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


Domingo, 25.10.15

BRCA1 Gene Expression May be Biomarker for Survival in Glioblastoma Multiforme

BRCA1 Gene Expression May be Biomarker for Survival in Glioblastoma Multiforme

BRCA1 protein expression may be an important predictive biomarker of overall survival in glioblastoma multiforme.
BRCA1 protein expression may be an important predictive biomarker of overall survival in glioblastoma multiforme.

Breast cancer type 1 susceptibility gene (BRCA1) protein expression may be an important predictive biomarker of overall survival in patients with glioblastoma multiforme (GBM), according to a study presented at the American Society for Radiation Oncology (ASTRO) 56th annual meeting in San Antonio, TX.

Researchers led by Maria Vasilakopoulou, MD, PhD, of the Pitié-Salpêtrière Hospital in Paris, France, analyzed tissue microarrays from archived GBM tumors from 66 patients who participated in the Radiation Therapy Oncology Group (RTOG) clinical trials in order to determine any association with the expression and prognostic significance of 4 molecular biomarkers.

Observed patients had similar overall survival and were treated with surgery, radiation, and non-temozolomide chemotherapy.

“Among the 4 biomarkers assessed, only BRCA1 protein expression had a statistically significant correlation with overall survival,” said Dr. Vasilakopoulou.

Patients with low tumor BRCA1 protein expression were found to have a median survival time of 18.9 months compared to those with high expression of the protein who had 4.8 months.

 

RELATED: Accelerated Partial Breast Not Inferior to Whole-breast Irradiation Following Surgery

“The study results suggest strongly that low BRCA1 protein expression in the GBM tumor, and the consequent low DNA repair, causes the cancer cells to be more susceptible to DNA-damaging cancer treatment,” said Dr. Vasilakopoulou.

She concluded that patients identified as high expressers could be treated with agents that downregulate BRCA1 in order to sensitize them to other cytotoxic therapies.

Reference

  1. BRCA1 expression in glioblastoma multiforme tumors predicts patient survival [press release]. NRG Oncology; October 21, 2015; http://www.eurekalert.org/pub_releases/2015-10/no-bei101615.php. Accessed October 23, 2015.

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por cyto às 18:56

Quinta-feira, 13.08.15

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy; Muraro E, Comaro E, Talamini R, Turchet E, Miolo G, Scalone S, Militello L, Lombardi D, Spazzapan S, Perin T, Massarut S, Crivellari D, Dolcetti R, Martorelli D; Journal of Translational Medicine 13 204 (2015)

 

BACKGROUND Locally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction.

METHODS The immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8(+) T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays.

RESULTS After NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8(+) T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response.

CONCLUSIONS These results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients. Trail registration:

TRIAL REGISTRATION NUMBER NCT02307227, registered on ClinicalTrials.gov ( http://www.clinicaltrials.gov , November 26, 2014).

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por cyto às 20:32

Quinta-feira, 23.07.15

New UW-Madison study links two unrelated cancer treatments

 

New UW-Madison study links two unrelated cancer treatments

Published on July 14, 2015 at 5:10 AM 

A new study at the University of Wisconsin-Madison has linked two seemingly unrelated cancer treatments that are both now being tested in clinical trials.

One treatment is a vaccine that targets a structure on the outside of cancer cells, while the other is an altered enzyme that breaks apart RNA and causes the cell to commit suicide. The study was published July 13 in the new journal of the American Chemical Society: ACS Central Science.

The new understanding could help both approaches, says UW-Madison professor of biochemistry Ronald Raines, who has long studied ribonucleases -- enzymes that break apart RNA, a messenger with multiple roles inside the cell. In 1998, he discovered how to alter one ribonuclease to avoid its deactivation in the body. Soon thereafter, he found that the engineered ribonuclease was more toxic to cancer cells than to others.

Raines patented the advance through the Wisconsin Alumni Research Foundation and with UW-Madison chemist Laura Kiessling cofounded Quintessence Biosciences in Madison. They remain shareholders in the firm, which has licensed the patent from WARF and begun early-phase human trials with the ribonuclease at the UW Carbone Cancer Center and MD Anderson Cancer Center in Houston.

The current study began as an effort to figure out why the ribonuclease was selective for cancer cells. To identify which structure on the cell surface helped it enter the cell, Raines screened 264 structures using a specially designed chip. The winner was a carbohydrate called Globo H.

"We were surprised -- delighted -- to see that because we already knew that Globo H is an antigen that is abundant in many tumors," Raines says. Antigens are complex molecules with structures that are recognizable to proteins called antibodies. "Globo H is under development as the basis for a vaccine that will teach the immune system to recognize and kill cancer cells," he says.

Working with Samuel Danishefsky, who solved the difficult problem of synthesizing Globo H at the Memorial Sloan-Kettering Cancer Center in New York, Raines found that reducing the Globo H display on the surface made breast cancer cells less vulnerable to ribonucleases like those that Quintessence is testing. "This was exciting, as we now have a much clearer idea of how our drug candidate is working."

Biochemistry Professor John Markley aided the research with studies of the structure of the molecules in question.

The picture that emerges from the work is of ribonucleases patrolling our bodies, looking for telltales of cancer cells, Raines says. "We are working to demonstrate this surveillance more clearly in mice, but don't have direct evidence yet."

As other scientists test whether using a vaccine will start an immune attack on Globo H, Raines says, "we are probing a different type of immunity. This innate immunity does not involve the immune system. It's a way for our bodies to fight cancer without using white blood cells or antibodies, just an enzyme and a carbohydrate."

Source:

University of Wisconsin-Madison

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por cyto às 22:46

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

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

Segunda-feira, 18.05.15

way for noninvasive detection of early stage liver cancer

Research leads way for noninvasive detection of early stage liver cancer

Published on May 15, 2015 at 9:02 AM ·

Led by Georgia State University, researchers have developed the first robust and noninvasive detection of early stage liver cancer and liver metastases, in addition to other liver diseases, such as cirrhosis and liver fibrosis.

Their findings were published Wednesday (May 13) in Proceedings of the National Academy of Sciences.

More than 700,000 people are diagnosed with liver cancer each year. It is the leading cause of cancer deaths worldwide, accounting for more than 600,000 deaths annually, according to the American Cancer Society. The rate of liver cancer in the U.S. has sharply increased because of several factors, including chronic alcohol abuse, obesity and insulin resistance.

"Liver cancers associated with high mortality rates and poor treatment responses are often diagnosed in the late stages because there is not a reliable way to detect primary liver cancer and metastasis at a size smaller than one centimeter," said Jenny Yang, lead author on the paper, Distinguished University Professor and associate director of the Center for Diagnostics and Therapeutics at Georgia State.

The liver is a common site for a variety of cancers, including melanoma, breast, pancreatic and colon cancers. Magnetic resonance imaging (MRI) is the leading imaging technique to detect disease without using radiation. MRI contrast or imaging agents aid MRI techniques to obtain tissue-specific images.

As reported by Yang, the applications of MRI contrast agents are not effective for early detection of cancerous tumors because they are hampered by uncontrolled blood circulation time, low relaxation rate or sensitivity, and low specificity. Most contrast agents, she said, are rapidly excreted from the liver, not allowing sufficient time to obtain quality imaging.

To more effectively detect cancerous tumors at an early stage, researchers from Georgia State, in collaboration with researchers from Emory University, Georgia Tech, the University of Georgia and the University of Virginia, have developed a new class of protein-based contrast agents (PRCAs) and an imaging methodology that provides robust results for the early detection of liver cancer and other liver diseases.

ProCA32, the researchers' newly developed contrast agent, allows for imaging liver tumors that measure less than 0.25 millimeters. The agent is more than 40 times more sensitive than today's commonly used and clinically approved agents used to detect tumors in the liver.

ProCA32 widens the MRI detection window and is found to be essential for obtaining high-resolution quality images of the liver. This application has important medical implications for imaging various liver diseases, the origin of cancer metastasis, monitoring cancer treatment and guiding therapeutic interventions, such as drug delivery.

"Our new agents can obtain both positive and negative contrast images within one application, providing double the accuracy and confidence of locating cancerous tumors," Yang said. "These agents are also expected to be much safer with reduced metal toxicity."

The researchers have shown proof-of-concept that ProCA32 can be used to detect cancerous liver tumors at an early stage with high sensitivity. They have also demonstrated that these new agents better aid the imaging of multiple organs, including the kidney and blood vessels, in addition to the liver and tumors.

"ProCA32 may have far-reaching implications in the diagnosis of other malignancies, which in turn would facilitate development of targeted treatment along with effective monitoring of reduction of tumor burden," Yang said. "Our agent and methodology can also be applied to study the brain and monitor treatment outcomes in a number of disorders, including stroke and recovery after stroke, Alzheimer's disease, brain tumors and gliomas,"

Source:

Georgia State University

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por cyto às 14:03

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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