And chemoprevention of colon cancer: an interview with Dr. John Letterio, School of Medicine of Case Western Reserve University

And chemoprevention of colon cancer: an interview with Dr. John Letterio, School of Medicine of Case Western Reserve University -

Interview by April Cashin -Garbutt , BA Hons (Cantab)

Dr. John Letterio THOUGHT LEADERS SERIES ... overview of the world's foremost experts

How is defined chemoprevention?

The basic idea of ​​cancer chemoprevention is to stop or reverse the progression of premalignant cells to full malignancy, using physiological mechanisms that do not kill healthy cells.

approach involves using either pharmacological or natural agents that inhibit the development of invasive cancer, either by blocking the DNA damage that initiates the carcinogenesis or by stopping or reversing the progression of precancerous cells in where such damage has already occurred.

ideal chemoprevention agent will be safe, orally bioavailable and well tolerated, so that it can be acceptable for routine use as an approach to reduce the risk of cancer an individual .

The term "chemoprevention" was invented back nearly four decades. How much progress has been made since then?

Michael Sporn coined the term in an article chemoprevention 1976 Federation Proceedings when writing about the work of his group was done with vitamin A analogues

Dr. Sporn, then a member of Carcinogenesis Program at the National cancer Institute, led the first work with agents that might be used to prevent cancer.

Since then, there has been tremendous progress in the field of preclinical research where many studies by leading researchers in the field have demonstrated the utility of this approach in animals experimental.

Indeed, in these preclinical models, it is now possible to prevent the onset of cancer in almost all public bodies in which human carcinoma occurs. However, this success has not been limited to human disease models as chemoprevention has been validated in people.

For example, the use of selective estrogen receptor modulators (SERMs), granted as much as a five fold reduction in breast cancer incidence in estrogen receptor-positive women

These compounds -. including tamoxifen, raloxifene and lasofoxifene - have the advantage of eliminating osteoporosis. Fenretinide, for which we have data value of nearly 20 years, provides a significant prevention of breast cancer in premenopausal women.

Yet despite these successes, the general acceptance of chemoprevention still an obstacle that must be overcome and it is. real concern that the concept is not only misunderstood by the general public, but not yet fully embraced by the cancer community

Could you please brief introduction to the class of molecules you worked - synthetic triterpenoids?

triterpenoids are a class of biologically active plant metabolites biosynthesized six isoprene units and cyclized in a variety of skeletal scaffolds.

The acid natural triterpenoid oleanolic has been shown to be an effective platform for synthetic derivatization to generate chemoprevention agents that target the antioxidant and factor erythroid 2-factor (NF-E2) concerning nuclear PI 2 (Nrf2) transcriptional cytoprotective path between other pathways involved in inflammation and cancer.

Indeed, the synthetic triterpenoid used in our recently published in JCI study was derived from oleanolic acid. This natural triterpene is representative of a broad class of molecules ubiquitously present in the plant kingdom, with many widely used in Asian medicine and continually isolated and studied for anti-inflammatory, hepatoprotective, analgesic, antimicrobial, immunomodulatory and effects tonics.

Because many plants containing triterpenoids are readily eaten by wild animals and humans, it could be expected that the content of the plant are relatively nontoxic and could serve as platforms as safe for drug discovery.

In preclinical studies, these triterpenoids have also been shown to be neuroprotective. Our own data showed the ability of synthetic triterpenoids selected to completely reverse the clinical signs of neurodegeneration in mouse models of multiple sclerosis. (Http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242013/?tool=pubmed)

It was announced recently that these molecules carry enormous potential to remove colon cancer associated colitis. Why do patients with inflammatory bowel disease have a higher risk of colon cancer?

It is well established that people with Crohn's disease and ulcerative colitis (the most common forms of IBD) are at a higher risk of developing colorectal cancer (CRC) that the population General. Actually, IBD with colon involvement is among the first three conditions at high risk for CRC, which represents nearly 15% of deaths in patients with IBD.

The link between inflammation and cancer is well established and inflammation undoubtedly contributes to other forms of sporadic and hereditary forms of colon cancer.

A number of very elegant studies in preclinical models have shed enormous light on the mechanisms involved. The picture that emerges is that there are distinct roles for specific immune cells, cytokines and other soluble mediators in the initiation, promotion, progression and metastasis of colon cancer.

A proposed mechanism is that the chronic inflammation of the intestine leads to colorectal dysplasia and the optionally colorectal cancer. Chronic inflammation is characterized by the production of proinflammatory cytokines that can induce mutations in oncogenes and tumor suppressor genes (eg., p53, APC ) and genomic instability through various mechanisms.

Chronic inflammation can act favoring CAC activating proliferation and anti-apoptotic (pro-survival) properties precancerous cells, and also enhance their potential for tumor progression and metastasis by influencing the microenvironment in which they grow.

This effect, in part, is related to the ability of inflammatory cytokines as mediators to activate STAT3 and NFkB, which are important in many inflammatory pathways, but also closely involved in the regulation of tumorigenesis.

The critical point is that all these mediators can be modulated in strategies to halt the progression of the disease. CRC is highly treatable at an early stage, it is important not only to understand the risk, but also recognize the signs and symptoms -. And why regular screenings and early detection are essential

However, the potential that we can further reduce the risk through the application of chemopreventive strategies that target these inflammatory mediators is very real and must be exploited to the clinical benefit.

How are synthetic triterpenoids thought to help protect against colon cancer?

When examining the mechanisms of activity for this class of small molecules it is very important to know and understand their nature "multi-functional", ie, their ability to influence several targets within a cell. Indeed, it is this property that may underlie their unique potential as chemopreventive

For example, triterpenoids directly inhibit the function of both STAT3 and NF? B, key intermediates in colon tumorigenesis process .

Dr. Sporn began synthesis triterpenoids in 1995, shortly after leaving the NCI for Dartmouth. Since then, Dr. Sporn was a collaborator on more than 100 publications have described the mediation mechanisms of several synthetic triterpenoids activities and have demonstrated their effectiveness in cancer chemoprevention in numerous preclinical models of epithelial cancers.

When I entered Case Western Reserve University in 06, I began to interact with Dr. Markowitz, who described 15-PGDH as a suppressor large tumor in colon cancer and as a related molecule to "celecoxib nature."

We were intrigued by the finding that inflammatory cytokines, such as TNF-α, could suppress the expression of 15-PGDH and wondered if the triterpenoids may reverse this suppression.

it proved to be true, showing potentially important mechanisms by which this class of small molecules can suppress colon cancer associated colitis, and may improve the response to COX-2 inhibitors.

What are the next steps in your research?

Our current studies focus on the analysis of this triterpenoid (CDDO-Me / bardoxolone methyl) in other models of IBD and in additional models of colon cancer, and the new data these studies are corroborating the results reported in JCI.

We are also very interested in the potential that natural triterpenoids with similar properties could provide a similar benefit. Our efforts in this regard involves both the isolation of the natural product and similar characterization in vitro analyzes and through in vivo Studies of cancer chemoprevention.

As our data with these mature Triterpenes natural, we expect these collective observations will pave the way for human trials in which cancer chemoprevention by triterpenoids may be achieved in patients who are at risk significantly high.

This may be particularly beneficial in patients with IBD, multiple mechanisms of triterpenoid activity (eg suppression of NFkB and STAT3 signaling, induction of TGF signaling -β, activation of antioxidant Nrf2 response), all can work together to achieve improvements in most clinical IBD.

are there plans to continue human trials in cancer chemoprevention with triterpenoids?

The synthetic triterpenoids, including CDDO-Me (bardoxolone methyl) and an analog bound (RTA 408) are currently being studied in clinical development in a wide range of indications by our collaborator Reata Pharmaceuticals.

Notably, Reata is assessing the immuno-oncology RTA 408 applications in the first clinical trials in melanoma and cancer non-small cell lung, and we expect that positive clinical data histologies interest will be expanded in the future.

In addition to this program, we also have an active effort focused on isolating and unique derivatization, natural triterpenoids.

this initiative involves university-industry collaboration has recently established between Case Western Reserve University (CWRU) and Modularix, by which individual candidate molecules and developed CWRU are selected for their potential as immune modulators and their ability to suppress cancer metastasis.

what do you think the future chemoprevention of colon cancer?

The argument for the continuation of these cancer chemoprevention trials is strong, and has been elegantly defended by Dr. Sporn for many decades.

we could say that we have an obligation to patients suffering from diseases such as IBD and other conditions that increase the risk of cancer :. the obligation to develop these safe and multi-functional agents as an approach to minimize their risk of many diseases of clinical manifestations, including cancer

There are many questions that remain unanswered:

• triterpenoid what will be the safest and most effective in this context
• may benefit clinically be achieved with intermittent exposure, rather? by continuous administration? This will likely be one approach to reduce the risk of complications.
• these triterpenoids may be used in combination with other agents for clinical benefit more?

clinical trials designed with care and a collaborative approach between industry and academia are needed to answer these questions, but there is no doubt that the data led us to where we really have an obligation to do so.

where readers find more information?

• http://www.nature.com/nature/journal/v471/n7339_supp/full/471S10a.html
• http://www.nature.com / nrclinonc / newspaper / v2 / n10 / full / ncponc0319.html
• http://www.ncbi.nlm.nih.gov/pubmed/20420949

About Dr. John Letterio

John Letterio is the director of the Institute of cancer Angie Fowler Adolescent & Young adult hematology and head / pediatric oncology in University hospitals Case Medical Center and Case Western Reserve University in Cleveland, Ohio. Dr. Letterio obtained his Ohio University's medical school State University of Medicine in 1984 completed a pediatric oncology fellowship at the National Cancer Institute in Bethesda, Maryland in 1993. NIH, Dr. Letterio became a permanent researcher and head of the Laboratory of Immune.

After 16 years at NIH, he was recruited at the Case Western Reserve University in 06 to lead the development of programs for children, adolescents and young adults with cancer to blood disorders. As a member of the case Comprehensive Cancer Center and president Jane & Lee Pediatric Cancer Innovation, he leads a core team of scientists and clinical investigators whose efforts are focused on the development and application of new agents for the chemoprevention and cancer treatment.

His research is actively supported by several NIH institutes, including the NCI, NHLBI and NIS, and the Ministry of Defence. His research team has provided important information about the mechanisms linking inflammation to cancer and other diseases. Her most recent studies have demonstrated the potential of synthetic triterpenoids in chemoprevention of colon cancer and appear in the Journal of Clinical Investigation in June 2014.

Somatuline Clarinet Phase III study Ipsen published online in NEJM

Somatuline Clarinet Phase III study Ipsen published online in NEJM -

The US subsidiary of Ipsen (Euronext: IPN, ADR: IPSEY) announced aujourd 'hui the New England Journal of Medicine published the results of clinical trials showing that Somatuline ^® Autogel ^® / Somatuline ^® Depot ^® (lanreotide) injection 0 mg (referred Somatuline ^® ) achieved a statistically significant prolongation of progression free survival (PFS) compared to placebo in patients with metastatic neuroendocrine gastroenteropancreatic tumors (GEP-NETs ). Clarinet ^® , an experimental phase III randomized, double-blind, placebo-controlled anti-proliferative effects of Somatuline ^® was conducted in 48 centers in 14 countries. The article "lanreotide in metastatic neuroendocrine tumors Enteropancreatic" is available online at NEJM.org and was published in July 17 edition (N Engl J Med 2014; 371: 224-233 ..)

data collected from 204 GEP-NET patients on the 96-week study showed that patients treated with placebo had a median PFS of 18.0 months and 33.0% has not progressed or died at 96 weeks, while the median PFS for Somatuline ^® of patients was not reached and 65.1% had not progressed or died at 96 weeks (stratified log-rank test, p <0.001 .) This represents a 53% reduction in risk of disease progression or death based on a hazard ratio of 0.47 (95% CI 0.30 to 0.73) These statistically effects. and clinically significant antiproliferative Somatuline ^® were observed in a broad population of patients with grade G1 or G2 (classification of the World Health Organization) GEP-NETs, ​​and independent of tumor volume liver (≤25% or> 25%). Quality of life measures were not different between Somatuline ^{® groups} and placebo. The safety data generated by the study are consistent with the known safety profile of Somatuline ^® .

"The Clarinet ^® The data are convincing because no progression similar GEP-NET there are survival data without a somatostatin analogue in a large population studied multinational" said Dr Martyn Caplin, Professor of gastroenterology and gastrointestinal neuroendocrinology, Royal free Hospital (London, UK) and lead author and principal investigator of the Clarinet ^® study.

"published peer-CLARINET ^® results in the New England Journal of Medicine highlights the robust data that showed an anti-proliferative effect of Somatuline ^® in the treatment of GEP-NETs, ​​"said Claude Bertrand, Executive Vice President R & D and Chief scientific Officer." based on these significant results, Ipsen has launched a registration program in the world and the July 1, 2014, the presentation of a supplementary New Drug Application for Somatuline ^® for the treatment of neuroendocrine tumors gastroenteropancreatic (GEP-NET) to the FDA and the variations marketing authorization in 25 countries EU were announced. "

" These are potentially interesting news for physicians GEP-NET, data have shown anti-tumor activity and a delay in disease progression in patients treated with Somatuline ^® Depot ^® , "said Dr. Alexandria Phan, Clarinet researcher, IM Director medical oncology at Houston Methodist Cancer Center.

the data Clarinet ^® is considered experimental, as Somatuline ^® are not indicated for the anti-proliferative treatment of neuroendocrine gastroenteropancreatic tumors (GEP-NET) in a market. Somatuline ^® is approved for treatment symptoms associated with neuroendocrine tumors, which may include the treatment of GEP-NET patients with symptoms of carcinoid syndrome in many markets where it is marketed as Somatuline ^® Autogel ^® . Somatuline ^® is not approved in the US to treat GEP-NETs or symptoms thereof, where it is marketed as Somatuline ^® Depot ^® of acromegaly.

common genetic variation in the gene may modify cardiovascular benefit of aspirin

common genetic variation in the gene may modify cardiovascular benefit of aspirin -

Aspirin is the gold standard antiplatelet therapy for aspirin and low daily dose is widely prescribed for the prevention of cardiovascular disease.

Now, a new study suggests that common genetic variation in the gene for catechol-O-methyltransferase (COMT) can modify the cardiovascular benefit of aspirin, and in some people, can impart a slight evil . The results, led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women's Hospital (BWH) appear online in the journal American Heart Association Arteriosclerosis, Thrombosis, and Vascular Biology .

"This is one of the rare cases where you can identify a single gene polymorphism has a significant interaction with aspirin as it affects whether or not it protects against heart disease" says first author Kathryn hall, PhD, MPH, an investigator in the general medicine division and primary care at BIDMC and researcher at Harvard medical School.

COMT is a key enzyme in the metabolism of catecholamines , a group of hormones that include adrenaline, noradrenaline and dopamine. "These hormones are involved in a wide range of disorders, including hypertension," says Hall, "first, we were interested in whether the COMT gene affected the vulnerability to cardiovascular incident such as myocardial infarction or ischemic stroke. "Knowing that aspirin is commonly prescribed for the prevention of cardiovascular diseases of the incident, investigators also wanted whether genetic variation in COMT influence potential benefit of aspirin.

To answer these questions, the researchers used data from genomics women's health study, a cohort of more than 23,000 women who were followed for 10 years in a randomized controlled trial against placebo double-blind, the low-dose aspirin or vitamin E in the primary prevention of cardiovascular disease in the incident. Their analysis included val158met, a common variant in the COMT gene: People who are homozygous for valine highly active form of the enzyme, the "val / vals," have been shown to have lower levels of catecholamines compared to persons who are homozygous for methionine the low activity form of the enzyme, the "met / metastasis." the val / met are heterozygous between.

"When we looked at women in the placebo arm of the test, we found that 23 percent of women who were "val / vals' were naturally protected against cardiovascular disease incident," says lead author Daniel I. Chasman, PhD, genetic epidemiologist in the Division preventive medicine at Brigham and Women's Hospital and associate professor of medicine at Harvard medical School. "This discovery has been replicated in two other studies based on the population, was in itself a significant interest." But, he adds, the investigation also revealed the surprising discovery that when women with the Val / Val polymorphism were allocated to aspirin, this natural protection has been eliminated.

"As we continued to examine the effects of the drug benefit, we found that val / val women who were randomly assigned to aspirin had more cardiovascular events than val / vals that were assigned to placebo, "said Chasman. Of the 28 percent of women who met / met, the opposite was true, and women had fewer cardiovascular events when assigned to aspirin compared with placebo. The benefit of aspirin compared with placebo allowance encountered / Metastases raised to the reduction of cases of incident cardiovascular disease in 91 women treated over 10 years of follow-up studies. However, the harm of aspirin compared with placebo allowance for the val / val women was an increase of one case per 91 treaties.

The researchers also found that rates of cardiovascular disease were also reduced in met / met women assigned to vitamin E compared with those assigned to placebo.

the authors point out that the results will require further research and replication to understand their potential clinical impact. However, they note that, since aspirin is preventive prescribed to millions of people and the COMT gene variant is extremely common, this study highlights the potential importance of individualizing therapy based on genetic profiles.

"What this study suggests is that we can be smarter about groups of patients who would likely benefit from aspirin," says study co-author Joseph Loscalzo, MD, PhD, chair of the Department of medicine and chief physician at BWH. "Rather than give aspirin to all patients with risk factors for heart disease, we need to use genomics and modern genetics to identify persons for whom aspirin has the greatest benefit and the least risk of side effects. "

One possible reason for the val / val protection could lie in the role of COMT in the allocation of adrenaline, the hormone "fight or flight", which is closely related to the regulation of the cardiovascular system.

"When adrenaline levels increase in response to stress, blood pressure rises and blood pressure is a precursor of heart disease, "says hall. "One possibility is that individuals val val / less epinephrine that meets / met individuals because of their COMT is more efficient at decomposing This could help protect the course against cardiovascular disease. - Who is our working hypothesis It is more difficult to explain why. effect is modified by aspirin and that is what we are in the laboratory aggressively try to understand. "

Researchers discover new genetic links to schizophrenia

Researchers discover new genetic links to schizophrenia -

The discovery of more than a hundred genetic risk factors for schizophrenia provides new clues in the vital understanding of what causes the condition and will kick off the search for new treatments, according to scientists from the United Kingdom.

In the largest molecular genetic study of schizophrenia ever undertaken, genetics psychiatric Consortium (PGC), led by Professor Michael O'Donovan of the MRC Centre of Cardiff University for Neuropsychiatric Genetics and Genomics combined all schizophrenia samples available in a new analysis, only systematic.

study is the result of several years of work by the psychiatric Schizophrenia Working Group Genomics Consortium, an international, multi-institutional collaboration of over 300 scientists in 35 countries worldwide.

"We were able to detect genetic risk factors on a massive scale and unprecedented and shed new light on the biological basis of the state", according to Professor O Donovan who led 'study.

a total examination of 80,000 samples from patients with schizophrenia and healthy volunteers worldwide study, published in Nature , has found 108 specific locations in the human genome linked to schizophrenia, 83 were entirely new.

The new findings also suggest new biological mechanisms and pathways. For example, as the authors had expected, the study involves genes expressed in brain tissue, but it also found genes associated with schizophrenia have been particularly active in the immune system.

"These remarkable results have been made possible through collaboration comprehensive approach," according to Professor Sir Michael Owen, Director of the MRC Centre of Cardiff University for Neuropsychiatric Genetics and Genomics.

"Detecting biological risk factors at this level shows that schizophrenia can be treated with the same approaches that have transformed the results for people with other diseases.

" We believe that now they can also do for schizophrenia which has hitherto been so misunderstood, "he added.

schizophrenia is a debilitating psychiatric disorder that affects more than 24M people the world.

the disorder is highly variable, but is characterized by a combination of hallucinations, delusions such as paranoia, mood swings, apathy and social withdrawal, among others, often emerges in teens and early 20s

His lifelong impact on individuals and society is high, both in terms of healthy life years lost to disability and in terms financial cost.

Many respond well to treatment, but for many who do not meet the options are limited largely because biological mechanisms underlying schizophrenia are not included.

The Professor O'Donovan now hope the wealth of new discoveries will help initiate the search for new treatments he added: "While we are very excited by the results, it is important not to exaggerate or misinterpret. "We are still in the early days of trying to understand what causes the disease but collaborations such as this and new genetic tools mean that we are in a unique position.

" Make full use this research to the treatment will be a long game medium, but since some of our findings emphasize already known targets for existing treatments, it is reasonable to expect that others could do the same within a time shorter time.

"The wealth of new discoveries provides a large number of launch pads for the understanding of the disease and will revive the stalled process of developing new treatments for patients and their families who are still today stigmatized and blamed for the condition.

"The main challenge now is to translate this new knowledge about the biological basis of schizophrenia, new diagnostic tools and new treatments for patients and finally put an end to 60 years of waiting for new treatments for people around the world. "

Zilico receives funding to develop the diagnostic device for oral cancer

Zilico receives funding to develop the diagnostic device for oral cancer -

Zilico Ltd began its development work on a medical device that uses electrical impedance spectroscopy (EIS) in the detection and diagnosis of cancer oral Technology Strategy Board funding, the innovation agency of the United Kingdom.

both prices are Feasibility of Biomedical Catalyst funding and smart. The funds will help support a thorough analysis of the UK market, providing a specification for an oral diagnostic device and a protocol for a multi-center trial.

The funding builds on proven concept-study that was recently introduced and is part of a wider development program leading to a multi-center trial. The awards will help support development projects worth £ 0k.

flagship Zilico ZedScan EIS uses its proprietary technology to detect dysplasia and cervical cancer. Oral cancer following neoplastic way similar to the cervix, DIE can be used to detect changes in oral epithelium cells progress from normal to precancerous and then cancerous.

The University of Sheffield Professor of Oral Medicine, Martin Thornhill, presented on the use of EIA in the detection and diagnosis of oral cancer and dysplasia at the most influential group of experts oral medicine in America last year.

presentation of Professor Thornhill, using impedance spectroscopy to detect potentially malignant oral lesions, was delivered at the 67th Annual Meeting of the American Academy of Oral Medicine (AAOM) in San Antonio, Texas . The study on 50 patients was the result of a collaboration between the University of Sheffield, Sheffield Teaching Hospitals NHS Foundation Trust and Zilico Ltd.

The summary of the presentation was published in the oral surgery, oral pathology, oral medicine and oral Radiology Journal in September 2013. The full paper describing the study has been accepted for publication in the Journal Nanomedicine

Zilico chief Sameer Kothari said :.

We are delighted to have secured this funding which will allow us to build on the proof of concept study and positive feedback received data to the AAOM last year.

we are now well positioned to further develop the device and evaluate in a multi-center clinical study. There is a clear clinical need for accurate diagnosis in the patient's course.

Researchers working to develop new drugs for the treatment of chronic inflammatory diseases

Researchers working to develop new drugs for the treatment of chronic inflammatory diseases -

Science and industry work together to develop pharmaceuticals for the coming treatment of chronic inflammatory diseases. The drugs will fight against the immunological processes that have gone awry.

Statistics show that there are 300 million people with asthma worldwide, 0 million more people living with chronic pneumonia and up to 30% of the world population by supporting rhinitis allergic (allergic inflammation of the nasal airways). chronic inflammatory diseases may also affect other organs and parts of the body beyond the respiratory system; they can occur in the intestine (in the form of inflammatory bowel diseases such as ulcerative colitis), joints (rheumatoid arthritis), skin (scleroderma), or heart and blood vessels (arteriosclerosis). What each form of inflammatory disease has in common is that it comes from inflammation centers in the body that are prevented from healing by immunological processes that have gone awry.

This is where a new product manufactured by the Canadian company Nuvo Research Inc. comes in. It is already approved for use in many countries worldwide as a medicine to help the local healing, and Thailand is already punishable as a means to treat a variety of chronic diseases. Scientists at the Fraunhofer Institute for Cell Therapy and Immunology IZI in Leipzig to work now with a German subsidiary of the company Nuvo Research GmbH, and the Translational Centre for Regenerative Medicine at TRM Leipzig University to develop a platform that will enable them to better understand how the substance works. Their goal is to optimize the drug to make it easier to administer and better tolerated. Above all, scientists are eager to develop drug compounds with which it might be possible to mitigate an even wider range of chronic diseases, and prepare the products for approval in the European and Canadian markets. The cooperation project sponsored to the tune of 4.4 million euros, should be completed in June 2014.

regeneration process disrupted in the case of chronic inflammation

"L inflammation is the body's response emergency, but inflammation usually begins to decline when it starts. for the body to calm down and stabilize the immune system is temporarily suppressed. suppresses the body defense mechanisms until the inflamed tissue was able to resume its normal functions. this regeneration process is disrupted in the case of chronic inflammation, "says Professor Jürgen Arnhold, who is based in the Faculty of medicine from the University of Leipzig and also conducts research at TRM. Various complications may occur, such as infections and bacterial or fungal disturbances in the healing process. If such complications develop beyond a certain threshold, the immune system will suddenly jump back into the very violent action. It is this interaction between immunosuppression and immune overreaction that scientists are looking into the project. There is clearly a class of enzymes at work that would normally be activated by immune cells in a very specific time. If this activation occurs in an uncontrolled manner, the last phase of the inflammatory process is interrupted and becomes chronic. This is especially when the little low molecular weight substance, developed by Nuvo in: "The studies we have conducted on isolated immune cells indicate that it should be possible to alter the function of certain enzymes involved," said Professor Arnhold.

When scientists TRM studying how immune cells respond to selected drug in Canada, IZI's researchers are interested in examining its effect on the body as a whole. The result of these investigations is that, for the drug to be approved in Europe and North America, the authorities require complex and time-consuming studies to be conducted in its safety, tolerability and efficacy. "We are testing the drug on mice that have the same kinds of symptoms that patients with chronic inflammatory diseases," says Dr. Franziska Lange, responsible for inflammation and Immunodiagnostics unit models IZI. " my work group focuses on three conditions: .. asthma, lung and scleroderma smoker, a disease of autoimmune connective tissue We have 20 different model systems with which we are able to simulate different aspects of Crohn This allows us to record the effects and side effects of different doses of the drug on mice. We see ourselves as a service unit and offer many ways to perform preclinical testing of potential drugs, "she goes on to explain. Three other IZI working groups are testing the drug on mice that have suffered a stroke or who colitis to see if the symptoms of the animals better. They are also investigating whether the drug could be useful in breast cancer treatment.

the three cooperation partners have already conducted two studies and both proved the efficacy and safety of the basic active ingredient. currently, they hope to develop another project to improve drug application method. in Thailand it is currently administered by infusion, which means that patients have to travel to the clinic five days later for several hours at a time. the trio worked on the preparation of the drug in such a way that it can also be injected by family physicians.

Scientists report first successful step towards a vaccine that targets the mutation in brain cancer

Scientists report first successful step towards a vaccine that targets the mutation in brain cancer -

astrocytomas and oligodendrogliomas are subtypes of brain cancer called "Glioma ". These incurable brain tumors arise from glial cells, a type of support cell in the central nervous system. "Low-grade gliomas," that grow relatively slowly, so diffuse spread throughout the brain and are very difficult to remove completely by surgery. In many cases, the effectiveness of treatment by chemotherapy and radiotherapy is very limited. gliomas can develop extremely aggressive glioblastoma

low-grade gliomas have a common feature :. Over 70% of the cases have the same gene mutation in tumor cells. the same "typo" in the DNA causes the exchange of one specific building block protein (amino acid) in an enzyme called isocitrate dehydrogenase 1 (IDH1) therefore, most cancer cells do not follow the original construction plan for the protein;. to the 132nd position in the sequence of the molecule, they insert amino acid histidine instead of arginine

"This frequent and highly specific mutation immediately aroused our attention to immunologists :. In cancer cells, the amino acid exchange Ready properties of new protein that can be recognized by the immune cells of the body itself, "says Prof. Dr. Michael Platten, who heads the Clinical Unit of cooperation "Neuroimmunology and Brain Tumor Immunology" at DKFZ; he also works as a senior consultant in neuro-oncology department at Heidelberg University Hospital.

No other tumor type appears the same mutation with such frequency. The mutant protein can surely be detected using a highly specific antibody developed by Prof. Dr. Andreas von Deimling, neuropathologist at the University Hospital and the DKFZ. This form of IDH1 is present on the surface of all tumor cells and it is quite specific to the tumor. "This suggests that we might be able to use a vaccine to alert the patient's immune system to IDH1 mutant, the fight against the tumor without damaging healthy cells," explained Platten.

In collaboration with a team of doctors and University Hospital of scientists from Heidelberg, DKFZ and the Universities of Mainz, T-Tübingen and Hamburg Platten and his colleagues have now made the first successful step towards a vaccine that specifically target the mutation in the tumor.

researchers built a synthetic version of IDH1 segment with the characteristic mutation using individual amino acids. This version of the peptide, which has 15 building blocks, exactly in correspondence of presenting molecules on the surface of tumor cells. This is essential because the immune cells respond only to a target that is presented in so-called "MHC molecules" on the cell surface. If there is no such statement of correspondence, the body is a response immune.

to draw conclusions about the human immune system from vaccination experiments, the researchers used mice whose cells were equipped with human MHC molecules. "After the vaccination of animals the peptide, we could detect immune cells and antibodies that specifically recognized the IDH1 altered tumor cells rather than normal form of the enzyme in healthy cells, "says Dr. Theresa Schumacher, first author of the study.

in laboratory animals, this specific immune response induced by vaccination stopped the growth of cancer cells which had the mutation IDH1 feature. As expected, the vaccination did not disrupt the operation of the normal IDH1 enzyme, which plays a role in energy metabolism of all the healthy cells in the body.

"In some patients with low-grade glioma, we also found Spontaneous immune responses against IDH1 changed," says Platten. "This is a good sign, it suggests that the peptide-based vaccines can indeed support the immune system of the body in the fight against cancer cells." This gives a "vaccine therapy" a good chance of success, according to the Heidelberg doctors. In a clinical trial is expected to begin next year, with the support of the German Consortium for Translational Cancer Research (DKTK), they plan to consider the safety of the vaccine against gliomas based on IDH1 mutant in human patients for the first time.

"most low-grade gliomas can not be completely removed by surgery and therefore often return , "said Professor Wolfgang Wick, medical Director of neuro-oncology department and head of the clinical cooperation Unit" neuro-oncology "at DKFZ. "Patients should benefit greatly from a vaccine that prevents this from happening."

European approval process for gallium-68 generator Eckert & Ziegler ended with success

European approval process for gallium-68 generator Eckert & Ziegler ended with success -

Radiopharma Eckert & Ziegler GmbH has received a recommendation from the European Agency drugs for approval of its pharmaceutical ⁶⁸ Ge / ⁶⁸ Ga generators. This achievement marks the conclusion of a comprehensive evaluation procedure and decentralized first gallium generator was approved for the clinical development of highly specific diagnostic agents. Approval for sale in the respective countries is planned in the next two months.

Gallium generators provide an inexpensive alternative to radiolabeling diagnostic probes using positron emission tomography (PET), an imaging process that can be used to determine whether the diseased tissue. The process is primarily used in the treatment of cancer. So far, fluorine-18 or carbon-11 isotopes PET has generally been used to radiolabel diagnostic probes; these radioisotopes are produced using cyclotrons which are capitally intensive large-scale facilities dedicated requiring million investment. However, gallium generator is about the size of a thermos and can come from a lot less money, reducing costs and increasing flexibility in nuclear medicine clinics.

Once it was approved, Eckert & Ziegler will also submit its documents to the US Food and Drug Administration (FDA), the establishment of a Drug Master File with the agency. This will allow parties interested in developing new drugs to consult the file and use the generator in clinical trials of drugs and other parameters.

Dr. André Heβ, member of the Board of Eckert & Ziegler AG and head of Radiopharma segment, said, "We are proud to have got the ball rolling on the first approval of the world a pharmaceutical product ⁶⁸ Ge / ⁶⁸ Ga generator. We also would like to encourage the departments of research and academic development in the global pharmaceutical industry to introduce more substances which may be radiolabeled with Ga-68 in clinical development. approaches 'Theranostic' that combine the diagnosis using Ga -68 PET with treatment using Yttrium-0, coupled using the same carrier molecule, are also very promising. "

TAS-102 Phase III study for metastatic colorectal cancer showed improved survival

TAS-102 Phase III study for metastatic colorectal cancer showed improved survival -

ESMO 16th World Congress on the GI gastrointestinal cancer

The new TAS-102 combination agent is able to improve overall survival compared to placebo in patients with metastatic colorectal cancer refractory to standard treatments, the researchers said global ESMO 16 Congress gastrointestinal cancer intestinal Barcelona.

"About 50% of patients with colorectal cancer develop metastases but eventually many of them do not respond to standard treatments," said Takayuki Yoshino of the Hospital East National Cancer Center Chiba, Japan, the lead author of the Phase III trial RESORT. "The study shows that RESORT TAS-102 improves overall survival in these patients compared to placebo. I believe that this agent will become one of the standards of care in the context refractory metastatic colorectal cancer in Japan and the world."

TAS-102 is a novel anti-tumor nucleoside consists of trifluridine agent (FTD) and tipiracil hydrochloride (TPI). DFT is the active component of TAS-102 and is directly incorporated into the DNA of cancer, leading to dysfunction of DNA. However, where FTD is taken orally, it is largely degraded to an inactive form. TPI prevents the degradation of FTD. This mechanism of action is different from that fluoropyrimidine, oxaliplatin, and irinotecan.

The Phase II trial of TAS-102 had found an overall survival benefit in Japanese patients with refractory colorectal cancer metastases to fluoropyrimidine 5-fluorouracil (5-FU), irinotecan and oxaliplatin.

The current study was a RESORT global phase III trial conducted in 13 countries at 114 centers. The patients had refractory metastatic colorectal cancer to all standard therapies, including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and cetuximab or panitumumab in patients with KRAS wild type tumors. The patients were randomized 2: 1 to TAS-102 (534 patients) or placebo (266 patients). The primary endpoint was overall survival

The researchers found that TAS-102 prolonged overall survival compared to placebo (hazard ratio 0.68) :. Median overall survival was 7.1 months for TAS-102 and 5.3 months for the placebo group. TAS-102 also improved progression-free survival compared to placebo (hazard ratio 0.48), which was a secondary endpoint. Yoshino said. "We found a statistically significant difference in overall survival and progression-free and clinically significant improvement"

"TAS-102 has a soft safety profile and the most common side effect is hematologic toxicity including neutropenia. patients with refractory to standard therapies of metastatic colorectal cancer now have a strong treatment option. "

Commenting on these data, ESMO spokesperson Jean Yves Douillard, Professor of oncology medical Institute of Meteorology Canc-West (ICO) Ren- Gauducheau, Saint-Herblain, France, said: "the trial of TAS-102 phase III is a comprehensive study and confirms the results of the study Phase II in Japanese patients, whose response to fluoropyrimidine is slightly different from patients in Europe and the United States. It is good to know that the magnitude of the benefit shown in smaller phase II trial is confirmed in Phase III testing more and that the results are applicable to Asians and Caucasians alike. "

TAS-102 is a combination of two components. tipiracil hydrochloride (ITP) prevents degradation of trifluridine (FTD) and also has an angiogenic activity. "This is probably why TAS-102 is effective in fluoropyrimidine 5-fluorouracil classic (5-FU) resistant patients. The drug is very promising, the tolerance is good and is manageable with supportive care."

Douillard concluded "in RESORT, TAS-102 was tested in patients who received any type of chemotherapy available for colorectal cancer, I'd probably move this drug in an earlier line of treatment and I would also combine either irinotecan or oxaliplatin with .. "

Researchers are developing a new way to identify potential therapeutic targets for melanoma resistant to drugs

Researchers are developing a new way to identify potential therapeutic targets for melanoma resistant to drugs -

Their analysis process will identify potential new therapeutic targets

researchers Moffitt Cancer Center developed a new way to identify possible therapeutic targets for patients with melanoma drug resistant. It involves the use of the liquid mass spectrometry control of the reaction multiple chromatography to measure biomarkers or molecules in the blood and tissue that indicates cancer is present. These measures may help researchers determine whether a patient is responding to treatment.

Scientists have made significant progress identifying important molecules that contribute to melanoma growth and metastasis, such as BRAF and MEK proteins. Therapeutic agents that target these molecules have shown promising results in the clinic, and many patients have significant reductions in tumor growth and tumor burden.

"Although drugs targeted therapy, such as inhibitors of BRAF and MEK, have been associated with impressive responses in melanoma patients, most patients eventually fail therapy," said Keiran Smalley, Ph.D., associate member of the cancer biology and Evolution program at Moffitt.

tumors can develop different mechanisms of resistance and adapt targeted agents in order to survive and continue to grow. "It is likely that the long-term management of melanoma patients will require combinations of drugs, "said Smalley.

the molecular changes that lead to drug resistance varies between patients and each tumor. the identification these molecular changes with current scientific approaches is difficult, expensive and time consuming.

Smalley the team, in collaboration with the laboratory of John Koomen, Ph.D. in chemical biology and Moffitt molecular medicine program, developed a multiple liquid chromatography assay reaction monitoring mass spectrometry to analyze more than 80 proteins known to be important in melanoma progression and resistance to targeted therapies. They showed that melanoma cells that are resistant to drugs that target MEK have alterations in a number of different cell signaling pathways. The results of this kind will enable the development of new treatment strategies.

The researchers plan to accelerate the identification of proteins involved in resistance of melanoma by use of multiple chromatography reaction monitoring mass spectrometry liquid medications. The platform for the simultaneous detection of multiple proteins in small amounts of tissue samples. This also results in highly reproducible data that can be easily validated between different laboratories.