compared with standard therapy in 46 patients with newly diagnosed glioblastoma multifome, a type of brain cancer that has limited treatment options and poor survival.11

 

RELATED: Older Adults with Head and Neck Cancers May Need More Cautious Treatment Strategies

Two studies assessing the impact of CAR T cells in patients with relapsed/refractory acute lymphocytic leukemia and two forms of NHL found that the immunotherapy induced a high complete response rate and durable response, respectively.12,13

It is clear that the use of immunotherapy for the treatment of cancer is expanding. As FDA-approved biologics demonstrate efficacy in other cancer types and new biologics are displaying efficacy in combination with other biologics and chemotherapy, the role of immunotherapeutic agents for patients with cancer continues to grow.

References

  1. Lorusso D, Ferrandina G, Colombo N, et al. Randomized phase II trial of carboplatin-paclitaxel (CP) compared to carboplatin-paclitaxel-bevacizumab (CP-B) in advanced (stage III-IV) or recurrent endometrial cancer: the MITO END-2 trial.  J Clin Oncol. 2015;33(suppl; abstr 5502).
  2. Dickler MN, Barry WT, Cirrincione CT, et al. Phase III trial evaluating the addition of bevacizumab to letrozole as first-line endocrine therapy for treatment of hormone-receptor positive advanced breast cancer: CALGB 40503 (Alliance).  J Clin Oncol. 2015;33(suppl; abstr 501).
  3. Filon O, Orlov S, Burdaeva O, et al. Efficacy and safety of BCD-021, bevacizumab biosimilar candidate, compared to Avastin: results of international multicenter randomized double blind phase III study in patients with advanced non-squamous NSCLC.  J Clin Oncol. 2015;33(suppl; abstr 8057).
  4. Hosomi Y, Yoh K, Kasahara K, et al. Docetaxel + ramucirumab (DR) versus docetaxel + placebo (D) as second-line treatment for advanced non-small cell lung cancer (NSCLC): a randomized, phase II, double-blind, multicenter trial in Japan. J Clin Oncol. 2015;33(suppl; abstr 8054).
  5. Sehn LH, Chua NS, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;33(suppl; abstr LBA8502).
  6. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (CheckMate 067). J Clin Oncol. 2015;33(suppl; abstr LBA1).
  7. Hodi FS, Postow MA, Chesney JA, et al. Clinical response, progression-free survival, and safety in patients with advanced melanoma receiving nivolumab combined with ipilimumab versus IPI monotherapy in CheckMate 069 study. J Clin Oncol. 2015;33(suppl; abstr 9004).
  8. Pembrolizumab (MK-3475) plus low-dose ipilimumab in patients with advanced melanoma or renal cell carcinoma: data from the KEYNOTE-029 phase I study. J Clin Oncol. 2015;33(suppl; abstr 3009).
  9. Advani RH, Flinn I, Sharman JP, et al. Two doses of polatuzumab vedotin in patients with relapsed/refractory follicular lymphoma: durable responses at lower dose level. J Clin Oncol. 2015;33(suppl; abstr 8503).
  10. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide/dexamethasone with/without elotuzumab in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2015;33(suppl; abstr 8508).
  11. Bloch O, Raizer JJ, Lim M, et al. Newly diagnosed glioblastoma patients treated with an autologous heat shock protein peptide vaccine: PD-L1 expression and response to therapy. J Clin Oncol. 2015;33(suppl; abstr 2011).
  12. Park JH, Riviere I, Wang X, et al. Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. J Clin Oncol. 2015;33(suppl; abstr 7010).
  13. Schuster SJ, Svoboda J, Nasta S, et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas.J Clin Oncol. 2015;33(suppl; abstr 8516).

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