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  • richardmitnick 3:02 pm on May 26, 2016 Permalink | Reply
    Tags: , Cancer, , TSRI Scientists Discover Mechanism that Turns Mutant Cells into Aggressive Cancers   

    From Scripps: “TSRI Scientists Discover Mechanism that Turns Mutant Cells into Aggressive Cancers” 

    Scripps
    Scripps Research Institute

    Scientists at The Scripps Research Institute (TSRI) have caught a cancer-causing mutation in the act.

    A new study shows how a gene mutation found in several human cancers, including leukemia, gliomas and melanoma, promotes the growth of aggressive tumors.

    “We’ve found the mechanism through which this mutation leads to a scrambling of the genome,” said TSRI Associate Professor Eros Lazzerini Denchi, who co-led the study with Agnel Sfeir of New York University (NYU) School of Medicine. “That’s when you get really massive tumors.”

    The research, published* May 26, 2016 by the journal Cell Reports, also suggests a possible way to kill these kinds of tumors by targeting an important enzyme.

    A Puzzling Finding

    The researchers investigated mutations in a gene that codes for the protein POT1. This protein normally forms a protective cap around the ends of chromosomes (called telomeres), stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.

    POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of an enzyme, called ATR, that triggers programmed cell death.

    Knowing this, scientists in recent years were surprised to find recurrent mutations affecting POT1 in several human cancers, including leukemia and melanoma.

    “Somehow those cells found a way to survive—and thrive,” said Lazzerini Denchi. “We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”

    It Takes Two to Tango

    Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in a gene called p53.

    “The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” said Lazzerini Denchi.

    P53, a well-known tumor suppressor gene, is a cunning accomplice. When mutated, it overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. These mutant cells go on to proliferate and become aggressive tumors.

    The findings led the team to consider a new strategy for killing these tumors.

    Scientists know that all cells—even cancer cells—will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a medicine that knocks out the remaining ATR could kill tumors without affecting healthy cells. “This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” said Lazzerini Denchi.

    The researchers plan to investigate this new therapeutic approach in future studies.

    In addition to Lazzerini Denchi and Sfeir, authors of the study, “Telomere replication stress induced by POT1 inactivation accelerates tumorigenesis,” were Angela Beal and Nidhi Nair of TSRI; Alexandra M. Pinzaru, Aaron F. Phillips, Eric Ni and Timothy Cardozo of the NYU School of Medicine; Robert A. Hom and Deborah S. Wuttke of the University of Colorado; and Jaehyuk Choi of Northwestern University.

    The study was supported by the National Institutes of Health (grants AG038677, CA195767 and GM059414), a NYSTEM institutional training grant (C026880), a scholarship from the California Institute for Regenerative Medicine, a Ruth L. Kirschstein National Research Service Award (GM100532), The V Foundation for Cancer Research, two Pew Stewart Scholars Awards and the Novartis Advanced Discovery Institute.

    *Science paper:
    Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

    See the full article here .

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 8:44 pm on May 24, 2016 Permalink | Reply
    Tags: , Cancer, New Stanford-developed tool allows easier study of blood cancers,   

    From Stanford: “New Stanford-developed tool allows easier study of blood cancers” 

    Stanford University Name
    Stanford University

    May 24, 2016
    Christopher Vaughan

    In the history of science and medicine, the breakthrough discoveries get a lot of deserved attention, but often overlooked are the invention of the tools that made those discoveries possible. Galileo discovered moons around other planets, but it was the invention of the telescope that made his observation possible. Leeuwenhoek discovered microbes only after he created a simple but powerful microscope.

    Researchers in the laboratory of Stanford’s Ravi Majeti, MD, PhD, have just created one such tool — a method of implanting cells to create a human bone-like structure in mice. This allows investigators to study a whole host of blood cancers and other diseases that they had trouble studying before. Majeti and colleagues published* the work this week in the journal Nature Medicine.

    “Transplanting human leukemia cells into mice has been an important way of studying the disease,” postdoctoral fellow Andreas Reinisch, MD, PhD, first author of the paper, recently explained. “This method has given us important insights into how cancer develops and has been the way that all new anti-leukemia drugs have been tested and developed.” Mice engrafted with human leukemia cells are even sometimes used to test possible drug treatments for patients currently undergoing treatment for the blood cancer, he added.

    The problem, said Reinisch, is that even in the best cases, researchers can get human leukemia to take up residence and multiply in mice only half the time. For many types of blood cancers, engraftment doesn’t happen at all. It’s like Galileo’s telescope could only be pointed at a small spot of sky visible through a hole in his roof.

    Majeti, Reinisch, and their co-workers have metaphorically blown the roof off by transplanting special bone marrow-derived cells called stromal cells in mice. These human stromal cells multiply and divide to create a miniature, bone-like structure, complete with a bony outer shell and an internal, marrow-like compartment. This structure allows implanted human blood cells to live and grow in their natural environment — human bone.

    “I’m really excited about this technique because we now have a way to look closely at all kinds of leukemia, as well as many other profilerative disorders of blood cells,” Majeti said. “It also opens up the study of other, non-blood diseases such as metastatic breast cancer, which often spreads to bone in humans but simply won’t spread in existing mouse models.”

    Science paper:
    A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells

    See the full article here .

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    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

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  • richardmitnick 4:25 pm on May 22, 2016 Permalink | Reply
    Tags: , Cancer, U Penn   

    From Penn: “Breaking Down Cancer Cell Defenses” 

    U Penn bloc

    University of Pennsylvania

    May 20, 2016
    No writer credit found

    Inhibiting Membrane Enzyme May Make Some Cancer Cells More Vulnerable to Chemotherapy, Finds Penn Study

    The mistaken activation of certain cell-surface receptors contributes to a variety of human cancers. Knowing more about the activation process has led researchers to be able to induce greater vulnerability by cancer cells to an existing first-line treatment for cancers (mainly lung) driven by a receptor called EGFR. The team, led by Eric Witze, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania, published* their findings this month in Molecular Cell.

    “We found that inhibiting an enzyme that adds the fatty acid palmitate onto proteins creates dependence by cancer cells on EGFR signaling for survival,” Witze said. By using a small molecule called 2-bromo-palmitate (2BP) that inhibits these palmitate-adding enzymes, the researchers surmise that cancer patients might be able to one day make their cells more sensitive to cancer-fighting EGFR inhibitors.

    Palmitate is the most common fatty acid found in animals, plants, and microbes, although is not well studied. Proteins that have palmitate bound to them are usually associated with the cell membrane. Palmitate allows these proteins to transfer chemical signals from outside the cell to inside via the cell membrane.

    EGFR itself is a transmembrane protein associated with palmitate, and by blocking palmitate, EGFR becomes hyperactivated. “We thought that this finding would be ‘good’ for the cancer, but ‘bad’ for a cancer patient,” Witze said. In cancers not related to EGFR signaling, this relationship is correct; however, in cancers related to EGFR, if the palmitate-adding enzyme is inhibited, EGFR is activated, but cancer cells grow more slowly.

    In addition, if genifitib, an inhibitor to EGFR itself on the market for lung cancer, is added to the cell, the cells die. This finding is somewhat counterintuitive with regard to cell growth since EGFR activation functions as a positive growth signal, the researchers note; however, that fact cells die when EGFR is inhibited is not counterintuitive, but shows the cells are now addicted to the EGFR signal.

    “It’s as if a switch is stuck on,” Witze said. “The cell loses control of the growth signal.” If no palmitate is associated with EGFR, then it the cell loses control of this signal, and if the EGFR inhibitor is added, cells die.”

    The research shows that the reversible modification of EGFR with palmitate “pins” the tail of EGFR to the cell, impeding EGFR activation. The researchers think when the tail is no longer able to be pinned to the membrane the switch is stuck in the “on” position.

    Currently, the experimental 2BP compound inhibits any enzyme that uses palmitate as a substrate, making it toxic to most cells. “We need to find a compound specific for the palmitate-adding enzyme and or modify 2BP to make it more specific to decrease unwanted side effects.” Witze said.

    Kristin B. Runkle, Akriti Kharbanda, Ewa Stypulkowski, Xing-Jun Cao, Wei Wang, and Benjamin A. Garcia, all from Penn are co-authors.

    This work was funded by the National Institute for Health (R01CA181633, T32-CA-557726-07), the American Cancer Society (RSG-15-027-01, IRG –78-002-34) and the Department of Defense (BC123187P1).

    *Science paper:
    Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling

    See the full article here .

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    U Penn campus

    Academic life at Penn is unparalleled, with 100 countries and every U.S. state represented in one of the Ivy League’s most diverse student bodies. Consistently ranked among the top 10 universities in the country, Penn enrolls 10,000 undergraduate students and welcomes an additional 10,000 students to our world-renowned graduate and professional schools.

    Penn’s award-winning educators and scholars encourage students to pursue inquiry and discovery, follow their passions, and address the world’s most challenging problems through an interdisciplinary approach.

     
  • richardmitnick 4:29 pm on May 21, 2016 Permalink | Reply
    Tags: , Cancer, Glowing tumors light a path to cancer treatment,   

    From MIT: “Glowing tumors light a path to cancer treatment” 

    MIT News
    MIT News

    MIT Widget

    May 20, 2016
    Kylie Foy | Lincoln Laboratory

    1
    An NIR-II band near-infrared fluorescence image of cancerous tissue. The “glowing” regions have single-walled carbon nanotube probes attached, showing precisely where the tumors are. Image courtesy of the researchers.

    2
    A Massachusetts General Hospital surgeon demonstrates the Lincoln Laboratory’s near-infrared fluorescence imaging (NIRF) system. The system’s camera detects probes attached to tumors, and displays their “glow” on a monitor as he performs surgery. Photo courtesy of the researchers.

    3
    The research team that developed and demonstrated the near-infrared fluorescence imaging system includes: (standing left to right) Nandini Rajan and Andrew Siegel of the Lincoln Laboratory; Angela Belcher of MIT; Michael Birrer, Lorenzo Ceppi, and Young Jeong Na of the Massachusetts General Hospital (MGH); (kneeling left to right) Neelkanth Bardhan of MIT; and Giulia Fulci of MGH. Photo courtesy of the researchers.

    Every year, 200,000 women worldwide are diagnosed with ovarian cancer, often in its late stages. Ovarian cancer is very hard to detect in its early stages, and once it is detected, the body is already riddled with dozens of tumors. A 2010 Massachusetts General Hospital (MGH) study found that if tumors down to millimeter size are removed during surgery, the patient’s lifespan could be greatly extended. Since then, a team of MIT Lincoln Laboratory staff, MIT researchers, and MGH surgeons has pursued a method for finding and removing tumors otherwise invisible to a surgeon’s eye.

    A team at MIT, headed by Professor Angela Belcher at the Koch Institute for Integrative Cancer Research, had been targeting a variety of cancers that pose challenges caused by delays in diagnosis. They developed novel fluorescent “probes” based on single-walled carbon nanotubes (SWNTs) — chemical compounds that re-emit light when excited by a laser. When injected into a patient, the SWNT probes bind only to tumors, so the tumors appear to glow when seen through an infrared camera.

    This fluorescent glow can best be detected in the optical spectrum ranging from 1000 nm to 1800 nanometers, called the near-infrared second-window (NIR-II) band. However, a video fluorescence imaging system, which would allow surgeons to view this phenomenon in real time, didn’t yet exist. Belcher, who wanted to test these SWNT probes on mice with the help of surgeons at the Birrer Lab at MGH, called on Lincoln Laboratory’s expertise to develop a near-infrared fluorescence (NIRF) imaging system in order to do this. “A few other labs were exploring NIR-II band imaging, but their equipment was designed for still imaging, not video,” says Nandini Rajan, a Lincoln Laboratory researcher who joined the project.

    “Honestly, I knew this would work the first time I saw tumors smaller than pinheads lighting up on the screen like fireflies,” says Andrew Siegel, describing his reaction to initial tests of the system. Siegel and Rajan, supported by colleagues, designed the NIRF imaging system to work seamlessly with the surgeon. During surgery, the system illuminates the patient’s tissue with an 808 nm infrared laser after the SWNT probe solution has been injected into the cancerous region. The tumors, now covered in fluorescent probes, convert the 808 nm light into a range of wavelengths in the NIR-II spectral band, which the system’s camera can detect. A “blocking” filter prevents laser light from reaching the camera, revealing a sharp view of the glowing tumors on a monitor. In contrast, healthy tissue, with no probes attached to it, appears dark.

    While the fluorescence made tumors easy to locate against a dark background, surgeons could no longer see their instruments in relation to the tissue. “So we introduced a novel feature: an ‘in-band’ light source that the NIR-II camera can see,” Siegel said. The in-band light reflects off tissue to create a realistic gray-scale image, appearing on the monitor almost the same as it would appear in visible light — a view surgeons are familiar with. The surgeons can use a footswitch to adjust the in-band light as they work, shifting between the gray-scale view and fluorescent view as needed. “Instead of surgeons having to switch their gaze back and forth between the NIRF display and the patient, they can perform the surgical procedure looking at the NIRF display the whole time,” Rajan says.

    The real challenge, according to Siegel, was proving that the NIRF imaging actually provided a measurable survival advantage to patients. Over the course of two years, MGH surgeons using SWNT probes with the NIRF imaging system performed more than 200 surgical procedures on mice. First, the surgeons removed all the tumors they spotted visually. Then, switching to fluorescent mode, the surgeons were able to see and remove tumors as tiny as 200 nm in diameter — smaller than a poppy seed. They also discovered many larger tumors they thought they had already removed. The data show promising results: Despite the “NIRF” mice’s undergoing longer surgeries, they survived longer than did the mice operated without the use of the NIRF. “Discovering that we actually observed a measurable increase in post-surgical survival, even with the negative confound created by the longer surgery these ‘NIRF’ mice endured, was a pleasant surprise,” Siegel says.

    This spring, aspects of this work were presented at national technical conferences, and a more detailed manuscript discussing the results of the survival study will be published later this year. Moving forward, the team plans to progress toward human trials on ovarian cancer patients. “Our MGH collaborators are currently applying for Federal Drug Administration approval for the SWNT probes,” Siegel says. In the meantime, Lincoln Laboratory researchers will likely be building a larger-scale system.

    “My ultimate goal would be to simplify this technology to the point that any general surgeon has the ability to provide sufficient tumor debulking to completely obviate the need for post-operative chemotherapy,” Rajan says. “Without early detection, this may be the best we can do.”

    See the full article here .

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  • richardmitnick 11:43 am on May 21, 2016 Permalink | Reply
    Tags: , Cancer,   

    From NOVA: “The Quest for a Simple Cancer Test” 

    PBS NOVA

    NOVA

    19 May 2016
    Jeffrey Perkel

    Embedded in a small translucent wafer measuring just under an inch a side, the spiraling coils—like neatly packed iPod earbuds—aren’t much to look at.

    But judging on appearance alone would sell short the brainchild of Chwee Teck Lim of National University Singapore and Jongyoon Han of the Massachusetts Institute of Technology. Those coils sift through millions upon millions of blood cells for faintly detectable indicators of a solid tumor lurking in a patient’s body—the handful of cancer cells that are often found circulating in the blood. Called circulating tumor cells, these cells may well be the seeds of distant metastases, which are responsible for 90% of all cancer deaths.

    Over the past several years, researchers and clinicians have become increasingly fixated on these circulating cells as cellular canaries-in-the-coalmine, indicators of distant disease. The blood of cancer patients is chock-full of potentially telling molecules, and researchers and clinicians are hotly investigating these materials for their efficacy as indicators and predictors of illness, disease progression, response to treatment, and even relapse.

    1
    Soon, a simple blood test could reveal whether a person has cancer.

    For patients with cancer, such tests could provide a welcome respite from painful, invasive, and sometimes dangerous biopsies that typically are used to track and diagnose disease—a fact reflected in the terminology often used to describe the new assays: liquid biopsy. For researchers and clinicians, they provide a noninvasive and repeatable way to monitor how a disease changes over time, even in cases when the tumor itself is inaccessible.

    And unlike the finger-stick testing used by the embattled company Theranos, which recently voided two years of results from their proprietary blood-testing machines, the liquid biopsy methods being researched and developed by teams of scientists around the world use standard blood-drawing techniques and have been subject to peer review.

    In the short term, researchers hope to use liquid biopsies to monitor tumor relapse, track a tumor’s response to targeted therapies, and match patients with the treatments most likely to be effective—the very essence of “personalized medicine.” But longer term, some envision tapping the blood for early diagnosis to catch tumors long before symptoms start, the time when they’re most responsive to treatment.

    For now, most such promises are just that: promises. With the exception of one FDA-approved test, a handful of lab-developed diagnostics, and a slew of clinical trials, few cancer patients today are benefitting from liquid biopsies. But many are betting they soon will be. Liquid biopsies, says Daniel Haber, director of the Massachusetts General Hospital (MGH) Cancer Center, “currently are aspirational—they don’t yet exist in that they’re not part of routine care. But they have the possibility to become so.”

    Revealing Information

    Despite its name, liquid biopsies are not exactly an alternative to solid tissue biopsies, says Mehmet Toner, a professor of biomedical engineering at MGH who studies circulating tumor cells. Patients who are first diagnosed with cancer via a liquid biopsy would likely still undergo a tissue biopsy, both in order to confirm a diagnosis and to guide treatment.

    But liquid biopsies do provide molecular intel that might otherwise be impossible to obtain—for instance, in the treatment of metastatic disease. Oncologists typically biopsy patients with metastatic disease only once, to confirm the diagnosis, says Keith Flaherty, director of the Henri and Belinda Termeer Center for Targeted Therapies at the MGH Cancer Center. But such a test reveals the genetics of the cancer only at the sampled site. Many patients harbor multiple metastases, some in relatively inaccessible locations like the lungs, brain, or bones, and each may contain cells with different genetic signatures and drug susceptibilities. “Liquid biopsies provide an aggregate assessment of a cancer population,” he says.

    Today, says Max Diehn, an assistant professor of radiation oncology at the Stanford University School of Medicine, oncologists can get a read on how a patient responds to therapy using a handful of protein biomarkers found in blood, urine, or other biofluids, such as prostate-specific antigen (PSA) in the case of prostate cancer, or using noninvasive imaging technologies like magnetic resonance imaging (MRI) or computed tomography (CT). But those tests often fall short. Many biomarkers aren’t specific enough to be useful, and imaging is relatively expensive and insensitive. Also, not everything that appears to be a tumor on a scan actually is. And, Flaherty notes, imaging studies reveal little or no molecular information about the tumor itself, information that’s useful in guiding the treatment.

    In contrast, liquid biopsies can reveal not only whether patients are responding to treatment, but also catch game-changing genetic alterations in real time. In one recent study, Nicholas Turner of the Institute for Cancer Research in London and his colleagues examined cell-free tumor DNA (ctDNA), or tumor DNA that’s floating free in the bloodstream, in women with metastatic breast cancer. They were looking for for the presence of mutations in the estrogen receptor gene, ESR1. Breast cancer patients previously treated with so-called aromatase inhibitors often develop ESR1 mutations that render their tumors resistant to two potential treatments, hormonal therapies that target the estrogen receptor and further use of aromatase inhibitors that block the production of estrogen. Turner’s team detected ESR1 mutant ctDNA in 18 of 171 women tested (10.5%), and those women’s tumors tended to progress more rapidly when treated with aromatase inhibitors than did women who lacked such mutations. Those findings had no impact on the patients in the study—the women were analyzed retrospectively—but they suggest that prospective use of ctDNA analysis might be used to shift treatment toward different therapeutic strategies.

    Viktor Adalsteinsson of the Broad Institute of MIT and Harvard, whose group has sequenced more than a thousand liquid biopsy genomes, calls the ESR1 study “promising and illuminating.” At the moment, he says, such data are not being actively used to influence patient treatment, at least not in the Boston area. But Jesse Boehm, associate director of the Broad Cancer Program, says he thinks it could take as little as two years for that to change. “I’ve been here at the Broad for ten years, and I don’t think I’ve ever seen another project grow from scientific concept to potentially game-changing so quickly,” he says.

    Varied Approaches

    Liquid biopsies generally come in one of three forms. One, ctDNA—Adalsteinsson’s material of choice—is the easiest to study, but also the most limited as it relies on probing short snippets of DNA in the bloodstream for a collection of known mutations. The blood is full of DNA, as all cells jettison their nuclear material when they die, so researchers must identify those fragments that are specifically diagnostic of disease. While the genetic mutations behind some prominent cancers have been identified, many more have not. Also, not all genetic changes are revealed in the DNA itself, says Klaus Pantel, director of the Institute of Tumor Biology at the University Medical Center Hamburg-Eppendorf.

    A second class of liquid biopsy focuses on tiny membrane-encapsulated packages of RNA and protein called exosomes. Exosomes provide researchers a glimpse of cancer cells’ gene expression patterns, meaning they can reveal differences that are invisible at the DNA level. But, because both normal and cancerous cells release exosomes, the trick, as with ctDNA, is to isolate and characterize those few particles that stem from the tumor itself.

    The third counts circulating tumor cells, or CTCs. They are not found in healthy individuals, but neither are they prevalent even in very advanced cases, accounting for perhaps one to 100 per billion blood cells, according to Lim. Researchers can simply count the cells, as CTC abundances tend to scale with prognosis.

    But there’s much more that CTCs can do, Pantel says. “You can analyze the DNA, the RNA, and the protein, and you can put the cells in culture, so you can get some information on responsiveness to drugs.” Stefanie Jeffrey, a professor of surgery at Stanford University School of Medicine, has purified CTCs and demonstrated that individual breast cancer CTCs express different genes than the immortalized breast cancer cells typically used in drug development. That, she says, “raises questions” about the way potential drugs are currently evaluated in the early stages of development.

    Similarly, Toner and Haber have developed a device called the CTC-iChip to count and enrich CTCs from whole blood. The size of a CD—indeed, the chips are fabricated using high-throughput CD manufacturing technology—these devices take whole blood, filter out the red cells, platelets, and white blood cells, and keep what’s left, including CTCs. The team has used this device to evaluate hundreds of individual CTCs from breast, pancreatic, and prostate tumor patients to identify possible ways to selectively kill those cells.

    Elsewhere, Caroline Dive, a researcher at the University of Manchester, has even injected CTCs isolated from patients with small-cell lung cancer into mice. The resulting tumors exhibit the same drug sensitivities as the starting human tumors, providing a platform that could be used to better identify treatment options.

    A Range of Uses

    According to Lim, liquid biopsies have five potential applications: early disease detection, cancer staging, treatment monitoring, personalized treatment, and post-cancer surveillance. Of those, most agree, the likely near-term applications are personalized treatment and treatment monitoring. The most difficult is early detection.

    Among other things, early detection requires testing thousands of early-stage patients and healthy volunteers to demonstrate that the tests are sufficiently sensitive to detect cancer early yet specific enough to avoid false positives. A widely adopted assay that was, say, 90% specific could yield perhaps millions of false positives, Pantel says. “I’m sure that’s fantastic for the lawyers, but not for the patients.”

    Still, researchers have begun demonstrating the possibility. In one 2014 study describing a new method for analyzing ctDNA, Diehn, the Stanford radiation oncologist, and his colleague, Ash Alizadeh, an assistant professor of medical oncology also at Stanford, showed that they could detect half of the stage I non-small-cell lung cancer samples it was confronted with, and 100% of tumors stage II and above. That’s despite the fact that ctDNA fragments are only about 170 bases long—a very short amount—and disappear from the blood within about 30 minutes. “There’s constant cell turnover in tumors,” Diehn says. “There’s always some cells dying, and that’s what lets you detect it.”

    In another study, Nickolas Papadopoulos, a professor of oncology and pathology at the Johns Hopkins School of Medicine, and his colleagues surveyed the ctDNA content of 185 individuals across 15 different types of advanced cancer. For some tumor types, including bladder, colorectal, and ovarian, they found ctDNA in every patient tested; other tumors, such as glioblastomas, were more difficult to pick up. “It made sense,” Papadopoulos says. “These tumors are beyond the blood-brain barrier…and they do not shed DNA into the circulation.” In later studies, the team demonstrated that some tumors are more easily found in bodily fluids other than blood. Certain head and neck cancers are readily detected in saliva, for example, and some urogenital cancers can be detected in urine. But in their initial survey, Papadopoulos and his colleagues also tested blood plasma for the ability to detect localized (that is, non-metastatic) tumors, identifying disease in between about half and three-fourths of individuals.

    Though 50% sensitivity isn’t perfect, it’s better than nothing, Papadopoulos says, especially for cancers of the ovaries and pancreas. “Right now, we get 0% of them because there’s no screening test for these cancers.”

    In the meantime, researchers are focusing on personalized therapy. Alizadeh and Diehn, for instance, have tested patients with stage IV metastatic non-small cell lung cancer, a grave diagnosis, who had been taking erlotinib, a drug that targets specific mutations in the EGFR gene. Over time, all patients develop resistance to these drugs, half of them via a new mutation, Diehn says. Diehn and Alizadeh have begun looking for that mutation in the ctDNA of patients whose disease progresses, or returns, as such tumors can be specifically targeted by a new drug, osimertinib. “It’s been shown in a couple of studies that such patients then have a good response rate,” Diehn says, with the median “progression-free survival” doubling from about ten months to 20.

    Toward the Clinic

    Most scientists working on liquid biopsies agree that the technology itself is mature. What’s needed to make a difference in patients’ lives is clinical evidence of sensitivity, selectivity, and efficacy.

    Fortunately, they’re working on it. According to the National Institutes of Health’s clinical trials database, clinicaltrials.gov, over 350 trials are currently studying the use of liquid biopsies in cancer detection, identification, or treatment.

    One recent trial, published in April in JAMA Oncology, examined the ability of ctDNA analysis to detect key mutations in two genes associated with treatment decision, response, and resistance in non-small cell lung cancer. The 180-patient prospective trial determined that the method used could detect the majority (64% –86%) of the tested mutations with no false-positive readings in most cases. Results were returned on average within three days, compared to 12 to 27 days for solid-tissue biopsy. The technique is ready for clinical use, the authors concluded.

    In an ongoing trial, Pantel and his colleagues are focusing on a breast cancer-associated protein called HER2. Several anticancer therapies specifically target HER2-positive tumors, including trastuzumab and lapatinib. The trial is looking for instances of HER2-expressing CTCs in patients with metastatic breast cancer whose original tumor did not express HER2. About 20% of HER2-negative tumors meet that criterion, Pantel says, but before liquid biopsies became an option, there was really no way to find them. Now, his team is testing “whether the change to HER2-positive CTCs is a good predictor for response to HER2-targeted therapy.” If it is, it could unlock potential treatments for patients.

    In another trial, Flaherty, the center director at MGH, and his colleagues are using a series of liquid biopsies in several hundred patients with metastatic melanoma to determine if they could retrospectively predict drug resistance by monitoring for mutations in a particular gene.

    In the meantime, diagnostics firms are developing assays of their own. Currently, there is only one FDA-approved liquid biopsy test on the market in the United States. But there also are a growing handful of lab-developed assays for specific genetic mutations available and several more in development.

    Early cancer screening is farther out, and while many researchers still express skepticism, the application received a high-profile boost in January when sequencing firm Illumina announced it was launching a spinoff company called Grail. The company, which has already raised some $100 million in funding, will leverage “very deep sequencing” to identify rare ctDNA mutations, and plans to launch a “pan-cancer” screening test by 2019.

    Only time will tell, though, whether Grail or any other company is able to fundamentally alter how patients are treated for cancer. But one thing is certain, Flaherty says: Genetic testing, however it is done, only addresses the diagnostics side of the personalized medicine challenge; progress is also required on the drug development side. After all, what good is a test if there’s no way to act on it?

    See the full article here .

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  • richardmitnick 8:47 pm on May 20, 2016 Permalink | Reply
    Tags: , Cancer,   

    From Scripps: “Researchers Pioneer a Breakthrough Approach to Breast Cancer Treatment” 

    Scripps
    Scripps Research Institute

    May 23, 2016
    Eric Sauter

    In a development that could lead to a new generation of drugs to precisely treat a range of diseases, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time designed a drug candidate that decreases the growth of tumor cells in animal models in one of the hardest to treat cancers—triple negative breast cancer.

    “This is the first example of taking a genetic sequence and designing a drug candidate that works effectively in an animal model against triple negative breast cancer,” said TSRI Professor Matthew Disney.

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    “The study represents a clear breakthrough in precision medicine, as this molecule only kills the cancer cells that express the cancer-causing gene—not healthy cells,” says Professor Matthew Disney. (Photo by James McEntee.)

    The study*, published online ahead of print the week of May 9, 2016, by the journal Proceedings of the National Academy of Sciences, demonstrates that the Disney lab’s compound, known as Targaprimir-96, triggers breast cancer cells to kill themselves via programmed cell death by precisely targeting a specific RNA that ignites the cancer.

    Short-Cut to Drug Candidates

    While the goal of precision medicine is to identify drugs that selectively affect disease-causing biomolecules, the process has typically involved time-consuming and expensive high-throughput screens to test millions of potential drug candidates to identify those few that affect the target of interest. Disney’s approach eliminates these screens.

    The new study uses the lab’s computational approach called Inforna, which focuses on developing designer compounds that bind to RNA folds, particularly microRNAs.

    MicroRNAs are short molecules that work within all animal and plant cells, typically functioning as a “dimmer switch” for one or more genes, binding to the transcripts of those genes and preventing protein production. Some microRNAs have been associated with diseases. For example, microRNA-96, which was the target of the new study, promotes cancer by discouraging programmed cell death, which can rid the body of cells that grow out of control.

    In the new study, the drug candidate was tested in animal models over a 21-day course of treatment. Results showed decreased production of microRNA-96 and increased programmed cell death, significantly reducing tumor growth. Since targaprimir-96 was highly selective in its targeting, healthy cells were unaffected.

    In contrast, Disney noted, a typical cancer therapeutic targets and kills cells indiscriminately, often leading to side effects that can make these drugs difficult for patients to tolerate.

    “In the future we hope to apply this strategy to target other disease-causing RNAs, which range from incurable cancers to important viral pathogens such as Zika and Ebola,” added Research Associate Sai Pradeep Velagapudi, the first author of the study and a member of the Disney lab.

    [Alex Perryman, formerly at Scripps, a veteran of the Scripps project FightAids@home on World Community Grid and now at Rutgers University is leading the new WCG project OpenZika. WCG also has OutsmartEbolaTogether at Scripps]

    WCGLarge

    Rutgers Open Zika

    Outsmart Ebola Together

    2
    “In the future we hope to apply this strategy to target other disease-causing RNAs, which range from incurable cancers to important viral pathogens such as Zika and Ebola,” says Research Associate Sai Pradeep Velagapudi.

    In addition to Disney and Velagapudi, authors of the study, “Design of a Small Molecule Against an Oncogenic Non-coding RNA,” were Michael D. Cameron, Christopher L. Haga, Laura H. Rosenberg, Marie Lafitte, Derek Duckett and Donald G. Phinney of TSRI.

    The work was supported by the National Institutes of Health (R01GM9455) and The Nelson Fund for Therapeutic Development.

    *Science paper:
    Design of a small molecule against an oncogenic noncoding RNA

    See the full article here .

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 11:43 am on May 20, 2016 Permalink | Reply
    Tags: , Cancer,   

    From ICL: “Imperial and ICR collaboration to drive innovation in cancer research” 

    Imperial College London
    Imperial College London

    20 May 2016
    Deborah Evanson

    1

    Imperial and the Institute of Cancer Research, London, are to partner on a research centre focused on tackling the disease, it was announced today.

    The Cancer Research Centre of Excellence (CRCE) will see academics and clinicians at the College and the Institute of Cancer Research (ICR) working together to deliver a world-leading programme of cancer research – paving the way for new therapies and interventions.

    The virtual centre will be headed by the ICR’s Chief Executive Professor Paul Workman, and will combine resources and infrastructure from both parties to help develop breakthrough cancer treatments, improve diagnosis, and find new ways to prevent the disease.

    The new partnership is in line with Imperial’s Strategy 2015-20, where the College commits to strengthening collaboration with external partners – including business, academia, and non-profit, healthcare and government institutions.

    2

    Professor Gavin Screaton, Dean of the Faculty of Medicine at Imperial, said: “Cancer is one of the most important challenges we’re facing in healthcare today, and Imperial has long been committed to tackling it.

    “Our world-leading research is already saving lives, but we know that through collaboration we can achieve more.

    “This important step will allow us to harness the expertise of Imperial – across the faculties of Medicine, Natural Sciences and Engineering – and the Institute of Cancer Research to drive pioneering and innovative advances in the prevention, diagnosis and treatment of cancer. Our plans are ambitious. We look forward to closer working with colleagues at the ICR as this partnership develops.”

    Professor Workman, Director of the new Cancer Research Centre of Excellence, said: “I am excited about this important new strategic partnership with Imperial that will allow the ICR to broaden the scope and raise the ambitions of our cancer research. By pooling our resources and expertise, and by working together in strategic collaboration, we will be able to do more together than we could have done alone.

    “The ICR will be able to expand its leadership role in cancer research – and through access to the wide-ranging resources of such a top class multi-faculty university, we will be able to move into important new areas of essential multidisciplinary science and accelerate our ability to make discoveries that bring benefit to cancer patients.”

    See the full article here .

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    Imperial College London

    Imperial College London is a science-based university with an international reputation for excellence in teaching and research. Consistently rated amongst the world’s best universities, Imperial is committed to developing the next generation of researchers, scientists and academics through collaboration across disciplines. Located in the heart of London, Imperial is a multidisciplinary space for education, research, translation and commercialisation, harnessing science and innovation to tackle global challenges.

     
  • richardmitnick 10:59 am on May 20, 2016 Permalink | Reply
    Tags: , , Cancer   

    From Brown: “Taking control of key protein stifles cancer spread in mice” 

    Brown University
    Brown University

    May 20, 2016
    David Orenstein

    1
    Spread stopped. All four mouse lungs had been exposed to cancer, but the two on the left were left untreated while the two on the right received an intervention that spurred one particular protein pathway to keep another in check. Ma, et. al.

    For cancer to spread, the cells that take off into the bloodstream must find a tissue that will permit them to thrive. They don’t just go looking, though. Instead, they actively prepare the tissue, in one case by co-opting a protein that suppresses defenses the body would otherwise mount. In a new study, scientists report that by wresting back control of that protein, they could restore multiple defenses in the lungs of mice, staving off cancer’s spread there.

    “Cancers are known to have the ability to co-opt or evade host anti-tumor responses,” said Dr. Jack A. Elias, dean of medicine and biological sciences at Brown University and corresponding author of the study* in the Nature journal Scientific Reports.

    A key protein that apparently becomes co-opted is Chitinase 3-like-1 (CHI3L1), which has a natural purpose in a wide array of organisms where it helps to fight infections and stimulates tissue healing. However, it is also susceptible to going awry where it contributes to the generation of a variety of diseases. In human diseases like idiopathic pulmonary fibrosis it mounts an overzealous response that leads to pulmonary scarring, and in diseases like asthma it sustains a harmful immune response. People have a directly analogous version of the protein called YKL-40 and, in patients with cancer, high levels of its expression correlate strongly with advanced cancer spread and a poor prognosis

    In a 2014 study**, Elias’s team at Brown and Yale found evidence that CHI3L1 has a central role in making tissues receptive to cancer spread.

    “It seems to be a very fundamental pathway,” said Elias, a specialist in pulmonary medicine and immunology. “It’s not a pathway that’s just in this disease or that disease. It’s a fundamental way that the body responds, and as a result it has many different consequences.”

    In the new study, the researchers not only explained more about how CHI3L1 promotes cancer spread but they also tested a new intervention that had especially widespread effects. The scientists exposed mice to melanoma or breast cancer cells and then treated different mice at different times over the next eight days to suppress expression of CHI3L1. In treated mice they restored several mechanisms that the body has to fight tumors and were able to prevent the lungs from becoming hospitable to the cancer. Mice left untreated as experimental controls quickly developed cancer in their lungs after exposure to cancer cells.

    Restoring defenses

    Several experiments revealed the details of what was going on in the lungs of the mice. They defined a pathway that contributes to cancer spread by stimulating CHI3L1, a novel pathway that blocks CHI3L1 and cancer spread,, and highlighted the ways that tumors evade this antitumor response.

    In the presence of cancer, for example, a protein called semaphorin 7A induces the expression of CHI3L1, which blunts a number of antitumor responses including those initiated by natural killer cells and a protein called PTEN. These studies also demonstrated that activation of a novel antiviral immune response pathway called the RIG-like helicase (RLH) pathway counteracts the ability of cancer cells to stimulate CHI3L1 and decreases the tumor-inducing effects that it mediates. Furthermore, they demonstrated that cancer cells stimulate another protein called NLRX1, which suppresses the RLH response that allows tumor cells to induce CHI3L1. Thus, Elias said, cancer cells stimulate CHI3L1 while simultaneously using NLRX1 to suppress the CHI3L1-inhibiting effects of the RLH pathway.

    The new intervention that Elias’s team tested was to bolster RLH immunity by stimulating its pathway with an RNA-like molecule called Poly(I:C). In mice this intervention reduced CHI3L1 production and its cancer-augmenting responses. While untreated mice went on to develop cancer in their lungs within two weeks, mice given Poly(I:C) fended the cancer off. Notably, among the effects was an increase in natural killer cells, natural killer cell recruiting proteins, stimulation of the proteins LIMK2 and PTEN and suppression of B-Raf and Nlrx1proteins. Recently scientists have attempted to develop cancer-fighting drugs by focusing on some of these individual proteins, but not multiple ones at the same time.

    “What we show in this paper is there is a very novel pathway, the RLH pathway, that can actually control the production of CHI3L1,” Elias said, “and when you can control the production of CHI3L1, you can control each of these pathways, and you can control the spread of cancer in these models”

    In several of the experiments the team didn’t just compare treated mice with untreated mice. Often they also used the additional controls of mice engineered to lack the gene that produces a particular protein, like CHI3L1. These steps helped to test whether the particular protein being investigated really played the suspected meaningful role.

    It was clear that giving RLH the upper hand against CHI3L1 proved meaningful for suppressing cancer spread in the lungs of the mice.

    “The thing that’s exciting is that [stimulating the RLH pathway] is going to allow multiple antitumor response to be augmented vs. just one,” Elias said. “If you can agonize the RLH pathway, you might get a really good effect in cancer.”

    The study’s lead author is Bing Ma, assistant professor of molecular microbiology and immunology at Brown. The paper’s other authors are Erica Herzog, Meagan Moore, Chang-Min Lee, Sung Hun Na and Chun Geun Lee.

    The National Institutes of Health (grants: R01HL093017, UH2HL108638, R01HL115813, HL109233, HL125850) and the Korea Drug Development Fund (KDDF-20132-11) supported the research.
    Note to Editors:

    *Science report:
    RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis

    **Science paper:
    Role of Chitinase 3-like-1 and Semaphorin 7A in Pulmonary Melanoma Metastasis

    See the full article here .

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 8:41 am on May 20, 2016 Permalink | Reply
    Tags: , Cancer,   

    From SA: “Investigating Immunologic Approaches to Cancer Treatment” Sponsored content 

    Scientific American

    Scientific American

    Sponsored content independent of Scientific American’s board of editors.

    At NewYork-Presbyterian Hospital and its affiliated medical schools, Columbia University College of Physicians and Surgeons and Weill Cornell Medical College, innovators in science and medicine are pursuing cancer research with the potential to redefine the field. There is an urgency in their work that is palpable as each day spent in research or with patients brings them closer to treatments for malignancies once considered insurmountable.

    1
    Credit: Thinkstock

    Facilitating Immunotherapy Drug Development

    Naiyer A. Rizvi, MD, an internationally recognized leader in the treatment of lung cancer and immunotherapy drug development, is Director of Thoracic Oncology and Immunotherapeutics in Medical Oncology at NewYork-Presbyterian/Columbia University College of Physicians and Surgeons. Dr. Rizvi’s research of antibodies that can reinvigorate T cells to recognize lung cancer cells as foreign and destroy the cancer cells has been a major development in thoracic oncology.

    Dr. Rizvi has led key trials using immune checkpoint blockade therapy which unleash a patient’s own T cells to kill tumors, an approach that is revolutionizing cancer treatment. He continues this research with a focus on developing new immunotherapy agents and immunotherapy combinations to reshape the landscape of cancer therapy.

    One of the latest immunotherapies to reach the market is a drug called nivolumab (Opdivo®), which the FDA recently approved for the treatment of patients with advanced squamous non-small cell lung cancer (NSCLC). “‘Groundbreaking’ and ‘revolutionary’ often overstate the case, but they truly apply to the impact of the new immunotherapy agents that target the PD-1 pathway for NSCLC by disabling the PD-1 protein on T cells and suppressing T cell activity,” says Dr. Rizvi.

    Dr. Rizvi led the trial, published* in the March 2015 issue of Lancet Oncology that was key to approval of nivolumab for squamous lung cancer. “When I first started treating patients with nivolumab in 2008, it was hard to imagine how dramatically this could help patients who were resistant to all of our standard treatments,” says Dr. Rizvi. “We have some patients who are still alive many years after taking this drug, with no evidence of cancer. This has never been seen with standard lung cancer treatment.”

    While some patients with NSCLC respond well to PD-1 inhibitors, others do not. Dr. Rizvi and his colleagues thought that the cancers that had accumulated the most DNA damage were more likely to have worn out the immune system and would likely be helped the most by PD-1 inhibitors. They tested this by sequencing tumor DNA from both responders and non-responders to treatment with pembrolizumab (KEYTRUDA®), a PD-1 inhibitor. Among their findings, published in April 2015 in Science, was that patients with a great deal of DNA damage were far more responsive to treatment than those with less DNA damage.

    “We were able to use advances in sequencing technology to study the entire exome – the protein-coding genes of the genome – of tumors from patients with NSCLC who were treated with pembrolizumab. We found that the more genetically damaged the tumor was, the more likely the patient was to respond to PD-1 inhibitors. This is an important first step toward being able to predict who will respond to PD-1 inhibitors and could be a new way to think about precision medicine based on the sequencing of tumor DNA,” says Dr. Rizvi. “This collaboration among clinical researchers, geneticists, and immunologists shows how a team of scientists can work together to help patients fight cancer.”

    In October 2015, KEYTRUDA – following a multicenter trial of 280 patients with metastatic non-small cell lung cancer received accelerated FDA approval for the treatment patients whose tumors express PD-L1 with disease progression on or after platinum-containing chemotherapy.

    Controlling Cancer Cell Growth with Radiotherapy and Immunotherapy

    Silvia C. Formenti, MD, Radiation Oncologist-in-Chief at NewYork-Presbyterian/ Weill Cornell Medical Center and Chair, Department of Radiation Oncology at Weill Cornell Medicine, is an international expert in the use of radiation therapy for the treatment of cancer and a recognized leader in radiation oncology and breast cancer research.

    Dr. Formenti’s groundbreaking work has transformed the paradigm in radiation biology, demonstrating the efficacy of combining radiotherapy with immunotherapy to control cancer cell growth in solid tumors. She has translated preclinical work into clinical trials in metastatic breast cancer, lung cancer, and melanoma, and has opened a new field of application for radiotherapy, whereby localized radiation can be used as an adjuvant to immunotherapy of solid tumors and lymphomas.

    “Combining radiotherapy with immunotherapy is exquisitely interdisciplinary work, leveraging the most modern integration of pathology, imaging, surgery, medical oncology, and radiation oncology,” Dr. Formenti says. Under Dr. Formenti’s leadership, scientists in the Department of Radiation Oncology are conducting high-impact basic, clinical, and translational research, and in particular, radiobiological research, exploring the effects of ionizing radiation on tumor and normal tissue with findings translated into preclinical models that can lead to improved, personalized patient care.

    Funded by the National Institutes of Health, the Department of Defense Breast Cancer Research program, and the Breast Cancer Research Foundation, Dr. Formenti has focused her research endeavors on personalized oncology – designing more effective, targeted treatments tailored to individual patients by combining radiotherapy with immunotherapy. Her laboratory discovered that this combination therapy overrides cancer’s ability to hijack the normal immune response that rejects tumor cells, creating a vaccine against the disease that is specific to each individual patient’s tumor. When applied to an experimental model of metastatic breast cancer, she found that this therapy was not only effective against primary tumors, but it also prevented the disease from spreading to the lungs by leveraging acquired immune memory. Dr. Formenti is investigating how this breakthrough, by tailoring the therapy to the specific molecular characteristics of individual tumors, can be rapidly adopted to treat patients suffering from various forms of metastatic cancer.

    These and other novel approaches to better understanding and ultimately treating the complexities of cancer are underway, moving at an accelerated pace spurred on by enlightened programs in precision medicine and collaborations that cross multiple disciplines. Immunotherapy, alone or in combination with other therapeutic advances, are making their mark in clinical care. Several cancers that were once considered terminal are now treatable with targeted therapies.

    *Science paper:
    Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial

    See the full article here .

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    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 12:49 pm on May 13, 2016 Permalink | Reply
    Tags: , Cancer,   

    From Rockefeller U: “Scientists find evidence that cancer can arise from changes in the proteins that package DNA” 

    Rockefeller U bloc

    Rockefeller University

    May 12, 2016
    No writer credit found

    newswire@rockefeller.edu
    Contact: Eva Kiesler |
    212-327-7963

    1
    Stuck dividing: In some cancers, including chondroblastoma and a rare form of childhood sarcoma, a mutation in histone H3 reduces global levels of methylation (dark areas) in tumor cells but not in normal cells (arrowhead). Rockefeller scientists found that the mutation arrests the cells in a proliferative state to promote tumor development.

    A mutation that affects the proteins that package DNA—without changing the DNA itself—can cause a rare form of cancer, according to new findings* in this week’s Science from researchers at Rockefeller University.

    The mutation is present in histones, the protein scaffolding around which DNA wraps. Researchers have known for some time that histones play a role in switching genes on or off in cells by exposing or covering up various parts of the genome, for instance. But they are just beginning to learn about how changes to these non-DNA structures can affect development and health—a field known as epigenetics—and how they are regulated. Now, for the first time, they’ve shown that a change to the structure of a histone can trigger a tumor on its own.

    “This is the first study to show that a genetic change to non-DNA structures in the cell—histones—is enough to cause cancer, with no other cooperating DNA mutations,” says co-author Chao Lu, a postdoctoral fellow in the lab of C. David Allis, Tri-Institutional Professor and Joy and Jack Fishman Professor in the Laboratory of Chromatin Biology and Epigenetics at Rockefeller University.

    A surprising source

    In earlier work, other researchers had found that in approximately 95 percent of samples of chondroblastoma, a benign tumor that arises in cartilage typically during adolescence, carry a mutation in a histone protein called H3.

    To explore whether and how the mutation causes the tumor, the researchers inserted the H3 histone mutation into mouse mesenchymal progenitor cells (MPCs), which generate cartilage, bone and fat. They then watched these mutant cells lose the ability to differentiate in the lab. Next, they injected the mutant cells into living mice, and the animals developed the tumors rich in MPCs, known as an undifferentiated sarcoma.

    “Although researchers knew that a certain type of tumor—chondroblastoma—carried a mutation in the H3 histone and no other mutation, this is the first study to show that the mutation indeed causes tumors, even without any other DNA mutation present,” says Lu.

    Next, the researchers tried to understand how the mutation causes the tumors to develop. They found that, when the mutation occurs, the cell becomes locked in a proliferative state—meaning it divides constantly, leading to tumors. Specifically, the mutation inhibits enzymes that normally tag the histone with chemical groups known as methyls, allowing genes to be expressed normally.

    In response to this lack of modification, another part of the histone becomes over-modified, or tagged with too many methyl groups. “This leads to an overall resetting of the landscape of chromatin, the complex of DNA and its associated factors, including histones,” says co-author Peter Lewis, a former postdoctoral fellow in the Allis lab and currently an assistant professor at the University of Wisconsin-Madison. This “resetting” is what locks the cell into its proliferative state.

    A new target

    The findings suggest that researchers should be on the hunt for more mutations in histones that might be driving tumors, says Lu. Meanwhile, he and his colleagues are trying to learn more about how this specific mutation in histone H3 causes tumors to develop. “For instance, we want to know which pathways cause the mesenchymal progenitor cells that carry the mutation to continue to divide, and not differentiate into the bone, fat, and cartilage cells they are destined to become,” he says.

    Once researchers understand more about these pathways, says Lewis, they can consider ways of blocking them with drugs, particularly in tumors such as MPC-rich sarcomas—which, unlike chondroblastoma, can be deadly. In fact, drugs that block the pathways may already exist and may even be in use for other types of cancers.

    “One long-term goal of our collaborative team is to better understand fundamental mechanisms that drive these processes, with the hope of providing new therapeutic approaches,” says Allis.

    This research was supported by The Rockefeller University, a startup provided by the Wisconsin Institute for Discovery, The Greater Milwaukee Foundation, the Starr Cancer Consortium, the Sidney Kimmel Foundation, and the National Institutes of Health (grants P01CA196539, DP2OD007447, R01GM110174, DP2CA174499, K08CA151660, K08CA181475, and P30CA008748).

    *Science paper:
    Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape

    See the full article here .

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
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