Cancer Knowledge

New approach to treat drug-resistant HER2–positive breast cancer

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The discovery, published in the journal CELL Reports, provides the experimental evidence for the potential development of a novel combination therapy for HER2-positive breast cancer. The combination includes the FDA approved drug lapatinib and a new experimental drug called a BET bromodomain inhibitor, which works by disrupting the expression of specific genes.

This study, a collaboration of 20 University of North Carolina researchers, is the first time a BET bromodomain inhibitor has been shown to prevent the onset of resistance to drugs such as lapatinib in breast cancer cells.

“This research was done in cell lines of human HER2-positive breast cancer, not in patients; but the results are very striking,” said Gary Johnson, PhD, Kenan Distinguished Professor and chair of the department of pharmacology, member of the UNC Lineberger Comprehensive Cancer Center, and senior author of the paper. “The combination treatments are currently being tested in different mouse models of breast cancer. Our goal is to create a new kind of therapy that could help oncologists make the response to treatment more durable and lasting for breast cancer patients.”

The HER2-positive subtype accounts for 15 to 20 percent of all breast cancer diagnoses. Only about one-third of these patients respond well to standard therapy. But even patients that initially respond eventually develop resistance. This is a universal problem of drugs that target specific proteins called kinases that drive tumor growth. Kinases are essential for cellular activities, such as movement, division, and signaling to other proteins to promote cell survival and growth. In this subtype of breast cancer, HER2 is the primary kinase involved in the growth of these tumors. When it’s blocked with a drug like lapatinib, cancer cells have ways to get around the roadblock by using other kinases.

Tim Stuhlmiller, PhD, a postdoctoral fellow in Johnson’s lab and first author of the paper, conducted experiments using a technique to determine kinase activity on a global scale throughout a group of given cells – a technology that Johnson’s lab had previously developed.

Stuhlmiller was able to see what happened to HER2-positive human cancer cells when treated with the HER2 inhibitor lapatinib. As expected, each cell line developed resistance to the drug. But, surprisingly, each cell line resisted in different ways. Not just one or two kinases activated to beat the lapatinib. Many kinases responded. And they were not the same kinases from cell line to cell line. But they did the same thing: they ensured that the cancer cells survived and grew.

“It was amazing,” Stuhlmiller said. “We found this massive up-regulation of many different kinases that could either reactivate the main HER2 signaling pathway or bypass it entirely. In fact, we discovered that nearly 20 percent of the cell’s entire gene expression profile was dysregulated when we treated the cells with lapatinib.”

Dysregulated genes lead to abnormal amounts of proteins. These proteins – the kinases – drive resistance to anti-cancer drugs. This research strongly suggests that there are many different ways HER2-positive cancer cells can compensate for the initial blockage of the HER2 protein. Thus, targeting all of these specific kinases would be extremely difficult.

“Because of toxicity concerns, you couldn’t inhibit all these kinases that potentially help cancer cells compensate in the face of a HER2 inhibitor,” Stuhlmiller said. “The more drugs you try to use, the more toxic that would be for patients and the lower the dose people would be able to tolerate.

“So that’s one take home message,” he said. “But the main message is we used a different kind of drug to block that entire massive kinase response before it ever happened.”

For that, Johnson’s team used a BET bromodomain inhibitor. It’s part of a new class of drugs that targets proteins involved in gene transcription – when particular parts of DNA are copied into RNA; this is the first step in the creation of enzymes, such as kinases.

Johnson’s team tested several BET bromodomain inhibitors, including one currently in clinical trials to treat blood cancers and a specific type of leukemia. During experiments, Johnson’s team found that BET bromodomain inhibitors targeted the gene transcription of most of the kinases responsible for resistance. By combining lapatinib with a BET bromodomain inhibitor, Stuhlmiller found that the HER2 kinase was blocked, as planned. Also, the massive kinase activation that typically followed HER2 inhibition never happened. The second drug suppressed the kinase response.

“We blocked it before it could happen,” Stuhlmiller said. “In all five cell lines we tested, there were no cancer cells left because the combination therapy blocked their growth. Essentially, we made the activity of lapatinib durable.” As a result, the cancer cells were annihilated.

Johnson’s lab and their UNC collaborators are currently working to replicate their findings in animal models of HER2-positive breast cancer. They think these types of combination therapies are going to be necessary to prevent resistance in the clinic. They’re also studying the effects of BET bromodomain inhibitors on other breast cancer subtypes, such as triple-negative breast cancer, another subtype that is difficult to treat.

source : http://www.sciencedaily.com/releases/2015/04/150409133220.htm

Body’s cancer defenses hijacked to make pancreatic, lung cancers more aggressive

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The team, from the Cancer Research UK Centre at the UCL (University College London) Cancer Institute, found that mutations in the KRAS gene interferes with protective self-destruct switches, known as TRAIL receptors, which usually help to kill potentially cancerous cells.

The research, carried out in cancer cells and mice, shows that in cancers with faulty versions of the KRAS gene these TRAIL receptors actually help the cancer cells to grow and spread to new areas in the body.

These KRAS faults occur in 95 per cent of pancreatic cancers and 30 per cent of non small cell lung cancers.

Professor Henning Walczak, lead researcher of the study and scientific director of the Cancer Research UK-UCL Centre, said: “Our research has unveiled a new strategy used by some pancreatic and non small cell lung cancers to overcome our body’s natural defences against cancer. By understanding the faults in these cancers we think we can develop more tailored treatments, which could one day provide urgently-needed options for patients with these types of pancreatic and non small cell lung cancers.”

Each year in Great Britain 32,500 people are diagnosed with non small cell lung cancer and around 8,600 people are diagnosed with pancreatic cancer. Survival for these cancers has not shown much improvement for 40 years.

Nell Barrie, senior science information manager at Cancer Research UK, said: “Sadly survival from pancreatic and lung cancers remains far too low, partly because these cancers are very difficult to treat once they have spread.

“We urgently need better treatments, so it’s vital to delve deeper into the molecular workings of these cancers to find ways to combat them. This research may one day help us find a way to block cancer spread, which would be a vital step to save more lives.”

source : http://www.sciencedaily.com/releases/2015/04/150402132756.htm

Personalized melanoma vaccines marshal powerful immune response

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The tailor-made vaccines, given to three patients with advanced melanoma, appeared to increase the number and diversity of cancer-fighting T cells responding to the tumors. The finding is a boost to cancer immunotherapy, a treatment strategy that unleashes the immune system to seek out and destroy cancer.

The research is reported April 2 in Science Express, in a special issue devoted to cancer immunology and immunotherapy.

In a new approach, the cancer vaccines were developed by first sequencing the genomes of patients’ tumors and samples of the patients’ healthy tissues to identify mutated proteins called neoantigens unique to the tumor cells. Then, using computer algorithms and laboratory tests, the researchers were able to predict and test which of those neoantigens would be most likely to provoke a potent immune response and would be useful to include in a vaccine.

The vaccines were given to melanoma patients who had had surgery to remove their tumors but whose cancer cells had spread to the lymph nodes, an indicator the deadly skin cancer is likely to recur. These clinical findings set the stage for a phase I vaccine trial, approved by the Food and Drug Administration as part of an investigational new drug application. The trial will enroll six patients.

Data on the immune response seen in the first three patients is reported in the paper. If additional testing in more patients indicates the vaccines are effective, they may one day be given to patients after surgery to stimulate the immune system to attack lingering cancer cells and prevent a recurrence.

“This proof-of-principle study shows that these custom-designed vaccines can elicit a very strong immune response,” said senior author Gerald Linette, MD, PhD, a Washington University medical oncologist leading the clinical trial at Siteman Cancer Center and Barnes-Jewish Hospital. “The tumor antigens we inserted into the vaccines provoked a broad response among the immune system’s killer T cells responsible for destroying tumors. Our results are preliminary, but we think the vaccines have therapeutic potential based on the breadth and remarkable diversity of the T-cell response.”

It’s too early to say whether the vaccines will be effective in the long term, the researchers cautioned. The study was designed to evaluate safety and immune response; however, none of the patients has experienced adverse side effects.

Earlier attempts at vaccines have focused on targeting normal proteins commonly expressed at high levels in particular cancers. Those same proteins also are found in healthy cells, making it difficult to stimulate a potent immune response.

The new approach investigated by the Washington University team merges cancer genomics with cancer immunotherapy.

“This is about as personalized as vaccines can get,” said co-author Elaine Mardis, PhD, co-director of the McDonnell Genome Institute at Washington University, where the cancer genome sequencing, analysis and neoantigen prediction were performed. “The approach we describe is fundamentally different from conventional mutation discovery, which focuses on identifying mutated genes that drive cancer development. Instead, we’re looking for a unique set of mutated proteins in a patient’s tumor that would be most likely to be recognized by the immune system as foreign.”

Melanomas are notorious for having high numbers of genetic mutations caused by exposure to ultraviolet light. Biopsy samples of melanomas typically carry 500 or more mutated genes. Using prediction algorithms, the researchers narrowed their search for vaccine candidates by identifying neoantigens that not only were expressed in a patient’s tumor but also were likely to be seen by that patient’s immune system as “non-self.”

Biochemical validation of neoantigen peptide expression on the cancer cells’ surfaces was performed in collaboration with William Hildebrand’s group at the University of Oklahoma Health Sciences Center and provided critical assurance that the vaccine would elicit the most effective T cells to combat the melanoma.

“You can think of a neoantigen as a flag on each cancer cell,” said first author Beatriz Carreno, PhD, associate professor of medicine. “Each patient’s melanoma can have hundreds of different flags. As part of validating candidate vaccine neoantigens, we were able to identify the flags on the patients’ cancer cells. Then we created customized vaccines to a select group of flags on each patient’s tumor.”

Carreno and her colleagues selected a set of seven unique neoantigens for each vaccine and used specialized immune cells called dendritic cells, derived from the patients, to carry those neoantigens to the immune system. Dendritic cells play an important role in waking up the immune system, reminding T cells to attack the cancer.

After the vaccine infusions, the patients’ blood was drawn every week for about four months. By analyzing the blood samples, the researchers could see that each patient mounted an immune response to specific neoantigens in their vaccines. The vaccines also stimulated diverse clones of battle-ready T cells against neoantigens, suggesting this approach also could be used to activate a range of T cells and target them to mutations in other cancers with high mutation rates, such as lung cancer, bladder cancer and certain colorectal cancers.

“Our team has developed a new strategy for personalized cancer immunotherapy,” Linette said. “Many researchers have hypothesized that it would be possible to use neoantigens to broadly activate the human immune system, but we didn’t know that for sure until now. We still have much more work to do, but this is an important first step and opens the door to personalized immune-based cancer treatments.”

The research was supported by the Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Our Mark on Melanoma Foundation, Come Out Swinging Foundation, Blackout Melanoma Foundation, the National Cancer Institute, grants R21 CA179695 and P30 CA91842, and the National Human Genome Research Institute, grant 5U54HG00307, at the National Institutes of Health (NIH).

source : http://www.sciencedaily.com/releases/2015/04/150402161457.htm

Small RNA plays big role suppressing cancer

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Researchers at UC Davis have unraveled some of these relationships, identifying several interactions that directly impact liver and colon cancer. The work provides new insights into how miR-22 operates and could potentially lead to new cancer therapies. The study was published in the Journal of Biological Chemistry.

“There are quite a few molecules present in the gastrointestinal (GI) tract that regulate miR-22,” said Yu-Jui Yvonne Wan, vice chair for research in the Department of Pathology and Laboratory Medicine and senior author on the paper. “If so many chemicals in the GI tract can regulate miR-22, it must be physiologically significant. We needed to better understand the molecules that regulate miR-22 in cancer, as well as the pathways miR-22 controls.”

Micro RNAs, like miR-22, play a major role in gene expression by selectively silencing particular genes. To understand the role of miR-22 in liver and colon cancer, Wan and her colleagues studied mice that lacked the bile acid receptor, farnesoid x receptor (FXR), which balances bile acid and cholesterol. Without FXR, mice spontaneously develop liver cancer. They also examined the expression of miR-22 in human liver cancer and colon cancer specimens.

The researchers found that the journey begins with bile acids, such as hydrophilic chenodeoxycholic acid, which activates FXR. In turn, FXR increases miR-22, which reduces the expression level of Cyclin A2, a protein that influences cell division and protects liver and colon cells from excessive proliferation.

The team confirmed these results using different models and found there is an inverse relationship between miR-22 and Cyclin A2 expression levels in liver and colon cancer cells.

The research also showed that miR-22 can be activated by vitamin D3, which can reduce the toxicity of hydrophobic bile acids. These pieces of information highlight the potential impact of diet and vitamins on GI cancer formation.

“People who are obese, or eating a high-fat Western diet, tend to have dysregulated bile acid synthesis,” said Wan. “When that happens, FXR can be inactivated, potentially decreasing the level of miR-22, increasing the expression of Cyclin A2 and disrupting the cell cycle. So this pathway may play a role in Western diet-associated carcinogenesis.”

In addition, miR-22 has a complicated relationship with a number of cancers, including breast and lung, and may offer promise as a cancer therapeutic target. In addition to targeting Cyclin A2, miR-22 also inhibits the expression level of histone deacetylases (HDACs), proteins that control gene expression by modification of histone structure. A number of HDAC inhibitors are FDA- approved anti-cancer drugs, and miR-22 can potentially be used to treat cancer.

“I’m not so sure miR-22 is all good,” said Wan. “We don’t know what it will target in normal cells. Our next step is to identify more miR-22 effects.”

source : http://www.sciencedaily.com/releases/2015/04/150402161646.htm

Herpesvirus activates RIG-I receptor to evade body’s immune system

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Led by Pinghui Feng, Ph.D., associate professor of molecular microbiology and immunology at the Keck School of Medicine of USC, the team found that herpesvirus proteins activate retinoic acid-induced gene I (RIG-I) by removal of an amino group from the glutamine and asparagine amino acids through a process called deamidation. RIG-I is a cellular receptor that recognizes RNA derived from invading pathogens. Prior to this study, it was unclear whether RIG-I — whose activation is central to the body’s innate immune defense response — could be activated by a component other than viral RNA. This is the first example wherein host immune defense is activated by an enzymatic activity, implying that deamidation can be a highly regulated process, reshaping the conventional notion that deamidation is a non-specific process associated with protein decay. The team also identified the first bona-fide enzyme that causes protein deamidation in eukaryotes.

source : http://www.sciencedaily.com/releases/2015/04/150402183534.htm

Possible progress against Parkinson’s and good news for stem cell therapies

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Parkinson’s, which affect as many 10 million people in the world, is caused by a depletion of dopamine-producing neurons in the brain. Current treatments include medications and electrical implants in the brain which causes severe adverse effects over time and fail to prevent disease progression. Several studies have indicated that the transplantation of embryonic stem cells improves motor functions in animal models. However, until now, the procedure has shown to be unsafe, because of the risk of tumors upon transplantation.

To address this issue, the researchers tested for the first time to pre-treat undifferentiated mouse embryonic stem cells with mitomycin C, a drug already prescribed to treat cancer. The substance blocks the DNA replication and prevents the cells to multiply out of control.

The researchers used mice modeled for Parkinson’s. The animals were separated in three groups. The first one, the control group, did not receive the stem cell implant. The second one, received the implant of stem cells which were not treated with mitomycin C and the third one received the mitomycin C treated cells.

After the injection of 50,000 untreated stem cells, the animals of the second group showed improvement in motor functions but all of them died between 3 and 7 weeks later. These animals also developed intracerebral tumors. In contrast, animals receiving the treated stem cells showed improvement of Parkinson’s symptoms and survived until the end of the observation period of 12 weeks post-transplant with no tumors detected. Four of these mice were monitored for as long as 15 months with no signs of pathology.

Furthermore, the scientists have also shown that treating the stem cells with mitomycin C induced a four-fold increase in the release of dopamine after in vitro differentiation.

“This simple strategy of shortly exposing pluripotent stem cells to an anti-cancer drug turned the transplant safer, by eliminating the risk of tumor formation,” says the leader of the study Stevens Rehen, Professor at UFRJ and researcher at IDOR.

The discovery, reported on April in the journal Frontiers in Cellular Neuroscience, could pave the way for researchers and physicians to propose a clinical trial using pluripotent stem cells treated with mitomycin C prior to transplant to treat Parkinson’s patients and also other neurodegenerative conditions.

“Our technique with mitomycin C may speed the proposal of clinical trials with pluripotent cells to several human diseases,” says Rehen. “It is the first step to make this kind of treatment with stem cells possible.”

source : http://www.sciencedaily.com/releases/2015/04/150403104223.htm

One dollar blood test using gold nanoparticles outperforms PSA screen for prostate cancer, study suggests

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The simple test developed by University of Central Florida scientist Qun “Treen” Huo holds the promise of earlier detection of one of the deadliest cancers among men. It would also reduce the number of unnecessary and invasive biopsies stemming from the less precise PSA test that’s now used.

“It’s fantastic,” said Dr. Inoel Rivera, a urologic oncologist at Florida Hospital Cancer Institute, which collaborated with Huo on the recent pilot studies. “It’s a simple test. It’s much better than the test we have right now, which is the PSA, and it’s cost-effective.”

When a cancerous tumor begins to develop, the body mobilizes to produce antibodies. Huo’s test detects that immune response using gold nanoparticles about 10,000 times smaller than a freckle.

When a few drops of blood serum from a finger prick are mixed with the gold nanoparticles, certain cancer biomarkers cling to the surface of the tiny particles, increasing their size and causing them to clump together.

Among researchers, gold nanoparticles are known for their extraordinary efficiency at absorbing and scattering light. Huo and her team at UCF’s NanoScience Technology Center developed a technique known as nanoparticle-enabled dynamic light scattering assay (NanoDLSay) to measure the size of the particles by analyzing the light they throw off. That size reveals whether a patient has prostate cancer and how advanced it may be.

And although it uses gold, the test is cheap. A small bottle of nanoparticles suspended in water costs about $250, and contains enough for about 2,500 tests.

“What’s different and unique about our technique is it’s a very simple process, and the material required for the test is less than $1,” Huo said. “And because it’s low-cost, we’re hoping most people can have this test in their doctor’s office. If we can catch this cancer in its early stages, the impact is going to be big.”

After lung cancer, prostate cancer is the second-leading killer cancer among men, with more than 240,000 new diagnoses and 28,000 deaths every year. The most commonly used screening tool is the PSA, but it produces so many false-positive results — leading to painful biopsies and extreme treatments — that one of its discoverers recently called it “hardly more effective than a coin toss.”

Pilot studies found Huo’s technique is significantly more exact. The test determines with 90 to 95 percent confidence that the result is not false-positive. When it comes to false-negatives, there is 50 percent confidence — not ideal, but still significantly higher than the PSA’s 20 percent — and Huo is working to improve that number.

The results of the pilot studies were published recently in ACS Applied Materials & Interfaces. Huo is also scheduled to present her findings in June at the TechConnect World Innovation Summit & Expo in suburban Washington, D.C.

Huo’s team is pursuing more extensive clinical validation studies with Florida Hospital and others, including the VA Medical Center Orlando. She hopes to complete major clinical trials and see the test being used by physicians in two to three years.

Huo also is researching her technique’s effectiveness as a screening tool for other tumors.

“Potentially, we could have a universal screening test for cancer,” she said. “Our vision is to develop an array of blood tests for early detection and diagnosis of all major cancer types, and these blood tests are all based on the same technique and same procedure.”

Huo co-founded Nano Discovery Inc., a startup company headquartered in a UCF Business Incubator, to commercialize the new diagnostic test. The company manufacturers a test device specifically for medical research and diagnostic purposes.

source : http://www.sciencedaily.com/releases/2015/04/150403130826.htm

Most women with early-stage breast cancer avoid extensive lymph node removal

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Until now, it was unclear to what extent surgeons were following the recommendations of a landmark clinical trial published more than four years ago, known as the American College of Surgeons Oncology Group Z0011, or ACOSOG Z-11, trial. Those researchers reported that most early-stage breast cancer patients with tumor in their sentinel lymph node (the first draining node) who undergo lumpectomy do not benefit from surgical removal of the remaining lymph nodes in the underarm area, called completion axillary lymph node dissection (ALND). That study found no difference in cancer recurrence1 and five-year survival2 between patients who underwent ALND and those who did not but were monitored for recurrences.

The new study found a dramatic increase in the proportion of lumpectomy patients who underwent only a sentinel lymph node biopsy (SNB)–removal of the “gatekeeper” lymph nodes that the cancer is most likely to spread to first–without an ALND after discovery of cancerous sentinel nodes. According to the study authors, the SNB-alone rate more than doubled, from 23 percent in 2009, before publication of the first results1 of the ACOSOG Z-11 trial in September 2010, to 56 percent in 2011, the first year after publication.

“As far as I know, our study is the first to show that the findings from the ACOSOG Z-11 trial have changed clinical practice for breast cancer patients nationwide,” said lead author Katharine Yao, MD, FACS, director of the Breast Surgical Program at NorthShore University HealthSystem, Evanston, Ill., and clinical associate professor of surgery at the University of Chicago Pritzker School of Medicine. “The Z-11 trial has had a huge impact because of the lower risks for patients who undergo SNB alone.”

Removal of small numbers of lymph nodes in SNB alone, according to Dr. Yao, greatly lowers the lifetime risk of developing the often disabling complication of lymphedema. This buildup of lymph fluid under the skin results in swelling and sometimes pain.

For the new study, Dr. Yao and colleagues used the National Cancer Data Base (NCDB), a joint project of the American College of Surgeons Commission on Cancer (CoC) and the American Cancer Society. NCDB captures an estimated 70 percent of newly diagnosed cancer cases in the United States from approximately 1,500 cancer programs accredited by the CoC.

Although NCDB does not identify the type of lymph node dissection (SNB or SNB plus ALND) performed, the researchers used the number of lymph nodes removed as surrogates for these procedures. They categorized the removal of four or fewer lymph nodes as SNB only and removal of 10 or more nodes as ALND.

From the 2.72 million breast cancer cases diagnosed between 1998 and 2011 and listed in the database, the investigators found that 74,309 patients met the Z-11 trial’s eligibility criteria for having SNB alone. These patients underwent lumpectomy and radiation therapy to the whole breast; had tumors 5 centimeters or smaller (less than 2 inches) that appeared clinically node negative; had negative surgical margins (no cancer cells seen at the outer edge of the breast tissue removed); and had two or fewer tumor-positive sentinel lymph nodes.

The rate of SNB alone reportedly increased from 6.1 percent in 1998 to 56 percent in 2011, the most recent data at the time of the study. Because the Z-11 trial results were new in 2011, Dr. Yao said she expects the rate will have increased further in 2012.

Statistical analyses revealed that lumpectomy patients were more likely to undergo ALND if they had any of the following characteristics considered high risk: age younger than 50; black race; triple negative tumors (absence of the three most common types of receptors known to fuel most breast cancer growth); and larger tumors (3 cm or less). In addition, patients with two positive sentinel lymph nodes were twice as likely to have an ALND as patients with one tumor-positive sentinel node. Patients whose tumor metastases measured 2 mm (the width of two grains of rice) or larger were more than three times likelier to undergo ALND compared with patients who had a smaller spread of the cancer, called micrometastases.

Dr. Yao said their findings suggest that some practitioners may feel uncomfortable not performing ALND in high-risk patients, although the Z-11 trial included them. She called for more education for surgeons regarding the applicability of the Z-11 trial findings to these high-risk subgroups and for longer follow-up of these high-risk patients.

The researchers also analyzed 400,052 breast cancer cases that did not meet one of the Z-11 trial’s eligibility criteria. Dr. Yao said these results were “somewhat surprising.”

They reported that more than 22 percent of patients who underwent a mastectomy in 2011 had only SNB despite mastectomy patients not being included in the Z-11 trial. In addition, SNB without ALNB

occurred in more than 50 percent of patients who had tumors larger than the recommended 5 cm or those who received no or partial radiation therapy, rather than whole-breast irradiation.

“It is a little concerning that patients who fall outside the Z-11 eligibility criteria are getting SNB alone,” Dr. Yao said. “It’s controversial to perform SNB alone in mastectomy patients because we don’t know if it affects overall outcomes.”

source : http://www.sciencedaily.com/releases/2015/03/150326130955.htm

Ebola whole virus vaccine shown effective, safe in primates

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The vaccine, described today (March 26, 2015) in the journal Science, was developed by a group led by Yoshihiro Kawaoka, a University of Wisconsin-Madison expert on avian influenza, Ebola and other viruses of medical importance. It differs from other Ebola vaccines because as an inactivated whole virus vaccine, it primes the host immune system with the full complement of Ebola viral proteins and genes, potentially conferring greater protection.

“In terms of efficacy, this affords excellent protection,” explains Kawaoka, a professor of pathobiological sciences in the UW-Madison School of Veterinary Medicine and who also holds a faculty appointment at the University of Tokyo. “It is also a very safe vaccine.”

The vaccine was constructed on an experimental platform first devised in 2008 by Peter Halfmann, a research scientist in Kawaoka’s lab. The system allows researchers to safely work with the virus thanks to the deletion of a key gene known as VP30, which the Ebola virus uses to make a protein required for it to reproduce in host cells. Ebola virus has only eight genes and, like most viruses, depends on the molecular machinery of host cells to grow and become infectious.

By engineering monkey kidney cells to express the VP30 protein, the virus can be safely studied in the lab and be used as a basis for devising countermeasures like a whole virus vaccine. The vaccine reported by Kawaoka and his colleagues was additionally chemically inactivated using hydrogen peroxide, according to the new Science report.

Ebola first emerged in 1976 in Sudan and Zaire. The current outbreak in West Africa has so far claimed more than 10,000 lives. There are no proven treatments or vaccines, although several vaccine platforms have been devised in recent years, four of which recently advanced to the clinical trial stage in humans.

The new vaccine reported by Kawaoka has not been tested in people. However, the successful tests in nonhuman primates conducted at the National Institutes of Health (NIH) Rocky Mountain Laboratories, a biosafety level 4 facility in Hamilton, Montana, may prompt further tests and possibly clinical trials of the new vaccine. The work at Rocky Mountain Laboratories was conducted in collaboration with a group led by Heinz Feldmann of NIH.

Those studies were conducted with cynomolgus macaques, which are very susceptible to Ebola. “It’s the best model,” Kawaoka says. “If you get protection with this model, it’s working.”

Ebola vaccines currently in trials include:

— A DNA-based plasmid vaccine that primes host cells with some of the Ebola proteins.

— A vaccine based on a replication incompetent chimpanzee respiratory virus engineered to express a key Ebola protein.

— A live attenuated virus from the same family of viruses that causes rabies, also engineered to express a critical Ebola protein.

— A vaccine based on a vaccinia virus and engineered to express a critical Ebola protein.

Each of those strategies, Kawaoka notes, has drawbacks in terms of safety and delivery.

Whole virus vaccines have long been used to successfully prevent serious human diseases, including polio, influenza, hepatitis and human papillomavirus-mediated cervical cancer.

The advantage conferred by inactivated whole virus vaccines such as the one devised by Halfmann, Kawaoka and their colleagues is that they present the complete range of proteins and genetic material to the host immune system, which is then more likely to trigger a broader and more robust immune response.

Early attempts to devise an inactivated whole virus Ebola vaccine through irradiation and the preservative formalin failed to protect monkeys exposed to the Ebola virus and were abandoned.

Although the new vaccine has surpassed that hurdle, human trials are expensive and complex, costing millions of dollars.

The Ebola vaccine study conducted by Kawaoka was supported by the National Institutes of Health and by the Japanese Health and Labour Sciences Research Grants.

source : http://www.sciencedaily.com/releases/2015/03/150326151426.htm

Bio-marker set forms the basis for new blood test to detect colorectal cancer

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Max Mazzone (VIB/KU Leuven): “This research demonstrates how important it is to gain a thorough understanding of the role of our immune system in cancer. In this case, this knowledge will hopefully result in a new, more sensitive test to detect colorectal cancer at an early stage, so that more patients can be cured. I hope that we can soon find an industrial partner to help us achieve the following step, which is the development of the test.”

Colorectal cancer: a growing medical problem

In 2012, a total of 1.4 million people worldwide were diagnosed with colorectal cancer, this figure is expected to increase to 2.4 million by 2035. This is a condition that affects a growing number of people each year. Colorectal cancer is very treatable if it is detected at an early stage, with approximately 95 % chance of a cure. If detected at a late stage, the chance of surviving 5 years after diagnosis is less than 10 %. Therefore, it is very important to be able to detect the disease in an early stage. And therein lies the rub.

Population screening

There are no global screening guidelines, but because early detection is so important, there are a number of national initiatives to screen the population. For example, in Flanders, the population group between the ages of 56 and 74 years is invited to undergo testing via the “immunological Fecal Occult Blood test” (iFOB), which detects blood in the stools. If this test is positive, a colonoscopy needs to be performed to confirm the presence of premalignant polyps or cancer.

Even though the iFOB test is the best test available, sensitivity is suboptimal. In other words the available test doesn’t detect all colon cancers. There is a need for a test that offers greater certainty and that can detect bowel cancer at an early stage and at the same time reaches the whole population. If this can be achieved with a blood test, this might lower the reluctance seen in patients towards the stool test.

Our immune system responds to cancer

If we are affected by cancer, our immune system responds to this and tries to remove the cancer cells from our body. A specific role in this process is assigned to a specific type of white blood cell: the peripheral blood monocyte. From the moment that colorectal cancer cells are present in the body, the peripheral blood monocytes respond to the substances secreted by the cancer cells.

Alexander Hamm (VIB/KU Leuven): “The substances secreted by the cancer cells activate specific genes in the monocytes. Now we have identified these genes, and they can be used to diagnose colorectal cancer through blood collection by using standard techniques.”

Hans Prenen (UZ Leuven): “This new test will probably be more sensitive, because it detects tumor-induced changes directly and not merely blood in the stools. An additional benefit is that this process takes place at a point when the tumor is forming, the earliest stage of tumor development. Since this test is based on how our body reacts to the presence of colorectal cancer cells, it can also be used to detect distant metastasis even after the primary tumor has been removed. This unique potential makes it a valid tool for patient follow-up after the primary tumor has been removed through surgery.”

Set of bio-markers identified

For the identification of the genes involved in this process, Hans Prenen (UZ Leuven) and his colleagues from oncology centers in Brussels, Heidelberg and Rome collected samples from patients. This allowed the researchers led by Max Mazzone (VIB/KU Leuven) to identify 43 relevant genes.

Wouter Van Delm (VIB Nucleomics Core Facility): “As 43 different genes are too many genes to incorporate in a diagnostic test, it was important to find a more limited gene set with the same predictive value. We eventually succeeded in creating a set of 23 genes, but we are still trying to further reduce this number.”

The challenge facing the investigators now is to develop a test using a minimal set of bio-markers. They are looking for an industrial partner for the development of the test.

source : http://www.sciencedaily.com/releases/2015/03/150327090912.htm