April 16, 2015Imperial College London Scientists have discovered a protein that plays a central role in promoting immunity to viruses and cancer, opening the door to new therapies. Experiments in mice and human cells have shown that the protein promotes the proliferation of cytotoxic T cells, which kill cancer cells and cells infected with viruses. The discovery was unexpected because the new protein had no known function and doesn’t resemble any other protein. Scientists have discovered a protein that plays a central role in promoting immunity to viruses and cancer, opening the door to new therapies. Experiments in mice and human cells have shown that the protein promotes the proliferation of cytotoxic T cells, which kill cancer cells and cells infected with viruses. The discovery was unexpected because the new protein had no known function and doesn’t resemble any other protein. Researchers from Imperial College London who led the study are now developing a gene therapy designed to boost the infection-fighting cells, and hope to begin human trials in three years. The study also involved researchers at Queen Mary University of London, ETH Zurich and Harvard Medical School. Their discovery, which has been six years in the making, is reported today in the journal Science. Cytotoxic T cells are an important component of the immune system, but when faced with serious infections or advanced cancer, they are often unable to proliferate in large enough quantities to fight the disease. By screening mice with genetic mutations, the Imperial team discovered a strain of mice that produced 10 times as many cytotoxic T cells when infected with a virus compared with normal mice. These mice suppressed the infection more effectively, and were more resistant to cancer. They also produced more of a second type of T cells, memory cells, enabling them to recognise infections they have encountered previously and launch a rapid response. The mice with enhanced immunity produced high levels of a hitherto unknown protein, which the researchers named lymphocyte expansion molecule, or LEM. They went on to show that LEM modulates the proliferation of human T cells as well as in mice. The researchers now aim to develop a gene therapy designed to improve immunity by boosting the production of LEM. With the support of Imperial Innovations, the technology commercialisation company for the College, the researchers have filed two patents. A company called ImmunarT has been formed with the aim of commercialising the technology. Professor Philip Ashton-Rickardt from the Section of Immunobiology in the Department of Medicine at Imperial, who led the study, said: “Cancer cells have ways to suppress T cell activity, helping them to escape the immune system. Genetically engineering T cells to augment their ability to fight cancer has been a goal for some time and techniques for modifying them already exist. By introducing an active version of the LEM gene into the T cells of cancer patients, we hope we can provide a robust treatment for patients. “Next we will test the therapy in mice, make sure it is safe and see if it can be combined with other therapies. If all goes well, we hope to be ready to carry out human trials in about three years.” Dr Claudio Mauro, who led the research from the Centre for Biochemical Pharmacology, based within Queen Mary University of London’s William Harvey Research Institute, said: “This study has identified the novel protein LEM and unlocked an unexpected way of enhancing the ability of our immune system to fight viruses or cancers. This is based on the ability of the protein LEM to regulate specific energy circuits, and particularly mitochondrial respiration, in a subset of white blood cells known as cytotoxic T cells. This discovery has immediate consequences for the delivery of innovative therapeutic approaches to cancer. Its ramifications, however, are far greater as they can help explaining the biological mechanisms of widespread human diseases involving altered immune and inflammatory responses. These include chronic inflammatory and autoimmune disorders, such as atherosclerosis and rheumatoid arthritis.” The research was funded by the Medical Research Council, the Wellcome Trust and the British Heart Foundation. Dr Mike Turner, Head of Infection and Immunobiology at The Wellcome Trust, said: “The discovery of a protein that could boost the immune response to not only cancer, but also to viruses, is a fascinating one. Further investigation in animal models is needed before human trials can commence, but there is potential for a new type of treatment that capitalises on the immune system’s innate ability to detect and kill abnormal cells.”
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sexta-feira, 17 de abril de 2015
Scientists discover protein that boosts immunity to viruses and cancer
quinta-feira, 19 de fevereiro de 2015
New weapon in the fight against cancer could be in your body already
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Lithocholic acid, a bile acid produced in the liver, is particularly effective in killing cancer cells. Where can you find the next important weapon in the fight against cancer? Just do a little navel-gazing. New research from Concordia confirms that a tool for keeping the most common forms of cancer at bay could be in your gut. In a report published in the International Journal of Molecular Sciences, Vladimir Titorenko, a professor of biology at Concordia, and his colleagues show that lithocholic acid, a bile acid produced in the liver, is particularly effective in killing cancer cells. For the study, the research team tested thousands of chemicals found in the body with the help of a robot and discovered more than 20 that could delay the aging process, something inevitably linked to cancer. Most effective was lithocholic acid. When entering a cancer cell, the acid goes to "energy factories" called mitochondria and then sends molecular signals that lead to the cells' demise. It not only helped slow the aging process but also had an anti-tumour effect, killing cells of breast, prostate and neuroblastoma cancer -- in a petri dish, that is. Indeed, these results aren't applicable to humans -- yet. Titorenko performed the first round of studies using yeast because the ways aging progresses, and the ways it can be delayed by some diets, are similar in both yeast and humans. "Various cancers are associated with aging -- the older you get, the more instances we see of diseases like breast and prostate cancer -- so studying how diet can slow that aging process is important," says Titorenko, who holds a Concordia Research Chair in genomics, cell biology and aging. In collaboration with Thomas Sanderson from the INRS-Institut Armand-Frappier in Laval, Titorenko is now testing whether the same bile acid can delay the development of prostate cancer in laboratory mice. If those trials confirm the anti-tumour effect of lithocholic acid, the hope is that it will have a similar effect in human patients, along with the possibility of slowing the human aging process in general. The study progresses the fundamental knowledge of how to naturally slow down aging of non-cancerous cells as well as how to kill cancer cells. "We are attempting to understand what kind of molecular processes within our cells are responsible for cell aging and aging-associated death," Titorenko says. "Satisfying our curiosity as scientists pursuing new fundamental knowledge fits with our other objective: to find ways that natural chemical products can delay aging and the diseases associated with it." Story Source: The above story is based on materials provided by Concordia University. Note: Materials may be edited for content and length. Journal Reference:
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terça-feira, 3 de fevereiro de 2015
Whose numbers determine if a targeted cancer therapy is 'worth it? '
Health economics helps insurers, health care systems and providers make treatment decisions based on the cost of extra "units" of health arising from a specific treatment. By calculating the cost for each year of life or quality-adjusted year of life gained, these groups can decide whether changing treatments or adding in a new treatment beyond the existing standard of care is "worth it."However, while the resulting incremental cost effectiveness ratio (ICER) is often presented as an absolute measure upon which to base these decisions, an opinion published by University of Colorado Cancer Center researchers D. Ross Camidge, MD, PhD, and Adam Atherly, PhD, suggests that the consumers of these data need to be much more aware of the assumptions underlying these calculations. "Increasingly physicians are being presented with health economic analyses in mainstream medical journals as a means of potentially influencing their prescribing. However, it is only when you understand the multiple assumptions behind these calculations that you can see that they are by no means absolute truths," Camidge says. Take the case of targeted treatment for non-small cell lung cancer (NSCLC). Treating ALK+ lung cancer with crizotinib rather than with either 1st or 2nd line chemotherapy controls patients' cancer longer and with fewer side effects -- but is it cost effective? One of the most prominent health economic assessments of crizotinib occurred within a Canadian study which showed that introducing crizotinb for ALK+ lung cancer would cost $255,970 per quality-adjusted life year gained (taking into account screening for the ALK abnormality, the cost of the drug, its benefits and side effects compared to standard second-line chemotherapy). This is above the threshold most insurers will pay and so according to this ICER, it seems as if treating ALK+ lung cancer with crizotinib is not necessarily worth it. "But what if we change some of the assumptions used in the Canadian model?" Camidge and Atherly ask. For example, based on reports of people returning to normal lives after treatment with crizotinib, what if the assumption is that the drug offers 90 percent quality of life, as opposed to the approximate 50 percent quality of life assumed in the Canadian study? If crizotinib returns a patient to 90 percent quality of life, as has been common, the cost effectiveness ratio of the drug drops dramatically to $143,421 per quality-adjusted life year gained. Similarly, as physicians become more familiar with the best use of a new drug and more informed about the diseases it treats, assumptions of a drug's benefit used in an ICER may also change. For example, in the data used in the Canadian study only the 2nd line use of the drug was explored, but benefit in the 1st line setting now seems to be greater. If use of the drug results in more quality-adjusted life years gained, the drug is less expensive per unit. Likewise, what if our evolving understanding of who and how we test for the ALK rearrangement makes us able to find this gene alteration in a greater percentage of the screened population? Perhaps early testing cost $50,000 to test 50 people to find one case of ALK+ lung cancer. That's a cost of $50,000 to find one treatable case. But if optimized testing procedures are able to discover five cases of ALK+ cancer per every 50 tests, the testing cost per treatable case drops to $10,000. As each component in the overall calculation is explored, Camidge and Atherly show that the resulting ICER can change to a greater or lesser extent. "Something that might seem clear-cut from the outside really gets tricky and much less definite when you pull it apart," Atherly says. "The cost per unit of health that is used to determine if a drug is or isn't used seems like an unequivocal fact, but is often highly equivocal." "With multiple other examples of giving specific targeted drugs to specific molecular subtypes of disease occurring, it is becoming vitally important to accurately address the health economics of these personalized medicine scenarios. For if we don't address the feasibility of actually delivering these breakthroughs to patients in the real world they will not be breakthroughs at all," they write. Story Source: The above story is based on materials provided by University of Colorado Cancer Center. Note: Materials may be edited for content and length. Journal Reference:
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quarta-feira, 10 de dezembro de 2014
Cancer therapy shows promise for nuclear medicine treatment
Cancer therapy can be much more effective using a new way to customize nuclear medicine treatment, researchers say in the December 2014 issue of The Journal of Nuclear Medicine. The process could also be useful for other diseases that could benefit from targeted radiation.Targeted therapy with radiopharmaceuticals--radioactive compounds used in nuclear medicine for diagnosis or treatment--has great potential for the treatment of cancer, especially for cancer cells that have migrated from primary tumors to lymph nodes and secondary organs such as bone marrow. These disseminated tumor cells can be difficult to treat with a single targeting agent because there are dramatic differences in the number of targetable receptors on each cell. In the study, breast cancer cells were treated with different concentrations of a cocktail of four fluorochrome-conjugated monoclonal antibodies. The amount of each antibody bound to each cell was determined using flow cytometry. Formulas were developed to "arm" the antibodies with the desired radionuclide and activity, calculate the absorbed dose to each cell, and perform a simulation of the surviving fraction of cells after exposure to cocktails of different antibody combinations. Simulations were performed for three alpha-particle emitters. "Our approach moves radiation treatment planning for cancer therapy from the tumor level to the molecular and cellular level, with nuclear medicine serving as the treatment engine," stated Roger Howell, Ph.D., lead researcher. "The concepts are not restricted to cancer therapy but can be applied more widely to other diseases that may benefit from a targeted approach with cocktails of radiopharmaceuticals. The approach can also be extended to cocktails consisting of radiopharmaceuticals and non-radioactive agents." The effect of the radiopharmaceutical cocktails was compared to that of single antibodies. In certain activities, cocktails outperformed single antibodies by a factor of up to 244. These findings suggest that targeted alpha therapy can be improved with customized radiolabeled antibody cocktails. Depending on the antibody combination and specific activity of the radiolabeled antibodies, cocktails can provide a substantial advantage in tumor cell killing. The methodology used in this analysis provides a foundation for pretreatment prediction of tumor cell survival in the context of personalized cancer therapy. "This method is preferable, as it accounts for behavior of the drugs in the patient's body," Howell continues. "The beauty of either approach for planning a treatment is that the patient is not subjected to any radiopharmaceutical injections during the planning phase, which uses only fluorescent-labeled drugs. The patient is not injected with radiopharmaceuticals until the treatment phase, whereupon only a cocktail specifically optimized for that individual is administered. This spares the patient from receiving ineffective cocktails that may damage normal tissues and prevent further treatment." Story Source: The above story is based on materials provided by Society of Nuclear Medicine. Note: Materials may be edited for content and length. Journal Reference:
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domingo, 28 de setembro de 2014
Strategy to reduce side effects in modern cancer therapy
The new strategy activates the EGFR inhibitor specifically under hypoxic conditions (indicated by blue fluorescence).
The occurrence of severe side effects and the development of resistance are two of the biggest problems facing modern cancer therapy. Even the latest, highly targeted cancer drugs such as the tyrosine kinase inhibitors Tarceva(R) or Sutent(R) are affected by these problems, which can ultimately lead to treatment having to be stopped. The effect of this class of inhibitors is based on the specific inhibition of proteins that are over-activated in cancer cells and which drive abnormal cell growth. However, clinical practice has shown that, as a result of the physiological functions of these proteins in healthy tissue, their inhibition can cause severe side effects. As a result, there is an acute need for strategies to restrict the effect of these highly promising new drugs more selectively to the malignant tumour.
The aim of the research was to develop an improved tyrosine kinase inhibitor that is actually inactive and which is only activated selectively in the malignant tissue. This is intended to prevent damage to healthy tissue and therefore minimise side effects for patients. As part of the paper published in the journal Angewandte Chemie [Applied Chemistry], International Edition, a new inhibitor has been successfully synthesised and coordinated to cobalt(III). This leads to initial drug inactivation and, thus, no activity under normal physiological conditions. Only in tumour tissue where, due to the rapid growth, unusually low-oxygen conditions prevail, the inactive cobalt(III) compound is reduced to cobalt(II) and as a result releases the active drug. The tumour-selective effectiveness of this approach has been demonstrated both in living cells and in tumor-bearing organisms.
The development of this complex idea and strategy was made possible by the outstanding interdisciplinary collaboration organised in the context of the "Translational Cancer Therapy Research" platform led by Bernhard Keppler, Dean of the Faculty of Chemistry at the University of Vienna, and Walter Berger, Professor at the Medical University of Vienna. This research platform promotes constant scientific exchange between synthetic chemists at the University of Vienna and cancer researchers at the Medical University of Vienna. It is only through these opportunities that the team of university assistants Christian Kowol (University of Vienna) and Petra Heffeter (Medical University of Vienna) has been able, based on two diploma theses (by Claudia Karnthaler-Benbakka, MSc., and Diana Groza, MSc.), to produce these results. The study was funded by the City of Vienna fund for "innovative interdisciplinary cancer research," the Austrian Science Fund (FWF) and COST CM1105. In view of the highly promising results, the new combination class has been patented by the two universities and currently a partner for further (clinical) development is searched.
So far there has been no comparable strategy for reducing the (severe) side effects of tyrosine kinase inhibitors. As a result, there is hope that, in future, the approach presented here will improve the tolerance of the therapy and allow this treatment to benefit patients who have previously had to discontinue it.
Story Source:
The above story is based on materials provided by University of Vienna. Note: Materials may be edited for content and length.
Journal Reference:
- Claudia Karnthaler-Benbakka, Diana Groza, Kushtrim Kryeziu, Verena Pichler, Alexander Roller, Walter Berger, Petra Heffeter, Christian R. Kowol. Tumor-Targeting of EGFR Inhibitors by Hypoxia-Mediated Activation. Angewandte Chemie International Edition, 2014; DOI: 10.1002/anie.201403936