viernes, 20 de octubre de 2017

NOTICE TO READERS

the blog´s editor says: between the days Sunday 22 (included) October and Sunday October 29 (included), the blog will not be updated. Personal issues will keep me away from any possibility of updating since I will undergo surgery that will require a long recovery. I hope you know how to understand, just as I hope to find you on my/your return, next week, sometime, always. A hug to all of you and thank you for accompanying me day after day unconditionally . OCTOBER 20, 2017.-

Scientists receive critical funding to study treatments for three deadly cancers

Scientists receive critical funding to study treatments for three deadly cancers

News-Medical

Scientists receive critical funding to study treatments for three deadly cancers





Immunotherapy for leukemia patients has been nothing short of a miracle. Now scientists hope to use that science and other forms of gene therapy to tackle three of the deadliest forms of cancer: glioblastoma (brain cancer), sarcoma (bone cancer) and ovarian cancer. Three scientists have received $1.3 million in critical funding from the Alliance for Cancer Gene Therapy (ACGT), the nation's only nonprofit dedicated exclusively to cell and gene therapies for cancer. These new grants will be used to study immunotherapy and virotherapy in the treatment of glioblastoma, sarcoma and ovarian cancer.
"We have big hopes for these grants," said John Walter, CEO and president of ACGT. "ACGT was one of the first funders to support Dr. Carl June's work at the University of Pennsylvania in successfully treating leukemia with gene therapy when it was still deemed 'risky' science. The recent FDA approval of the first gene therapy treatment to come out of this research, Kymriah, validates the promise of this science. With these three new clinical investigator grants, we hope to see similar results with immunotherapy and virotherapy in treating hard-to-combat solid tumor cancers."
The new grants are:
Nori Kasahara, MD, PhD - Virotherapy for Glioblastoma Brain Cancer
Co-Leader Viral Oncology Program
Sylvester Comprehensive Cancer Center, University of Miami
Dr. Kasahara's research focuses on translational application of gene transfer technologies to cancer, transplantation and regenerative medicine. Dr. Kasahara will use his ACGT grant to advance a clinical trial for a virotherapy for glioblastoma. Using a modified retrovirus to deliver chemotherapy directly into cancer cells, these "suicide genes" continue to replicate to prevent recurrence. The work will take the experience in the lab and translate it to a patient clinical trial.
Seth Pollack, M.D. - Immunotherapy for Sarcoma
Fred Hutchinson Cancer Research Center, Seattle, Washington
Dr. Pollack's research is focused on developing novel immunotherapies for patients with advanced sarcoma, specifically synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL). Dr. Pollack's ACGT grant will further his research by using immunotherapy to target this rare form of cancer that grows in connective tissue - cells that support other body tissues such as in bones, muscles, tendons, etc. The initial clinical trial will deploy two different types of genetically engineered T cells to target the cancer and to assess efficacy and safety.
Daniel Powell, Jr., PhD -- Immunotherapy for Ovarian Cancer
Director of Immunotherapy for Division of Gynecology
University of Pennsylvania Perelman School of Medicine
Dr. Powell's research focuses on the development of innovative immunotherapeutic strategies, including adoptive immunotherapy, using chimeric antigen receptor (CAR) T cells. Dr. Powell will used his ACGT grant to enroll nine ovarian cancer patients in a new clinical trial. Immune system killer T cells will be developed outside the body and reinserted to establish an offense against the disease and a defense against recurrence.
"ACGT's Clinical Investigator grants allow these scientists to advance their research from the laboratory to the bedside for patients in clinical trials, providing for an opportunity to see these treatments work in actual patients and hopefully save lives," noted Walter. "Our goal at ACGT is to truly make an impact on how cancer is treated through the use of gene and cell therapies so that one day, cancer will be a treatable and manageable disease."
ACGT has now issued a total of 55 grants, including 19 clinical translation grants and 36 Young Investigator grants totaling more than $28 million. This is particularly exciting given ACGT's commitment to contributing 100 percent of donations directly to research. ACGT-funded work is also attracting increasing attention from the pharmaceutical industry, which is swiftly discovering the potential of cell and gene therapies.​​

MIT researchers develop new technique to screen for genes that protect against diseases

MIT researchers develop new technique to screen for genes that protect against diseases

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MIT researchers develop new technique to screen for genes that protect against diseases

Using a modified version of the CRISPR genome-editing system, MIT researchers have developed a new way to screen for genes that protect against specific diseases.
CRISPR is normally used to edit or delete genes from living cells. However, the MIT team adapted it to randomly turn on or off distinct gene sets across large populations of cells, allowing the researchers to identify genes that protect cells from a protein associated with Parkinson's disease.
The new technology, described in the journal Molecular Cell, offers a new way to seek drug targets for many diseases, not just Parkinson's, says Timothy Lu, an MIT associate professor of electrical engineering and computer science and of biological engineering.
"The state of the art right now is targeting two or three genes simultaneously and then looking at the effects, but we think that perhaps the gene sets that need to be modulated to address some of these diseases are actually broader than that," says Lu, who is the senior author of the study.
The paper's lead authors are postdoc Ying-Chou Chen and graduate student Fahim Farzadfard.
Turning genes on or off
The CRISPR genome-editing system consists of a DNA-cutting enzyme called Cas9 and short RNA guide strands that target specific sequences of the genome, telling Cas9 where to make its cuts. Using this process, scientists can make targeted mutations in the genomes of living animals, either deleting genes or inserting new ones.
In the new study, the MIT team deactivated Cas9's cutting ability and engineered the protein so that after binding to a target site, it recruits transcription factors (proteins that are required to turn genes on).
By delivering this version of Cas9 along with the guide RNA strand into single cells, the researchers can target one genetic sequence per cell. Each guide RNA might hit a single gene or multiple genes, depending on the particular guide sequence. This allows researchers to randomly screen the entire genome for genes that affect cell survival.
"What we decided to do was take a completely unbiased approach where instead of targeting individual genes of interest, we would express randomized guides inside of the cell," Lu says. "Using that approach, can we screen for guide RNAs that have unusually strong protective activities in a model of neurodegenerative disease."
The researchers deployed this technology in yeast cells that are genetically engineered to overproduce a protein associated with Parkinson's disease, known as alpha-synuclein. This protein, which forms clumps in the brains of Parkinson's patients, is normally toxic to yeast cells.
Using this screen, the MIT team identified one guide RNA strand that had a very powerful effect, keeping cells alive much more effectively than any of the individual genes that have been previously found to protect this type of yeast cell.
Further genetic screening revealed that many of the genes turned on by this guide RNA strand are chaperone proteins, which help other proteins fold into the correct shape. The researchers hypothesize that these chaperone proteins may assist in the proper folding of alpha synuclein, which could prevent it from forming clumps.
Other genes activated by the guide RNA encode mitochondrial proteins that help cells regulate their energy metabolism, and trafficking proteins that are involved in packaging and transporting other proteins. The researchers are now investigating whether the guide RNA turns on each of these genes individually or whether it activates one or more regulatory genes that then turn the others on.
Protective effects
Once the researchers identified these genes in yeast, they tested the human equivalents in human neurons, grown in a lab dish, that also overproduce alpha synuclein. These human genes were also protective against alpha-synuclein-induced death, suggesting that they could be worth testing as gene therapy treatments for Parkinson's disease, Lu says.
Lu's lab is now using this approach to screen for genes related to other disorders, and the researchers have already identified some genes that appear to protect against certain effects of aging.

TGen project to develop standard operating procedures for single-cell RNA sequencing

TGen project to develop standard operating procedures for single-cell RNA sequencing

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TGen project to develop standard operating procedures for single-cell RNA sequencing

The Translational Genomics Research Institute (TGen) today announced grant support from the Chan Zuckerberg Initiative (CZI) donor advised fund, an advised fund of the Silicon Valley Community Foundation, that will help revolutionize how researchers identify the genetic source of diseases and how best to treat each patient.
The human body contains trillions of individual cells. Inside each cell is a unique genetic code. Sequencing -- or spelling out -- the billions of data bits of an individual's genetic code has relied, until recently, on sequencing multiple cells and using averages to get results. This new project will help enable researchers to get results by sequencing individual cells.
Led by TGen Director of Bioinformatics Dr. Jonathan Keats, and Assistant Professor Dr. Nicholas Banovich, the project will develop and test novel processing methods with the aim of creating the playbook used across all tissue types in the international Human Cell Atlas.
The grant to TGen was one of 38 announced simultaneously by CZI in support of the Human Cell Atlas, begun in 2016, to create comprehensive reference maps of all human cell-types for understanding human health and diagnosing, monitoring, and treating disease. Specifically, the TGen project will develop standard operating procedures for the processing and storage of solid tissues for single-cell RNA sequencing.
Single-cell RNA sequencing promises to enable researchers to more quickly and precisely identify the cellular processes underlying disease states and to predict if a diseased tissue will be susceptible, or resistant, to drug therapies and eventually lead to better patient care.
"What we do today is like mashing everything up in a blender and then taking the average, and you don't know what the individual cells contributed," said Dr. Keats, the project's principal investigator. "But by applying genomic analysis to a single cell, it's like you just turned on the lights in a dimly lit room and now you see all the detail beyond the one piece of furniture you could see previously."
Sequencing analysis of a single cell makes it possible to discover mechanisms, including genetic evolution, not seen when studying a bulk population of cells. This is particularly important in the study of cancer as cells are constantly mutating, and these patterns of mutation can be observed using single-cell sequencing.
"Single cell genomics promises to deliver a paradigm shift in our understanding of cell-types, cell diversity, and how cells interact," said Dr. Banovich. "By developing standards for the processing and storage of solid tissue in preparation for single-cell analysis, we hope to add value to all single-cell RNA studies and advance patient care."
Creating standardized processing methods will ensure that meaningful molecular signatures represent real biology and not processing artifacts. This is especially critical for solid tumors, such as breast cancer, Dr. Keats explained. Blood tumors, such as leukemia, naturally exist as the free-floating single-cells required by the technology. But the processes we use today for breaking, dissociating and converting solid tumors into single cells in a liquid solution can change how genes are expressed within each cell.

Criminal offenders with genetic mental disorders assigned more blame, harsher punishment

Criminal offenders with genetic mental disorders assigned more blame, harsher punishment

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Criminal offenders with genetic mental disorders assigned more blame, harsher punishment

Popular literature, crime dramas and recent trials dominating the media imply that defense attorneys who portray their clients as victims may have better outcomes. The belief is that jurors assign less blame to defendants they feel have been wronged. New research from the University of Missouri has shown that offenders with genetic mental disorders that predispose them to criminal behavior are judged more negatively than mentally disordered offenders whose criminal behavior may have been caused by environmental factors, such as childhood abuse. Additionally, offenders with genetic mental disorders are judged just as negatively as offenders whose mental disorder is given no explanation.
"We are used to thinking that if people who commit criminal acts suffer from a mental disorder, then that should be taken into account when assigning blame and punishment for their crimes," said Philip Robbins, an associate professor of philosophy in the MU College of Arts and Science. "In our study, we wanted to determine if it mattered why and how defendants acquired those mental disorders, and how that might affect the way society assigns blame and punishment when a crime is committed."
Robbins and Paul Litton, a professor in the MU School of Law, tested their hypothesis and explored its implications for philosophy, psychology, and the law. Robbins and Litton conducted two surveys with 600 participants; the results confirmed that if the cause of a mental disorder was genetic, study participants tended to assign more blame and harsher punishment for the crime compared to cases in which the offender had a mental disorder that was not genetic in origin.
Robbins and Litton also expected to find that different environmental explanations would elicit different judgments from those being surveyed. For example, they predicted that mitigation would be greater for someone who developed a mental disorder due to childhood abuse compared to someone whose mental disorder resulted purely by accident, such as falling off a bike.
"Our theory was that people who have been intentionally harmed by caregivers are seen as more victim-like than people who have suffered accidents," Robbins said. "If so, intentional harm should be associated with less negative moral judgment than non-intentional harm. However, we found that whether the harm was intentional or accidental, it didn't affect judgments of blame or punishment."
Robbins says further research will be required to determine why there is no difference between intentional and unintentional causes of harm. However, their study adds to empirical research for defense attorneys to consider when constructing their case for a more lenient sentence. The findings suggest that presenting evidence of severe childhood abuse suffered by the defendant will be more effective than explaining the crime in genetic terms.
"It's a little surprising that genetic explanations have no mitigating effect," Robbins said. "We think the reason is that with a genetically caused mental disorder, there is no pre-existing person who has been harmed, so the offender is not seen as a victim. In the environmental cases, the offender is seen as a victim. That's what makes the difference."

Surrogate liquid biopsy can provide genetic information about retinoblastoma tumors

Surrogate liquid biopsy can provide genetic information about retinoblastoma tumors

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Surrogate liquid biopsy can provide genetic information about retinoblastoma tumors

Retinoblastoma is a tumor of the retina that generally affects children under 5 years of age. If not diagnosed early, retinoblastoma may result in loss of one or both eyes and can be fatal. Unlike most cancers that are diagnosed using a biopsy, retinoblastoma tumors cannot be directly biopsied. Although it is one of the first cancers to have its genetic origin identified, ocular oncologists have not been able to use this information to optimize treatment since they can only access the tumor if the affected eye is removed (called enucleation) in the course of treatment. A recent study by a team of investigators at the Vision Center of Children's Hospital Los Angeles and the University of Southern California (USC) Roski Eye Institute, part of Keck Medicine of USC, provides proof of concept for a safe and effective way to derive genetic information from the tumor without removing the eye. Results of the study will be published in JAMA Ophthalmology on October 12, 2017.
Retinoblastoma was one of the first tumors to have its genetic origin identified; the RB1 retinoblastoma tumor suppressor gene mutation was discovered by A. Linn Murphree, MD, a co-author on this paper, who established the Retinoblastoma Program at Children's Hospital Los Angeles. However, ocular oncologists have been limited in their ability to use this genetic information to inform diagnosis and the application of personalized treatments since removing tissue from the tumor in the back of the eye could spread tumor cells outside of the eye or even to the rest of the body, resulting in a far worse prognosis for the patient.
Retinoblastoma is treated using chemotherapy given either intravenously or through the ophthalmic artery. There are limits, however, to the amount of drug that actually reaches the eye. As a result, relapse does occur due to small tumor particles that break off – or seed – from the main tumor. The treatment for these seeds changed dramatically in 2012 when intraocular injections of chemotherapy were shown to be safe and effective. In order to inject chemotherapy directly into the eye, it is first necessary to remove a small amount of fluid, called aqueous humor, from the front of the eye, to decrease the pressure within the eye prior to injection of the medication.
Previously, this fluid was simply dispensed after the procedure. "Just as I was discarding the aqueous humor, I wondered if there was a possibility it contained tumor-derived genetic material we could use to better treat our patients," said Jesse Berry, MD, ocular oncologist at CHLA, assistant professor of Clinical Ophthalmology at the USC Roski Eye Institute and first author on the study. "In fact, we found measurable amounts of tumor DNA – genetic information from the tumor that had previously been completely unavailable from an intact eye."
"Chromosomal changes from DNA found in the aqueous humor corroborates the chromosomal changes found in the retinoblastoma tumor," said James Hicks, PhD, professor of Biologic Sciences at the USC Michelson Center for Convergent Bioscience and professor at the Keck School of Medicine at USC. "These findings provide proof of principle that the aqueous humor can be used for a surrogate 'liquid' tumor biopsy."
The study reported on six samples from three eyes affected with retinoblastoma, in children less than 3 years of age. Two of the eyes had been removed primarily for treatment of the disease; the third eye was receiving intraocular injections as therapy but ultimately had to be removed due to disease recurrence. Aqueous humor was taken from all three eyes and allowed investigators to compare tumor DNA in the aqueous humor to DNA found in the retinoblastoma tumor.
"Until now, we could only do genetic analysis – and base therapy on the specific pathologic tumor features – when there was no longer a possibility of saving the eye," said Thomas C. Lee, MD, director of the Vision Center at CHLA and associate professor at the USC Roski Eye Institute. "In the future we hope to have the capability to specifically target therapy to the type of tumor and can anticipate better outcomes for children with retinoblastoma."
The team of investigators plans future studies to compare tumor DNA from eyes that have been saved to those that need to be removed due to tumor recurrence.
"This research has the potential to completely transform how we treat children with retinoblastoma," said Jonathan W. Kim, MD, director of the Retinoblastoma Program at CHLA and also director of the ocular oncology service at USC Roski Eye Institute. "This is one of the most significant findings in retinoblastoma research in the past 20 years."

Novel gene expression signature assay could help enhance lymphoma management

Novel gene expression signature assay could help enhance lymphoma management

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Novel gene expression signature assay could help enhance lymphoma management

Better subtyping of diffuse large B-cell lymphomas can enhance diagnosis and guide treatment, reports The Journal of Molecular Diagnostics
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer and the most frequently diagnosed non-Hodgkin lymphoma worldwide (nearly 40% of cases). Recent advancements indicate that both the prognosis and choice of treatment of DLBCL may depend on identifying its molecular subtype. In a report in The Journal of Molecular Diagnostics, researchers describe their development of a reliable, accessible, rapid, and cost-effective new gene expression signature assay that can enhance lymphoma management by helping to match tumors with the appropriate targeted therapy.
"DLBCLs are heterogeneous, with three major subtypes associated with different outcomes. According to the recent update of the World Health Organization (WHO) classification, this information should therefore be systematically provided at diagnosis. Moreover, many targeted therapies are under clinical evaluation and being able to distinguish these diseases routinely and accurately should soon become a major goal," explained lead author Victor Bobée, PharmD, of the Henri Becquerel Cancer Treatment Center, INSERM U1245 (Rouen, France).
For example, the germinal center B-cell-like subtype (GCB) has a favorable prognosis, with a five-year overall survival rate of almost 75%. In contrast, the subtype known as activated B-cell-like (ABC) is more aggressive and less responsive to current therapies but may respond to NF-kB pathway inhibitors, such as ibrutinib. "Accurate diagnostic methods capable of discriminating these subtypes are thus needed," said co-investigator Philippe Ruminy, PhD, of the Henri Becquerel Cancer Treatment Center, INSERM U1245 (Rouen, France).
The described assay is a novel gene expression profiling DLBCL classifier based on reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA). It has the capability to simultaneously evaluate the expression of 21 markers, allowing differentiation of the three subtypes of DLBCLs (GCB, ABC, and primary mediastinal B-cell lymphoma, PMBL) as well as other individualized disease characteristics, such as Epstein Barr infection status.
One hundred fifty RNA samples extracted from biopsies were tested. Forty-two percent of the samples had the ABC subtype, 37% the GCB subtype, and 10% molecular PMBL. Eleven percent of samples could not be classified. Overall, the RT-MLPA assay correctly assigned 85.0% of the cases into the expected subtypes compared to 78.8% with immunohistochemistry.
The assay was also able to detect the MYD88 L265P mutation, one of the most common genetic abnormalities found in ABC DLBCLs. This information can influence treatment, since the presence of the mutation has been suggested to be predictive of ibrutinib sensitivity.
Currently, in most institutions the identification of the different DLBCL subtypes at diagnosis is addressed through immunohistochemistry, which often relies on the skills of experienced hemato-pathologists with expertise in the field of lymphoma.
RT-MLPA is a robust, efficient, rapid, and cost-effective alternative to the current methods used in the clinic to establish the cell-of-origin classification of DLBCLs. In contrast to other technological approaches such as RNA sequencing or nanostring technologies, its implementation requires only common laboratory equipment and not dedicated and expensive platforms. Another advantage is that it can be applied to formalin-fixed, paraffin-embedded samples. Other types of diagnostic methods may not provide the level of detail needed and may also be limited by poor reproducibility and lack of adaptability to routine use in standard laboratories.
"Because we have provided the classification algorithms, other laboratories will be able to verify our results and adjust the procedures to suit their environment," noted Dr. Ruminy. "It is our hope that the assay we have developed, which addresses an important recommendation of the recent WHO classifications, will contribute to better management of these tumors and improved patient outcomes."

New model predicts how E. coli bacteria respond to temperature changes, genetic mutations

New model predicts how E. coli bacteria respond to temperature changes, genetic mutations

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New model predicts how E. coli bacteria respond to temperature changes, genetic mutations

Researchers at the University of California San Diego have developed a genome-scale model that can accurately predict how E. coli bacteria respond to temperature changes and genetic mutations. The work is aimed at providing a comprehensive, systems-level understanding of how cells adapt under environmental stress. The work has applications in precision medicine, where adaptive cell modeling could provide patient-specific treatments for bacterial infections.
A team led by Bernhard Palsson, a professor of bioengineering at UC San Diego, published the work on Oct. 10 in Proceedings of the National Academy of Sciences.
"In order to have full control over living cells, we need to understand the fundamental mechanisms by which they survive and quickly adapt to changing environments," said Ke Chen, a postdoctoral researcher at UC San Diego and the study's first author.
A fundamental principle behind this work is that changes in the environment cause changes in a cell's protein structure. For example, higher temperatures destabilize protein molecules. The new genome-scale computational model, called FoldME, predicts how E. coli cells respond to temperature stress and then reallocate their resources to stabilize proteins. "The more the proteins destabilize, the more resources are devoted to re-stabilize them, making resources less available for growth and other cellular functions," Palsson explained.
To construct FoldME, the team first compiled the structures of all the protein molecules in E. coli cells and then integrated that data into existing genome-scale models of metabolism and protein expression for E. coli. Next, they calculated a biophysical profile that represents how well each protein folds at different temperatures. Since proteins usually need small molecules called chaperones to help them fold at high temperatures, the researchers also incorporated chaperone-assisted folding reactions into the model. They then set the model to maximize cell growth rate.
FoldME accurately simulated the response of E. coli cells throughout a wide temperature range and provided details on the strategies they used to adapt at each different temperature. The model's predictions were consistent with experimental findings. For example, it correctly reproduced the variations in E. coli cell growth rate at different temperatures. FoldME simulations also showed that E. coli cells consume a different type of sugar at high temperatures.
The model also evaluated how mutations in a single gene affect E. coli cells' response to stress. It predicted that point mutations in a single metabolic gene called DHFR result in the differential expression of a large number of proteins. This was also confirmed by experimental findings.
Another important aspect of this work is that it highlights the systems-level regulatory role of the chaperone network, which has been overlooked in previous studies, Chen said. Chaperones provide a critical service in that they help proteins fold under stress (at higher temperatures), but their service is a limited resource that's shared by all the proteins in the cell. Helping one protein fold means a chaperone isn't available to help other proteins to fold-;a limitation that affects the structural integrity of the rest of the cell's proteins. This also drains available resources from protein synthesis, setting a stringent translational constraint on all the proteins, researchers explained.
"Using first principles calculations, we can get a deep understanding of how multiple protein folding events, chaperone regulation and other intracellular reactions all work together to enable the cell to respond to environmental and genetic stresses," Chen said.
"It is worth noting that we know that adaptation to chemical stress and changing nutrients typically only require a handful of mutations, while adaptation to temperature stress is much more difficult and predicted to require a large number of mutations," Palsson added.
Next steps involve experimental tests on the model that are aimed at exploring how bacteria adapt at higher temperatures. The team is also planning to study the adaptation processes of other disease-causing bacteria-;such as diarrhea-causing E. coliM. tuberculosis and staph bacteria-;under stresses that mimic conditions in their native human habitats.

New genomics study aims to evaluate effectiveness of blood test in detecting breast cancer

New genomics study aims to evaluate effectiveness of blood test in detecting breast cancer

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New genomics study aims to evaluate effectiveness of blood test in detecting breast cancer

Cancer researchers at Intermountain Medical Center and the Intermountain Precision Genomics Program in Salt Lake City are launching an exciting, new three-year study to determine if a blood test that looks for DNA from a cancer tumor can be used to complement mammography to improve the way breast cancer is diagnosed.
The goal of this new genomics study is to show whether screening patients for the presence of circulating tumor DNA, known as ctDNA, can successfully detect breast cancer using a blood draw.
Breast cancer is the second-leading cause of cancer deaths in women, behind only lung cancer, with an estimated 40,610 deaths each year from the disease. Nearly 253,000 new cases of invasive breast cancer are diagnosed each year, along with about 60,000 non-invasive, early-stage cases, according to the American Cancer Society.
The Intermountain study is unique in that researchers will also help develop a specific test to check for ctDNA, and will have access to both mammography results and the DNA blood test results, which will allow a direct comparison of the "liquid-based biopsy" to be made.
The idea behind the science is simple, though researchers say the execution is not yet proven: Little pieces of DNA that come from dying cells end up in the peripheral blood stream, including circulating tumor cells. The goal of researchers is to use those markers to identify breast cancer, perhaps even before mammography can detect it, said Lincoln Nadauld, MD, PhD, co-lead investigator of the study and executive director of the Intermountain Healthcare Precision Genomics Program.
"As a tumor is growing, some of the cells will die and their DNA will end up in the peripheral blood stream," Dr. Nadauld said. "We're able to distinguish DNA from cancer vs. DNA from normal cells. The idea is to leverage DNA to see if we can detect that it comes from a tumor."
In the study, patients with known breast cancer will be compared with those in a screening group.
"We don't know what we'll see yet," said Brett Parkinson, MD, co-lead investigator of the study, who is also imaging director and medical director of the Intermountain Medical Center Breast Care Center in Murray. "We might find those who have breast cancer will have a negative blood test and learn it's not a good screening tool."
Even a successful blood test isn't expected to replace mammography outright. If it detects the circulating tumor DNA, imaging would be needed to find the tumor. But it could help eliminate unneeded biopsies, Dr. Parkinson added.
Dr. Nadauld said cancers have mutations in their DNA that aren't always unique.
"Sometimes those are the same whether it's a breast cancer or a colon cancer. If we do create a blood test, it's possible it would detect mutant DNA, but it might look so similar it would be hard to tell what kind of cancer it came from," he said. "That's part of what this trial is going to accomplish. We want to determine the signature for early breast cancer."
If successful, a liquid biopsy might also be used to monitor a breast cancer survivor for recurrence, Dr. Nadauld said. It might even lead to development of similar tests for different types of cancer. But that would be a challenge for the future.
"We want to approach this with laser-like focus," he said. "It's needed to help us diagnose breast cancer. We need to detect it earlier, when it's curable."
Breast cancer survival depends largely on finding the disease early --and mammography is the only screening exam that's been shown by multiple randomized clinical trials to reduce the mortality rate for breast cancer. Since 1991, the death rate from breast cancer is down 38 percent, largely because mammography screening tests lead to early detection.
Although mammography finds most breast cancers, it may not detect malignancy in women who have dense breast tissue, especially premenopausal women, or those under 50.
"We pick up most breast cancer in women with average breast density," said Dr. Parkinson. "When breast tissue is denser, we can miss up to 30 percent of breast cancers."
Mammography also has a false-positive or call-back rate of 10 percent, which may subject women to additional imaging and emotional duress. Plus, a mammogram can be uncomfortable, since breast tissue is compressed for imaging, which also exposes a woman to a small amount of radiation. Mammography may also be inconvenient, often requiring women to take time off work, he noted.
For those, and perhaps other reasons, mammography screening rates in the United States are low. In Utah, only about 65 percent of eligible women are screened, despite Intermountain Healthcare's recommendations that women over 40 undergo yearly screening mammography. All major medical and advocacy organizations agree that screening every year after a woman is 40 saves more lives. About 20 percent of breast cancers occur in women under 50.
Dr. Nadauld said the unusual confluence of three factors weigh in Intermountain's favor on this quest, starting with access to a lot of patients in one place who are getting mammograms, which are the gold standard screening test for breast cancer. Second, the researchers have access to the results of those mammograms; they know if the results were positive or negative. The third major factor is Intermountain's genomic technology capability.
"This is the big conversation right now in all of oncology -- the use of liquid biopsy to determine how to screen for breast cancer, a woman's risk of recurrence, and how to monitor their treatment," Dr. Nadauld said.

Scientists discover new non-genetic cause of resistance to anti-cancer therapies

Scientists discover new non-genetic cause of resistance to anti-cancer therapies

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Scientists discover new non-genetic cause of resistance to anti-cancer therapies

The targeted anti-cancer therapies cetuximab and panitumumab are mainstays of treatment for advanced colorectal cancer, the second leading cause of cancer-related deaths in the United States. However, many patients have tumors with genetic mutations that make them resistant to these anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, or the cancers develop resistance during treatment. Researchers seeking to understand mechanisms of intrinsic and acquired resistance have focused on gene mutations, such as activating mutations in the oncogene KRAS.
Now, Vanderbilt investigators have discovered a novel non-genetic cause of resistance to cetuximab. Their findings, reported Oct. 16 in Nature Medicine, suggest a strategy for overcoming this resistance.
"It's sort of like we've all been looking under the light post - we look at genes, and we find mutations," said Robert Coffey Jr., M.D., Ingram Professor of Cancer Research and senior author of the current study. "What we found is that there is another form of resistance. It's not due to mutations in genes; it's an epigenetic mode of drug resistance."
Coffey and his colleagues used a 3-D cell culture system they developed to grow colon cancer cells, which were initially sensitive to cetuximab. After four months of cetuximab exposure, colonies of resistant cells grew in the culture system.
The researchers evaluated the cells for gene mutations linked to cetuximab resistance, but they didn't find any.
"Once we had excluded all known genetic causes of resistance, we figured something interesting was happening, and that led us to dig deeper," said Coffey, who is also professor of Medicine and Cell and Developmental Biology and director of the Epithelial Biology Center.
The investigators found increased expression of a long non-coding RNA called MIR100HG, which houses two microRNAs, miR-100 and miR-125b, that also had increased expression. Long non-coding RNAs and microRNAs are transcribed from the genome just like genes, but they do not encode proteins. Instead, these pieces of RNA coordinate complex epigenetic processes to regulate gene expression.
Coffey and his colleagues discovered that miR-100 and miR-125b collectively suppressed the expression of five different genes that are negative regulators of the Wnt signaling pathway. Removing these "brakes" resulted in increased Wnt signaling, which is known to promote cell proliferation.
When the investigators blocked Wnt signaling using both genetic and pharmacologic inhibitors, they were able to restore responsiveness to cetuximab in cultured colon cancer cells and in colorectal tumors in mice.
The researchers also examined tumor samples from patients with colorectal cancer who received cetuximab therapy and developed resistance to it. They found increased MIR100HG, miR-100 and miR-125b in six out of 10 patients. Tumors from two of the six patients also had genetic mutations. "We found that genetic and epigenetic resistance mechanisms can co-occur," Coffey said.
In addition, the same epigenetic mechanisms were present in other colon cancer cell lines and in head and neck cancer cell lines with both intrinsic and acquired resistance.
The findings suggest that epigenetic regulation to increase Wnt signaling may be a general mechanism cancer cells use to overcome therapeutic blockade of EGFR signaling.
For patients who are eligible for cetuximab (they're not already resistant because of known genetic mutations), it could be worthwhile to evaluate expression of MIR100HG and if it's elevated, to block Wnt signaling, Coffey said.
"Right now there aren't great drugs available to block Wnt signaling, but there are trials underway with a slew of different Wnt inhibitors," he said. "Ultimately, we could imagine giving cetuximab with a drug that would block Wnt - to enhance the activity of cetuximab or to prevent the emergence of resistance."
Coffey and his colleagues are using the 3-D culture system to explore mechanisms of drug resistance in other colon cancer cell lines. They are also developing ways to introduce selective blockers of microRNAs ("antagomiRs"), and their preliminary data suggest this strategy may confer cetuximab sensitivity to colon cancer cell lines with KRAS mutations.