Tagged: Cancer Toggle Comment Threads | Keyboard Shortcuts

  • richardmitnick 10:42 am on July 31, 2017 Permalink | Reply
    Tags: , Cancer, , , , It wouldn’t have been obvious that PTPN2 is a good drug target for the immunotherapy of cancer, , PD-1 checkpoint inhibitors have transformed the treatment of many cancers   

    From HMS: “Attack Mode “ 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    7.31.17
    KAT MCALPINE

    1
    Genetic screening for cancer immunotherapy targets. Cancer cells (colored shapes), each with a different CRISPR-Cas9-mediated gene knocked out. T cells (red) destroy the cancer cells that have had essential immune evasion genes knocked out. Image: Haining Lab, Dana-Farber/Boston Children’s.

    A novel screening method developed by a team at Harvard Medical School and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has revealed new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors, a promising new class of cancer immunotherapy.

    In findings published online today by Nature http://www.nature.com/nature/journal/v547/n7664/full/nature23270.html the Dana-Farber/Boston Children’s team, led by pediatric oncologist W. Nick Haining, reports that deletion of the PTPN2 gene in tumor cells made them more susceptible to PD-1 checkpoint inhibitors. PD-1 blockade is a drug that “releases the brakes” on immune cells, enabling them to locate and destroy cancer cells.

    “PD-1 checkpoint inhibitors have transformed the treatment of many cancers,” said Haining, HMS associate professor of pediatrics at Dana-Farber/Boston Children’s, associate member of the Broad Institute of MIT and Harvard, and senior author on the new paper. “Yet despite the clinical success of this new class of cancer immunotherapy, the majority of patients don’t reap a clinical benefit from PD-1 blockade.”

    That, Haining said, has triggered a rush of additional trials to investigate whether other drugs, when used in combination with PD-1 inhibitors, can increase the number of patients whose cancer responds to the treatment.

    “The challenge so far has been finding the most effective immunotherapy targets and prioritizing those that work best when combined with PD-1 inhibitors,” Haining said. “So, we set out to develop a better system for identifying new drug targets that might aid the body’s own immune system in its attack against cancer.

    “Our work suggests that there’s a wide array of biological pathways that could be targeted to make immunotherapy more successful,” Haining continued. “Many of these are surprising pathways that we couldn’t have predicted. For instance, without this screening approach, it wouldn’t have been obvious that PTPN2 is a good drug target for the immunotherapy of cancer.”

    Sifting through thousands of potential targets

    To cast a wide net, the paper’s first author Robert Manguso, a graduate student in Haining’s lab, designed a genetic screening system to identify genes used by cancer cells to evade immune attack. He used CRISPR-Cas9, a genome editing technology that works like a pair of molecular scissors to cleave DNA at precise locations in the genetic code, to systematically knock out 2,368 genes expressed by melanoma skin cancer cells. Manguso was then able to identify which genes, when deleted, made the cancer cells more susceptible to PD-1 blockade.

    Manguso started by engineering the melanoma skin cancer cells so that they all contained Cas9, the cutting enzyme that is part of the CRISPR editing system. Then, using a virus as a delivery vehicle, he programmed each cell with a different single-guide-RNA (sgRNA) sequence of genetic code. In combination with the Cas9 enzyme, the sgRNA codes—about 20 amino acids in length—enabled 2,368 different genes to be eliminated.

    By injecting the tumor cells into mice and treating them with PD-1 checkpoint inhibitors, Manguso was then able to tally up which modified tumor cells survived. Those that perished had been sensitized to PD-1 blockade as a result of their missing gene.

    Using this approach, Manguso and Haining first confirmed the role of two genes already known to be immune evaders—PD-L1 and CD47, drug inhibitors that are already in clinical trials. They then discovered a variety of new immune evaders that, if inhibited therapeutically, could enhance PD-1 cancer immunotherapy. One such newly found gene of particular interest is PTPN2.

    “PTPN2 usually puts the brakes on the immune signaling pathways that would otherwise smother cancer cells,” Haining said. “Deleting PTPN2 ramps up those immune signaling pathways, making tumor cells grow slower and die more easily under immune attack.”

    Gaining more ground

    With the new screening approach in hand, Haining’s team is quickly scaling up their efforts to search for additional novel drug targets that could boost immunotherapy.

    Haining says the team is expanding their approach to move from screening thousands of genes at a time to eventually being able to screen the whole genome and to move beyond melanoma to colon, lung, renal carcinoma and more. He’s assembled a large team of scientists spanning Dana-Farber/Boston Children’s and the Broad to tackle the technical challenges that accompany screening efforts on such a large scale.

    In the meantime, while more new potential drug targets are likely around the corner, Haining’s team is taking action based on their findings about PTPN2.

    “We’re thinking hard about what a PTPN2 inhibitor would look like,” said Haining. “It’s easy to imagine making a small molecule drug that turns off PTPN2.”

    This work was supported by the Broad Institute of Harvard and MIT (BroadIgnite and Broadnext10 awards) and the National Institute of General Medical Sciences (T32GM007753).

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 4:45 pm on July 27, 2017 Permalink | Reply
    Tags: , , Cancer, , Putting cancers’ vulnerabilities on the map   

    From Broad: “Here there be dependencies: Putting cancers’ vulnerabilities on the map” 

    Broad Institute

    Broad Institute

    07.27.17
    Tom Ulrich

    1
    No image caption or credit.

    Cancer cells thrive despite harboring mutations that should kill them. By mapping the dependencies cancer cells rely on for survival, researchers hope to reveal new treatment opportunities.

    Cancer cells can harbor a whole gamut of genetic errors, from small mutations to wholesale swaps of DNA between chromosomes — sometimes thousands of molecular flaws that should leave them dead. But when an error impacts a critical gene, a cancerous cell will compensate by adjusting other genes’ activity — increasing expression of another member of the same pathway, for instance.

    From a researcher’s perspective, these adaptations — which allow the tumor to persist — represent dependencies: vulnerabilities that provide deeper insight into cancer biology and might serve as targets for designing new therapies, or for repurposing existing ones.

    “Much of what has been and continues to be done to characterize cancer has been based on genetics and sequencing. That’s given us the parts list,” said William Hahn, an institute member in the Broad Cancer Program and an oncologist at Dana-Farber Cancer Institute. “Mapping dependencies ascribes function to the parts and shows you how to reverse engineer the processes that underlie cancer.”

    That reasoning underlies the Cancer Dependency Map, a joint effort bringing together researchers from the Cancer Program’s Project Achilles, the Broad’s Genetic Perturbation Platform (GPP), and other teams across the institute. The team has spent nearly 15 years conducting genome-wide RNA interference (RNAi) screens on a growing number of cancer cell lines, probing thousands of genes individually for possible vulnerabilities.

    In a study conducted as part of the Slim Initiative in Genomic Medicine for the Americas and reported in Cell, the Dependency Map team describes a major set of findings: 769 strong dependencies unique to cancer cells uncovered through RNA interference (RNAi) screens of 501 cell lines representing a range of tumors. The list reveals intriguing themes in cancer cells’ survival strategies, and may also open new avenues for cancer drug development.

    Fruition long coming

    The data in the Cell paper represents an effort that reaches back to the earliest days of the Broad.

    “In the early 2000s we worked out how to do pooled RNAi screens in mammalian systems well,” which gave researchers the tools to run genome-wide screens on many cell lines at once, said GPP director and institute scientist David Root, who, with Hahn, is one of the study’s co-senior authors. “That led us to doing genome wide screens on a dozen cancer cell lines,” work that he and his colleagues published in 2008.

    RNAi effectively silences genes using small pieces of RNA called small interfering RNAs (siRNAs). These RNA tidbits bind to and call for the destruction of messenger RNAs (mRNAs) transcribed from individual genes, perturbing their expression. To run a genome-wide RNAi screen, researchers expose cells to pools of siRNAs, track the cells’ behavior, and and work back to see which genes were silenced.

    “The simplest thing one can do with perturbed cells is allow them to keep growing over time and see which ones thrive,” Root explained. “If cells with a certain gene silenced disappear, for example, it means that gene is essential for proliferation.”

    Even those first dozen cell lines held revelations. For instance, tumor cells depended heavily on genes active in their original tissues (e.g., blood cancer cells needed blood-lineage genes, lung cells needed different genes). Other relationships were specific to individual cell lines, like one between cells from a chronic myelogenous leukemia (CML) line and ABL, a known CML driver gene.

    But the team knew even then that they were not close to seeing the whole picture. “A dozen cell lines was far too few to really probe the breadth of dependencies,” Root said.

    Cancer cells can harbor a whole gamut of genetic errors, from small mutations to wholesale swaps of DNA between chromosomes — sometimes thousands of molecular flaws that should leave them dead. But when an error impacts a critical gene, a cancerous cell will compensate by adjusting other genes’ activity — increasing expression of another member of the same pathway, for instance.

    From a researcher’s perspective, these adaptations — which allow the tumor to persist — represent dependencies: vulnerabilities that provide deeper insight into cancer biology and might serve as targets for designing new therapies, or for repurposing existing ones.

    “Much of what has been and continues to be done to characterize cancer has been based on genetics and sequencing. That’s given us the parts list,” said William Hahn, an institute member in the Broad Cancer Program and an oncologist at Dana-Farber Cancer Institute. “Mapping dependencies ascribes function to the parts and shows you how to reverse engineer the processes that underlie cancer.”

    That reasoning underlies the Cancer Dependency Map, a joint effort bringing together researchers from the Cancer Program’s Project Achilles, the Broad’s Genetic Perturbation Platform (GPP), and other teams across the institute. The team has spent nearly 15 years conducting genome-wide RNA interference (RNAi) screens on a growing number of cancer cell lines, probing thousands of genes individually for possible vulnerabilities.

    In a study conducted as part of the Slim Initiative in Genomic Medicine for the Americas and reported in Cell, the Dependency Map team describes a major set of findings: 769 strong dependencies unique to cancer cells uncovered through RNA interference (RNAi) screens of 501 cell lines representing a range of tumors. The list reveals intriguing themes in cancer cells’ survival strategies, and may also open new avenues for cancer drug development.

    But the team knew even then that they were not close to seeing the whole picture. “A dozen cell lines was far too few to really probe the breadth of dependencies,” Root said.

    Watching tumors express themselves

    Over the following years, Root, Hahn, and their collaborators — including the Broad Cancer Program’s Paquita Vazquez, Aviad Tsherniak, Cancer Program associate director Jesse Boehm, and Broad chief scientific officer and Cancer Program director Todd Golub — continued to systematically screen additional cell lines until they had comprehensive RNAi data (available via a dedicated online portal) from 501 lines curated by the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE), representing multiple cancer types.

    “Few places have tried to collect this kind of of data at this scale,” Hahn said. “But we felt that it was important to go after this many cell lines because it would give us a more comprehensive view.”

    The total dataset revealed some striking patterns in the genes and pathways cancer cells come to depend on. Many dependencies were cancer-specific, in that silencing them each affected only a subset of the cell lines. However, more than 90 percent of the cell lines had a strong dependency on at least one of a set of 76 genes, suggesting that many cancers rely on a relatively few genes and pathways.

    Using a set of molecular features (e.g., mutations, gene copy numbers, expression patterns) from each cell line, the team also generated biomarker-based models that helped explain the biology behind 426 of the 769 dependencies. Most of those biomarkers fell into four broad categories:

    mutation(s) of a gene

    loss of a copy or reduced expression of a gene

    increased expression of a gene

    reliance on a gene functionally or structurally related to another, lost gene (a.k.a., a paralog dependence)

    Surprisingly, more than 80 percent of the dependencies with biomarkers linked to changes (up or down) in a gene’s expression. Mutations (often used as the grounds for pursuing a gene as a drug target) accounted for merely 16 percent.

    Encouragingly, 20 percent of the dependencies the team discovered linked back to genes previously identified as potential drug targets.

    “We can’t say we’ve found everything, but we can say that the genes we’re seeing fall into a relatively small number of bins, some of which are familiar, some less so,” Hahn said. “That initial taxonomy is a great starting point for building a full map.”

    “Our results provide a starting point for therapeutic projects to decide where to focus their efforts,” said Vazquez, a study co-first author and a Cancer Dependency Map project leader. She added that while there was still much to do to validate the list, “it’s becoming increasingly easier to triangulate data and generate hypotheses as more genome-scale systematic datasets, like those from the CCLE, Genotype-Tissue Expression, and The Cancer Genome Atlas projects, become available.

    “Bringing of all the data together,” she continued, “will help us generate a truly comprehensive cancer dependency map.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 8:09 am on July 12, 2017 Permalink | Reply
    Tags: , Cancer, Chemotherapy before breast cancer surgery might fuel metastasis, , STAT,   

    From STAT via U Washington: “Chemotherapy before breast cancer surgery might fuel metastasis” 

    U Washington

    University of Washington

    1

    STAT

    July 10, 2017
    Sharon Begley

    2
    A breast cancer tumor imaged with a technique that highlights aspects of its microenvironment. National Cancer Institute/Univ. of Chicago Comprehensive Cancer Center. National Cancer Institute/Univ. of Chicago Comprehensive Cancer Center.

    When breast cancer patients get chemotherapy before surgery to remove their tumor, it can make remaining malignant cells spread to distant sites, resulting in incurable metastatic cancer, scientists reported last week.

    The main goal of pre-operative (neoadjuvant) chemotherapy for breast cancer is to shrink tumors so women can have a lumpectomy rather than a more invasive mastectomy. It was therefore initially used only on large tumors after being introduced about 25 years ago. But as fewer and fewer women were diagnosed with large breast tumors, pre-op chemo began to be used in patients with smaller cancers, too, in the hope that it would extend survival.

    But pre-op chemo can, instead, promote metastasis, scientists concluded from experiments in lab mice and human tissue, published in Science Translational Medicine.

    When breast cancer patients get chemotherapy before surgery to remove their tumor, it can make remaining malignant cells spread to distant sites, resulting in incurable metastatic cancer, scientists reported last week.

    The main goal of pre-operative (neoadjuvant) chemotherapy for breast cancer is to shrink tumors so women can have a lumpectomy rather than a more invasive mastectomy. It was therefore initially used only on large tumors after being introduced about 25 years ago. But as fewer and fewer women were diagnosed with large breast tumors, pre-op chemo began to be used in patients with smaller cancers, too, in the hope that it would extend survival.

    But pre-op chemo can, instead, promote metastasis, scientists concluded from experiments in lab mice and human tissue, published in Science Translational Medicine.

    The reason is that standard pre-op chemotherapies for breast cancer — paclitaxel, doxorubicin, and cyclophosphamide — affect the body’s on-ramps to the highways of metastasis, said biologist John Condeelis of Albert Einstein College of Medicine, senior author of the new study.

    Called “tumor microenvironments of metastasis,” these on-ramps are sites on blood vessels that special immune cells flock to. If the immune cells hook up with a tumor cell, they usher it into a blood vessel like a Lyft picking up a passenger. Since blood vessels are the highways to distant organs, the result is metastasis, or the spread of cancer to far-flung sites.

    Depending on characteristics such as how many tumor cells, blood vessel cells, and immune cells are touching each other, the tumor microenvironment can nearly triple the chance that a common type of breast cancer (estrogen-receptor positive/HER2 negative) that has reached the lymph nodes will also metastasize, Condeelis and colleagues showed in a 2014 study [NCBI] of 3,760 patients. The discovery of how the tumor microenvironment can fuel metastasis by whisking cancer cells into blood vessels so impressed Dr. Francis Collins, director of the National Institutes of Health, that he featured it in his blog.

    The new study took the next logical step: Can the tumor microenvironment be altered so that it promotes or thwarts metastasis?

    To find out, Einstein’s George Karagiannis spent nearly three years experimenting with lab mice whose genetic mutations make them spontaneously develop breast cancer, as well as mice given human breast tumors. In both cases, paclitaxel changed the tumor microenvironments in three ways, all more conducive to metastasis: The microenvironment had more of the immune cells that carry cancer cells into blood vessels, it developed blood vessels that were more permeable to cancer cells, and the tumor cells became more mobile, practically bounding into those molecular Lyfts.

    As a result, the mice had twice as many cancer cells zipping through their bloodstream and in their lungs compared with mice not treated with paclitaxel. Two other neoadjuvants, doxorubicin and cyclophosphamide, also promoted metastasis by altering the tumor microenvironment. “This showed that the tumor microenvironment is the doorway to metastasis,” Condeelis said.

    The scientists also analyzed tissue from 20 breast cancer patients who had undergone pre-op chemo (12 weeks of paclitaxel and four of doxorubicin and cyclophosphamide). Compared to before the chemo, the tumor microenvironment after treatment was more conducive to metastasis in most patients. In five, it got more than five times worse. No patient’s microenvironment got less friendly to metastasis.

    Pre-op chemo “may have unwanted long-term consequences in some breast cancer patients,” the Einstein researchers wrote.

    That finding is “fascinating, powerful, and very important,” said Julio Aguirre-Ghiso, of Mount Sinai School of Medicine, an expert in metastasis who was not involved in the study. “It raises awareness that we might have to be smarter about how we use chemotherapy.”

    Dr. Julie Gralow, a medical oncologist at the University of Washington, said that if pre-op chemo promoted metastasis, that should have shown up in studies that compared it to post-op chemo, but for the most part it hasn’t. However, that could be because only tumor cells containing certain proteins that make them especially mobile are affected in this way. “This is an interesting study, to say the least,” Gralow said. “I am willing to keep my mind open to the possibility that there are some breast cancer patients in whom things get worse” with pre-op chemo.

    One reason to question the findings, however, is that if pre-op chemo promotes metastasis in some patients, that might be expected to have shown up in studies of the therapy. Overall, in fact, those studies show [JCO] that “neoadjuvant chemotherapy does not seem to improve overall survival,” as the authors of an editorial in the Journal of Clinical Oncology wrote.

    That’s not as bad as decreasing survival, of course. But Einstein’s Dr. Maja Oktay, a co-author of the new research, cautioned that the typical length of the studies — six or so years — is too short to assess the risk of metastasis, “which can take more than 20 years” to appear, she said. Such patients might never be flagged as having metastatic cancer, let alone having it linked to pre-op chemo decades earlier, said Aguirre-Ghiso.

    On a brighter note, not all breast cancer patients have the kind of tumor microenvironment in which pre-op chemo can promote metastasis. Whether they do or not can be determined by a simple lab test, but one that is not routinely done, Condeelis said.

    Serendipitously, an experimental compound called rebastinib, being developed by Deciphera Pharmaceuticals, seems to be able to block the on-ramp to the metastasis highway. In a study currently recruiting patient volunteers [Clinical Trials.gov], the Einstein scientists (who have no financial relationship with Deciphera) are studying whether rebastinib can improve outcomes in metastatic breast cancer.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    u-washington-campus
    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.
    So what defines us —the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 10:13 am on July 10, 2017 Permalink | Reply
    Tags: , Cancer, , , Personalized cancer vaccines, Personalized Cancer Vaccines Vanquish Melanoma in Small Study,   

    From SA: “Personalized Cancer Vaccines Vanquish Melanoma in Small Study” 

    Scientific American

    Scientific American

    July 6, 2017
    Sharon Begley

    The therapy trains the immune system to attack tumors.

    1
    Metastatic melanoma cells. Credit: NIH Wikimedia

    A small pilot study raises hopes that personalized cancer vaccines might prove safer and more effective than immune-based therapies already in use or further along in development. In a paper published online in Nature on Wednesday, scientists reported that all six melanoma patients who received an experimental, custom-made vaccine seemed to benefit: their tumors did not return after treatment.

    Researchers not involved in the study praised its results, but with caveats. The scientists “did a beautiful job,” said MD Anderson Cancer Center’s Greg Lizee, an expert in tumor immunology, who called the results “very encouraging.” But because the study did not include a comparison group of patients who received standard treatment and not the vaccine, he cautioned, “it’s not completely proved yet that the lack of [cancer] recurrence was due to the vaccine.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Scientific American, the oldest continuously published magazine in the U.S., has been bringing its readers unique insights about developments in science and technology for more than 160 years.

     
  • richardmitnick 7:07 am on July 10, 2017 Permalink | Reply
    Tags: , Cancer, , Explainer: what is cancer radiotherapy and why do we need proton beam therapy?, , Proton Beam Therapy, Radiation cancer therapy,   

    From COSMOS via U Sidney: “Explainer: what is cancer radiotherapy and why do we need proton beam therapy?” 

    U Sidney bloc

    University of Sidney

    COSMOS

    10 July 2017
    Paul Keall

    Proton beam therapy is radiation therapy that uses heavier particles instead of the X-rays used in conventional radiotherapy.

    2
    1
    Both above from New Jersey’s ProCure Proton Therapy Center

    In the 2017 federal budget, the government dedicated up to A$68 million to help set up Australia’s first proton beam therapy facility in South Australia. The government says this will help Australian researchers develop the next generation of cancer treatments, including for complex children’s cancers.

    Proton beam therapy is radiation therapy that uses heavier particles (protons) instead of the X-rays used in conventional radiotherapy. These particles can more accurately target tumours closer to vital organs, which can be especially beneficial to patients suffering from brain cancer and children whose organs are still developing and are more vulnerable to damage.

    So, the facility will also be an alternative to conventional radiotherapy for treating certain cancer. But what is traditional radiotherapy, and how will access to proton beam therapy improve how we manage cancer?

    What is radiotherapy?

    Radiotherapy, together with surgery, chemotherapy and palliative care, are the cornerstones of cancer treatment. Radiotherapy is recommended for half of cancer patients.

    It is mostly used when the cancer is localised to one or more areas. Depending on the cancer site and stage, radiotherapy can be used alone or in combination with surgery and chemotherapy. It can be used before or after other treatments to make them more effective by, for example, shrinking the tumour before chemotherapy or treating cancer that remains after surgery.

    Most radiotherapy treats cancer by directing beams of high energy X-rays at the tumour (although other radiation beams, such as gamma rays, electron beams or proton/heavy particle beams can also be used).

    The X-rays interact with tumour cells, damaging their DNA and restricting their ability to reproduce. But because X-rays don’t differentiate between cancerous and healthy cells, normal tissues can be damaged. Damaged healthy tissue can lead to minor symptoms such as fatigue, or, in rare cases, more serious outcomes such as hospitalisation and death.

    Getting the right amount of radiation is a fine balance between therapy and harm. A common way to improve the benefit-to-cure ratio is to fire multiple beams at the tumour from different directions. If they overlap, they can maximise the damage to the tumour while minimising damage to healthy tissue.

    How it works

    3
    A drawing of the X-ray machine used by Wilhelm Röntgen to produce images of the hand. Golan Levin/Flickr, CC BY-SA

    Wilhelm Röntgen discovered X-rays in 1895 and within a year, the link between exposure to too much radiation and skin burns led scientists and doctors to pursue radiation in cancer treatment.

    There are three key stages in the radiotherapy process. The patient is first imaged – using such machines as computer tomography (CT) or magnetic resonance imaging (MRI). This estimates the extent of the tumour and helps to understand where it is with respect to healthy tissues and other critical structures.

    In the second stage, the doctor and treatment team will use these images and the patient’s case history to plan where the radiation beams should be placed – to maximise the damage to the tumour while minimising it to healthy tissues. Complex computer simulations model the interactions of the radiation beams with the patient to give a best estimate of what will happen during treatment.

    4
    A single radiotherapy treatment takes 15 to 30 minutes. IAEA Imagebank/Flickr, CC BY

    During the third, treatment-delivery stage, the patient lies still while the treatment beam rotates, delivering radiation from multiple angles.

    Each treatment generally takes 15 to 30 minutes. Depending on the cancer and stage, there are between one and 40 individual treatments, typically one treatment a day. The patient cannot feel the radiation being delivered.

    Benefits and side effects

    Radiotherapy’s targeting technology has made a significant difference to many cancers, in particular early-stage lung and prostate cancers. It is now possible to have effective, low toxicity treatments for these with one to five radiotherapy sessions.

    For early-stage lung cancer studies estimate with radiotherapy, survival three years after diagnosis is at 95%. For prostate cancer, one study estimates survival at the five year mark is about 93%.

    Side effects for radiotherapy vary markedly between treatment sites, cancer stages and individual patients. They are typically moderate but can be severe. A general side effect of radiotherapy is fatigue.

    5
    Radiotherapy is often used to treat brain tumours. Eric Lewis/Flickr, CC BY

    Other side effects include diarrhoea, appetite loss, dry mouth and difficulty swallowing for head and neck cancer radiotherapy, as well as incontinence and reduction in sexual function for pelvic radiotherapy.

    Long-term effects of radiotherapy are a concern, particularly for children. For instance, radiation to treat childhood brain tumours can have long-lasting cognitive effects that can affect relationships and academic achievement.

    Again doctors will need to weigh up the risks and benefits of treatment for individual patients. Proton beam therapy is arguably most beneficial in these cases.

    Other radiotherapy challenges

    There are several challenges to current radiotherapy. It is often difficult to differentiate the tumour from healthy tissue, and even experts do not always agree on where exactly the tumour is.

    Radiotherapy can’t easily adapt to the complex changes in patients’ anatomy when a patient moves – for instance, when they breathe, swallow, their heart beats or as they digest food. As a result, radiation beams can be off-target, missing the tumour and striking healthy tissue.

    Also, we currently treat all parts of the tumour equally, despite knowing some of the tumour’s regions are more aggressive, resistant to radiation and likely to spread to other parts of the body.

    The tumour itself also changes in response to the treatment, further confounding the problem. An ideal radiotherapy solution would image and adapt the treatment continuously based on these changes.

    Improvements in technology, including in imaging systems that can better find the tumour, can help overcome these challenges.


    Proton therapy requires large accelerators to give protons enough energy to penetrate deep into patients. No video credit.

    Proton beam therapy and other innovations

    Proton beam therapy will help maximise benefits for many patients, including those with cancers near the spinal cord and pelvis. It requires large accelerators to give protons enough energy to penetrate deep into patients. The energetic protons are transported into the treatment room using complex steering magnets and directed to the tumour inside the patient.

    Protons slow down and lose energy inside the patient, with most of the energy loss planned to occur in the tumour. This reduces energy loss in healthy tissues and reduces side effects.

    The problems of changing patient anatomy and physiology in other forms of radiotherapy are also challenges for proton beam therapy.

    The ConversationAustralia has a number of research teams tackling such challenges, including developing new radiation treatment devices, breathing aids for cancer patients, radiation measurement devices, shorter and more convenient treatment schedules and the optimal combination of radiotherapy with other treatments, such as chemotherapy and immunotherapy.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    U Sidney campus

    Our founding principle as Australia’s first university was that we would be a modern and progressive institution. It’s an ideal we still hold dear today.

    When Charles William Wentworth proposed the idea of Australia’s first university in 1850, he imagined “the opportunity for the child of every class to become great and useful in the destinies of this country”.

    We’ve stayed true to that original value and purpose by promoting inclusion and diversity for the past 160 years.

    It’s the reason that, as early as 1881, we admitted women on an equal footing to male students. Oxford University didn’t follow suit until 30 years later, and Jesus College at Cambridge University did not begin admitting female students until 1974.

    It’s also why, from the very start, talented students of all backgrounds were given the chance to access further education through bursaries and scholarships.

    Today we offer hundreds of scholarships to support and encourage talented students, and a range of grants and bursaries to those who need a financial helping hand.

     
  • richardmitnick 8:33 am on July 7, 2017 Permalink | Reply
    Tags: , Cancer, ,   

    From RIKEN: “Visualizing whole-body cancer metastasis at the single-cell level” 

    RIKEN bloc

    RIKEN

    July 6, 2017
    Adam Phillips
    RIKEN International Affairs Division
    Tel: +81-(0)48-462-1225 /
    Fax: +81-(0)48-463-3687
    pr@riken.jp

    1
    3D analysis of the metastatic patterns in experimental brain metastasis models

    Researchers at the RIKEN Quantitative Biology Center (QBiC) and the University of Tokyo (UTokyo) have developed a method to visualize cancer metastasis in whole organs at the single-cell level. Published in Cell Reports, the study describes a new method that combines the generation of transparent mice with statistical analysis to create 3-D maps of cancer cells throughout the body and organs.

    Recent research in optical clearing methods has made it possible to transparentize the bodies and organs of experimental animals. This has led to a new wave of anatomical studies that can combine tissue transparency with sophisticated cell-labeling techniques and light microscopy. Led by Hiroki Ueda at RIKEN QBiC/UTokyo and Kohei Miyazono at the UTokyo, the team has focused their efforts on being able to visualize and profile cancer metastasis throughout the body.

    “One of the biggest difficulties in studying cancer,” explains co-senior author Ueda, “is that tumor metastasis is started by just a few metastasized cells. Our new method makes it possible to image the whole body down to the individual cell level, and therefore we can detect cancer at spatial resolutions beyond what is possible using other current imaging techniques.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    RIKEN campus

    RIKEN is Japan’s largest comprehensive research institution renowned for high-quality research in a diverse range of scientific disciplines. Founded in 1917 as a private research foundation in Tokyo, RIKEN has grown rapidly in size and scope, today encompassing a network of world-class research centers and institutes across Japan.

     
  • richardmitnick 5:20 pm on July 2, 2017 Permalink | Reply
    Tags: , Cancer, Cancer hides in plain sight of the immune system, ,   

    From MedicalXpress: “New insights into why the immune system fails to see cancer” 

    Medicalxpress bloc

    MedicalXpress

    June 29, 2017
    No writer credit found

    1
    Killer T cells surround a cancer cell. Credit: NIH.

    Cancer hides in plain sight of the immune system. The body’s natural tumor surveillance programs should be able to detect and attack rogue cancer cells when they arise, and yet when cancer thrives, it does so because these defense systems have failed. A team of investigators led by Niroshana Anandasabapathy, MD, PhD, at Brigham and Women’s Hospital have uncovered a critical strategy that some cancers may be using to cloak themselves – they find evidence of this genetic program across 30 human cancers of the peripheral tissue, including melanoma skin cancer. Their results are published June 29 in Cell.

    “Our study reveals a new immunotherapy target and provides an evolutionary basis for why the immune system may fail to detect cancers arising in tissues,” said corresponding author Anandasabapathy, of BWH’s Department of Dermatology. “The genetic program we report on helps the immune system balance itself. Parts of this program prevent the immune system from destroying healthy organs or tissues, but might also leave a blind spot for detecting and fighting cancer.”

    The authors studied immune mononuclear phagocytes – a group of disparate cells that act as the “Pac man” of the immune system. When these cells detect foreign invaders and dying normal tissues, they devour or engulf their components. These cells then present these components on their surface teach T cells to maintain tolerance to healthy tissues, or to fight infections and pathogens. Despite differences in function, all immune mononuclear phagocytes found in the skin- (a peripheral tissue like lung and gut) share a common set of genetic programming, which is further enhanced when they enter the tissue. This program is conserved in fetal and adult development, and across species. And, the research team reports, is co-opted by multiple human cancers of tissue.

    The team finds that this program is prompted by an “instructive cue” from interferon gamma – a molecule that plays a critical role in regulating immunity. The authors find IFN-gamma for mononuclear phagocytes in development but that IFN-gamma and tissue immune signatures are much higher in skin cancer than in healthy skin. Having an immune response measured by IFN-gamma and tissue signatures correlated with improved metastatic melanoma survival outcomes, making these signatures potential biomarkers for cancer survival.

    The authors reasoned such a program might contain key molecules that help the immune system reduce inflammation, but that might also leave a blind spot to cancer detection. One of the key genes the researchers detected is suppressor of cytokine signaling 2 (SOCS2). When this gene was turned off in a mouse model, the immune system was able to robustly detect and reject cancer in models of melanoma and thymoma (cancer of the thymus). They also observed improved vaccination responses, and heightened auto-inflammation suggesting this gene normally dampens auto-inflammatory responses and contracts protective immunity.

    “Our research suggests that these cancers are co-opting tissue-specific immune development to escape detection, but we see that turning off SOCS2 unmasks them,” said Anandasabapathy. “This sheds new light on our understanding of how the immune system is programed to see cancers and also points the way toward new therapeutic targets for treating cancers that have these signatures.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Medical Xpress is a web-based medical and health news service that is part of the renowned Science X network. Medical Xpress features the most comprehensive coverage in medical research and health news in the fields of neuroscience, cardiology, cancer, HIV/AIDS, psychology, psychiatry, dentistry, genetics, diseases and conditions, medications and more.

     
  • richardmitnick 1:22 pm on June 30, 2017 Permalink | Reply
    Tags: , Cancer, , ,   

    From Science: “Cancer studies pass reproducibility test” 

    AAAS
    Science Magazine

    Jun. 27, 2017
    Jocelyn Kaiser
    1
    Though researchers have had general success reproducing cancer results, studies involving mice have proven difficult to replicate.
    Adva/Flickr (CC BY-NC 2.0)

    A high-profile project aiming to test reproducibility in cancer biology has released a second batch of results, and this time the news is good: Most of the experiments from two key cancer papers could be repeated.

    The latest replication studies, which appear today in eLife, come on top of five published in January that delivered a mixed message about whether high-impact cancer research can be reproduced. Taken together, however, results from the completed studies are “encouraging,” says Sean Morrison of the University of Texas Southwestern Medical Center in Dallas, an eLife editor. Overall, he adds, independent labs have now “reproduced substantial aspects” of the original experiments in four of five replication efforts that have produced clear results.

    In the two new replication efforts, however, one key mouse experiment could not be repeated, suggesting ongoing problems with the reproducibility of animal studies, says one leader of the Reproducibility Project: Cancer Biology.

    The unusual initiative was inspired by reports from two drugs companies that up to 89% of preclinical biomedical studies didn’t hold up in their labs. The project is having contract labs repeat key experiments from about 30 high-impact cancer papers published between 2010 and 2012. Whereas some researchers laud the effort, others have worried that contract labs lack the expertise to perform certain experiments as well as cutting-edge academic research labs and that any failures will unfairly tarnish the field.

    In January, critics’ fears were realized when the first five replications came out. Only two studies could be reproduced; one result was negative, and two studies were ruled inconclusive because of problems with mouse tumor models. The findings have led some experts to conclude that biomedicine suffers from a replication crisis.

    Now, scientists’ track records seem to be improving. In one of the new studies [eLIFE], a contract lab confirmed a 2010 report in Cancer Cell that mutations in genes called IDH1 and IDH2, found in some leukemias and brain cancers, cause cells to produce a metabolite that spurs cancer growth. The replicators also verified that levels of the metabolite in leukemia cells indicate whether a cancer patient has the IDH mutations. (The original paper’s lead author, Craig Thompson of Memorial Sloan Kettering Cancer Center in New York City, who co-founded a company that is testing IDH drugs in clinical trials, was traveling and unable to comment.)

    The second replication study [eLIFE]looked at a 2011 Nature paper reporting that a compound called a BET inhibitor, which controls whether genes are activated—can stop a type of leukemia. As in the original study, the compound, I-BET151, killed human leukemia cells in a dish and reduced their numbers in mice that had been injected with the cells. However, unlike in the original paper, these mice did not survive any longer than untreated mice with leukemia.

    Several scientists say that result doesn’t invalidate the overall conclusions that I-BET151 works against leukemia. The replication team did the mouse experiment differently, using a lower dose of I-BET151, for example. Given such differences, “I think we should be careful not to make too much of the absence of statistically significant differences in survival as an endpoint,” says Harvard University molecular biologist Karen Adelman, an eLife editor who oversaw reviews of the replication paper.

    And cancer biologist Tony Kouzarides of the University of Cambridge in the United Kingdom, who led the original Nature study, says this one negative result “highlights the pitfalls of biological research, namely that different labs may vary conditions that affect the outcome of a given experiment.”

    But Tim Errington of the Center for Open Science in Charlottesville, Virginia, which is co-sponsoring the reproducibility project, counters that the fact that the mouse survival experiment worked only under certain conditions raises questions about whether the paper’s overall findings are “robust.” He adds, “You want this to be generalizable.”

    The cancer biology project hopes to finish experiments for another 22 replications by the end of this year, when the grant funding the effort runs out, Errington says.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

     
  • richardmitnick 9:02 pm on June 29, 2017 Permalink | Reply
    Tags: , Cancer, CLIO-ICT, Glioblastoma, , New strategy to attack deadly glioblastoma tumor uses molecular scissors to release drug, , Temozolomide   

    From Stanford Scope: “New strategy to attack deadly glioblastoma tumor uses molecular scissors to release drug” 

    Stanford University Name
    Stanford University

    stanford-scope-icon

    Scope blog

    1
    No image caption or credit

    Molecular scissors sticking out from the surface of a hard-to-treat type of brain tumor could be harnessed to deliver drugs to exactly the right spot in the brain, a new Stanford study suggests.

    In the study, published this week in Molecular Cancer Therapeutics, a team led by pediatric radiologist Heike Daldrup-Link, MD, tried a new strategy to tackle a brain tumor called glioblastoma. Glioblastoma is a particularly awful tumor — the mean survival time after diagnosis is now 12 months in both children and adults. Daldrup-Link’s research was conducted in mice implanted with human glioblastoma tumors; the findings still need to be confirmed in people.

    The tumor is difficult to treat because a small group of aggressively malignant cells, called glioblastoma-initiating cells, are very good at hiding from existing forms of chemotherapy. When glioblastoma is surgically removed and treated with radiation and chemotherapy (the standard approach now), it recurs in 90 percent of patients. Researchers think GICs start the regrowth.

    But these nasty cells have a potential weakness: They rely on tumor blood vessels to survive. If these blood vessels can be destroyed, researchers think the GICs will die, too.

    Tumor blood vessels are leakier and less organized-looking than normal blood vessels, and some prior attempts to get chemo drugs into tumors have relied on the resulting “enhanced permeability and retention effect” [PubMed] — basically, the idea that drugs will leak into tumors more easily than into healthy tissue. But this leaky-pipe effect isn’t uniform enough to reliably wipe out GICs.

    Hence the Stanford team’s idea. They decided to try harnessing a different property of tumor tissue. Many copies of an enzyme called matrix metalloproteinase-14 stick out from glioblastoma cells. These enzyme molecules function as high-specificity scissors, able to snip a certain sequence of protein in two.

    To take advantage of the enzyme, the scientists built a sort of molecular Tinkertoy with three components: a cancer-drug precursor at one end, an iron nanoparticle at the other and a connector in the middle consisting of the protein targeted by the molecular scissors.

    Early tests in a different tumor model suggested this system worked as the researchers hoped. The cancer enzyme snipped the middle of the “Tinkertoy”, which the researchers call CLIO-ICT, in two, releasing and activating the cancer drug exactly where it was needed.

    In the new study, the team showed that their strategy helped fight glioblastoma. The drug caused collapse of tumor blood vessels, appeared to starve GICs (the very nasty cells) and slowed tumor growth. There was another advantage, too: After the molecular scissors did their job and released the cancer drug, the iron nanoparticles from the other end of CLIO-ICT hung around the tumor and showed up on MRI scans. The iron helped researchers monitor the shrinkage of the tumor.

    In the new study in mice, the scientists also confirmed that CLIO-ICT doesn’t hurt healthy organs such as the heart and lungs. In these healthy organs, absent the cancer enzyme, the cancer drug isn’t released or activated, preventing possible toxicity. And CLIO-ICT worked even better when given in combination with a second cancer drug, temozolomide, that is already used to treat glioblastoma.

    The scientists hope their new approach will ultimately be used to improve survival in people with the brain tumor.

    See the full article here .

    Please help promote STEM in your local schools.
    STEM Icon

    Stem Education Coalition

    Scope is an award-winning blog founded in 2009 and produced by the Stanford University School of Medicine. If you’re curious about the latest advances in medicine and health and enjoy compelling, fresh and easily digestible news and features, then we’ve got just the thing. We’ve written quite a bit (7,000 posts and counting!), and we’re quite proud of it — so please enjoy.

    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

    Stanford University Seal

     
  • richardmitnick 3:30 pm on June 29, 2017 Permalink | Reply
    Tags: , , , , Cancer, , neutral sphingomyelinase (nSMase2) allow cancer cells to pass DNA and proteins to other cells to change their behavior, Stony Brook U   

    From Stony Brook: “Researchers Define Structure of Key Enzyme Implicated in Cancer, Neurological Disease” 

    Stoney Brook bloc

    Stoney Brook

    Jun 29, 2017
    No writer credit found

    1
    Stony Brook-led research into the structure of a key enzyme involved with cell growth regulation could offer important clues to understanding cancer and neurodegenerative diseases, including Alzheimer’s disease. The finding, published in PNAS, reveals the first visualization of the enzyme and could provide insight into how the enzyme is activated.

    The enzyme, neutral sphingomyelinase (nSMase2), is one of the major enzymes that produces ceramide in the body. Ceramides are oil-like lipids that are produced in response to chemotherapy and other cell stresses. The ceramides that nSMase2 produces allow cancer cells to pass DNA and proteins to other cells to change their behavior. This plays a significant role in aiding the cancerous cells to spread into other regions as ceramides are produced. With this first visual of the structure of the enzyme, the researchers hope to understand how to de-activate the enzyme. Information on de-activating the enzyme could lead to a way to design cancer drugs that inhibit nSMase2.

    The different colors of this structural visualization of nSMase2 indicate parts of the enzyme that may change their shape when the protein is switched ‘on,’ encouraging cancer cells to spread.

    “Our finding is promising because the way in which we determined the structure reveals an unexpected mechanism for how nSMase2 is activated to generate ceramide,” said Mike Airola, PhD, Assistant Professor of Biochemistry and Cell Biology and lead author. To obtain this structure, the researchers screened thousands of different samples to have this protein form very small crystals that could be captured visually via X-rays. These X-rays bounce off the protein, and based on the angle of movements they calculated what structure looks like.

    Once they defined structure in this way, the research team made hypotheses as to how the shape of this important enzyme changes in order to be activated and then tested these hypotheses. Their findings suggested the same region that kept nSMase2 off was crucial for turning it on.

    The researchers determined the enzyme consists of two parts: one that partitions inside the oil-like membrane and one that soluble in water. Their work with the structure revealed that to turn nSMase2 ‘on,’ these two parts come together to switch the enzyme from off to on. They found that by removing some of these parts, they were able to obtain a picture of the enzyme trapped in its ‘off’ state. Using the structure, Dr. Airola and colleagues added back different parts of the enzyme, and then they were able to turn it back on to its on, or activated state.

    Dr. Airola explained that while much is known about the cellular functions of nSMase2, there is limited scientific knowledge into the molecular mechanisms regulating its activity. This latest research presents the crystal structure of the enzyme and enabled the researchers to understand its molecular mechanism to a level not known before.

    The next step in their research is to get a picture of the enzyme in its activated ‘on’ state. They are also working to identify new scaffolds that could be used as drugs to inhibit this enzyme. Their long-term goal is to understand how this enzyme is turned on and stop it from working as potential therapeutic strategy.

    Co-authors on the paper include Stony Brook University researchers Lina M. Obeid, Yusuf A. Hannun and Can E. Senkal of the Stony Brook University Cancer Center; Miguel Garcia-Diaz and Kip Guja of the Department of Pharmacological Sciences; Prajna Shanbhogue and Rohan Maini of the Department of Biochemistry and Cell Biology; Achraf Shamseddine of the Department of Medicine; and Nana Bartke and Bill X. Wu of the Medical University of South Carolina.

    The research was supported in part by the National institutes of Health. Some of the research was completed with access to the facilities at the Synchrotron Light Source and Brookhaven National Laboratory.

    BNL NSLS-II


    BNL NSLS-II

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Stoney Brook campus

    Stony Brook’s reach extends from its 1,039-acre campus on Long Island’s North Shore–encompassing the main academic areas, an 8,300-seat stadium and sports complex and Stony Brook Medicine–to Stony Brook Manhattan, a Research and Development Park, four business incubators including one at Calverton, New York, and the Stony Brook Southampton campus on Long Island’s East End. Stony Brook also co-manages Brookhaven National Laboratory, joining Princeton, the University of Chicago, Stanford, and the University of California on the list of major institutions involved in a research collaboration with a national lab.

    And Stony Brook is still growing. To the students, the scholars, the health professionals, the entrepreneurs and all the valued members who make up the vibrant Stony Brook community, this is a not only a great local and national university, but one that is making an impact on a global scale.

     
c
Compose new post
j
Next post/Next comment
k
Previous post/Previous comment
r
Reply
e
Edit
o
Show/Hide comments
t
Go to top
l
Go to login
h
Show/Hide help
shift + esc
Cancel
%d bloggers like this: