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Archive - Dec 2019

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December 20th

Ratio of Neutrophils to T Cells in Tumor Environment Can Help Predict Which Patients Will Respond to Checkpoint Inhibitor Immunotherapy in Lung Cancer; Study Suggests That Neutrophil-Blocking Drugs May Boost Effectiveness of Checkpoint Inhibitors

For many lung cancer patients, the best treatment options involve checkpoint inhibitors. These drugs unleash a patient's immune system against their disease and can yield dramatic results, even in advanced cancers. But checkpoint inhibitors come with a huge caveat: They only help a small subset of patients. Doctors struggle to predict who these patients are and -- just as important -- who they aren't. Results from a new study published online on December 18, 2019 in JCI Insight could help improve those forecasts. The open-access article is titled “Neutrophil Content Predicts Lymphocyte Depletion and Anti-PD1 Treatment Failure In NSCLC.” After analyzing tumor samples from 28 patients with non-small cell lung cancer(NSCLC), researchers linked a common immune cell with treatment failure. The culprit: neutrophils, the most abundant type of white blood cell. The paper shows that the balance between neutrophils and another type of immune cell -- disease-fighting T cells -- could accurately predict which patients would respond or not. If more neutrophils than T cells were crowded into a tumor, the drugs did not curb the patients' cancers. But if the balance was reversed, checkpoint inhibitors revved up patients' immune systems against their disease. "The study is the first to implicate neutrophils in the failure of checkpoint inhibitors," said senior author Dr. McGarry Houghton, MD, a lung cancer immunologist at Fred Hutchinson Cancer Research Center in Seattle, Eashington. "Our findings also hint at a way to help patients who have this cellular signature." In a mouse model of NSCLC, the researchers administered a drug that decreased the number of neutrophils in and around tumors. That, in turn, boosted the efficacy of checkpoint inhibitors -- T cells now had a clear path to attack diseased cells in the mice.

December 20th

Combination of Chemo Drug (Imatinib) and Diabetes Drug (Metformin) Shows Potential for Treating Ewing Sarcoma

Ewing sarcoma, an aggressive tumor that commonly affects bones in adolescents and young adults, is diagnosed in approximately 225 American children and teens every year, accounting for about 1 percent of pediatric cancers. Although Ewing sarcoma has been studied for decades, it has no effective cure and a survival rate of just 20-30% for patients who relapse; furthermore, most treatments require surgical resections or amputation and this impacts quality of life of the patients. But a research team at Houston Methodist aims to change those odds. A new possibility for treatment is proposed by Stephen Wong (photo), PhD, John S. Dunn Sr. Presidential Distinguished Chair in Biomedical Engineering and Professor of Computer Science and Bioengineering in Oncology at Houston Methodist. He is proposing a combination of two well-known drugs as a new treatment option for Ewing sarcoma--the chemotherapy drug imatinib and the diabetes drug metformin. A report describing the research of Dr. Wong and colleagues on this possible treatment option was published in the January 2020 issue of Cancer Letters. The article is titled “Imatinib Revives the Therapeutic Potential of Metformin on Ewing Sarcoma by Attenuating Tumor Hypoxic Response and Inhibiting Convergent Signaling Pathways.”

[Press release] [Cancer Letters abstract]

Triplet Therapeutics Launches with $59 Million in Financing to Further Its Development of Transformative Treatments for Triplet Repeat Disorders; Company Targets DNA Damage Repair (DDR) Pathway in Huntington’s Disease and Nearly 40 Other Diseases

On December 17, 2019, Triplet Therapeutics, Inc., a biotechnology company harnessing human genetics to develop treatments for repeat expansion disorders at their source, launched today with $59 million in financing including a $49 million Series A financing led by MPM Capital and Pfizer Ventures U.S. LLC, the venture capital arm of Pfizer Inc. (NYSE: PFE). Atlas Venture, which co-founded and seeded Triplet with a $10 million investment, also participated in the Series A financing, alongside Invus, Partners Innovation Fund and Alexandria Venture Investments. Triplet Therapeutics was founded in 2018 by Nessan Bermingham, PhD, a serial biotech entrepreneur and venture partner at Atlas Venture, along with Atlas Venture and Andrew Fraley, PhD, to pursue a transformative approach to developing treatments for repeat expansion disorders, a group of more than 40 known genetic diseases associated with expanded DNA nucleotide repeats. A significant body of human genetic evidence has identified that one central pathway, known as the DNA damage response (DDR) pathway, drives onset and progression of this group of disorders, which include Huntington’s disease, myotonic dystrophy, and various spinocerebellar ataxias. Triplet is developing antisense oligonucleotide (ASO) and small interfering RNA (siRNA) development candidates to precisely knock down key components of the DDR pathway that drive repeat expansion. This approach operates upstream of current approaches in development, targeting the fundamental driver of these diseases. By precisely reducing activity of select DDR targets, Triplet’s approach is designed to halt onset and progression across a wide range of repeat expansion disorders. The company has a fully assembled senior management team of industry veterans.

December 19th

Cryo-EM & Supercomputer Analyses Reveal Asymmetry in Active Sites of B-Raf Kinases; Possible Key Clue to Solving Melanoma Mystery

It starts off small, just a skin blemish. The most common moles stay just that way -- harmless clusters of skin cells called melanocytes, which give us pigment. In rare cases, what begins as a mole can turn into melanoma, the most serious type of human skin cancer because it can spread throughout the body. Scientists are using powerful supercomputers to uncover the mechanism that activates cell mutations found in about 50 percent of melanomas. The scientists say they're hopeful their study can help lead to a better understanding of skin cancer and to the design of better drugs. In 2002, scientists found a link between skin cancer and mutations of B-Raf (Rapidly Accelerated Fibrosarcoma) kinase (image), a protein that's part of the signal chain that starts outside the cell and goes inside to direct cell growth. This signal pathway, called the Ras/Raf/Mek/Erk kinase pathway, is important for cancer research, which seeks to understand out-of-control cell growth. According to the study, approximately 50 percent of melanomas have a specific single mutation on B-Raf, known as the valine 600 residue to glutamate (V600E). B-Raf V600E thus became an important drug target, and specific inhibitors of the mutant were developed in the following years. The drugs inhibited the mutant, but something strange happened. Paradoxically, quieting the mutant had a down side. It activated the un-mutated, wild-type B-Raf protein kinases, which again triggered melanoma. "With this background, we worked on studying the structure of this important protein, B-Raf," said Yasushi Kondo, PhD, a postdoctoral researcher in the John Kuriyan Lab at UC Berkeley. Dr.

Large-Scale Generation of Functional mRNA-Encapsulating Exosomes Achieved by Nanoporation; Advance May Enable New Gene Therapy Strategies; Initial Study Done on Gliomas

Scientists have developed a new gene-therapy technique by transforming human cells into mass producers of tiny nano-sized particles full of genetic material that has the potential to reverse disease processes. Though the research was intended as a proof of concept, the experimental therapy slowed tumor growth and prolonged survival in mice with gliomas, which constitute about 80 percent of malignant brain tumors in humans. The technique takes advantage of exosomes, fluid-filled subcellular vesicles that cells release as a way to communicate with other cells. While exosomes are gaining ground as biologically friendly carriers of therapeutic materials – because there are a lot of them and they don’t elicit an immune response – the trick with gene therapy is finding a way to fit those comparatively large genetic instructions inside the tiny exosomes on a scale that will have a therapeutic effect. This new method relies on patented technology that prompts donated human cells such as adult stem cells to release millions of exosomes that, after being collected and purified, function as nanocarriers containing a drug. When they are injected into the bloodstream, these exosomes know exactly where in the body to find their target – even if it’s in the brain. “Think of them like Christmas gifts: The gift is inside a wrapped container that is postage-paid and ready to go,” said senior study author L. James Lee, Phd, Professor Emeritus of Chemical and Biomolecular Engineering at The Ohio State University. And they are gifts that keep on giving, Dr. Lee noted: “This is a Mother Nature-induced therapeutic nanoparticle.” The new study was published online on December 16, 2019 in Nature Biomedical Engineering. The article is titled “Large-Scale Generation of Functional mRNA-Encapsulating Exosomes Via Cellular Nanoporation.”

December 18th

Three-Drug Combination Improves Lung Function in Most Common Genetic Form of Cystic Fibrosis

A phase three clinical trial that the University of Texas (UT) Southwestern Medical Center participated in has determined that a three-drug combination improved lung function and reduced symptoms in cystic fibrosis (CF) patients who have a single copy of the most common genetic mutation for the disease. Earlier this month, the Food and Drug Administration approved the therapy based on the results of this international study, published online on October 31, 2019 and in the November 7, 2019 issue of the New England Journal of Medicine. The article is titled “Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.” A companion investigation, appearing simultaneously in The Lancet, reported on people with one or two copies of the mutation. The Lancet article, published online on October 31, 2019 and in the November 23, 2019 issue, is titled “Efficacy and Safety of the Elexacaftor Plus Tezacaftor Plus Ivacaftor Combination Regimen in People with Cystic Fibrosis Homozygous for the F508del Mutation: A Double-Blind, Randomised, Phase 3 Trial.” A commentary article (“Entering the Era of Highly Effective CFTR Modulator Therapy”) also appears in The Lancet. Raksha Jain (photo), MD, Associate Professor of Internal Medicine at UT Southwestern Medical Center, is corresponding author of the NEJM article and an investigator on The Lancet study. Dr. Jain presented both studies at the North American Cystic Fibrosis Conference 2019 in Nashville October 31 to November 2. CF is a chronic, progressive, and frequently fatal genetic disease that affects the respiratory and digestive systems in children and young adults. The sweat glands and the reproductive system are usually also involved. Individuals with CF have a shortened lifespan.

Study Reveals Domestic Horse Breed (Cleveland Bay) Has Third-Lowest Genetic Diversity, Just Higher Than Friesian & Clydesdale Breeds

A new study by Dr. Gus Cothran, Professor Emeritus at the Texas A&M School of Veterinary Medicine & Biomedical Sciences (CVM), has found that the Cleveland Bay (CB) horse breed has the third-lowest genetic variation level of domestic horses, ranking above only the notoriously inbred Friesian and Clydesdale breeds. This lack of genetic diversity puts the breed at risk for a variety of health conditions. Genetic variation refers to the differences between different individuals' DNA codes. Populations where there is high genetic diversity will have a wider range of different traits and will be more stable, in part because disease traits will be more diluted. In populations with low genetic variation, many individuals will have the same traits and will be more vulnerable to disease. The CB is the United Kingdom's oldest established horse breed and the only native warm-blood horse in the region. Used for recreational riding, driving, and equestrian competition, the CB is considered a critically endangered breed by the Livestock Conservancy. Because maintaining genetic diversity within the breed is important to securing the horses' future, Dr. Cothran and his team worked to gain comprehensive genetic information about the breed to develop more effective conservation and breeding strategies. In this study, published online on Septembr 20, 2019 in Diversity, researchers genotyped hair from 90 different CB horses and analyzed their data for certain genetic markers. These samples were then compared to each other, as well as to samples from other horse breeds to establish the genetic diversity within the breed and between other breeds.

MicroRNA-1 Alleviates Protein Accumulation by Controlling Autophagy; Finding May Be Key to New Therapeutic Approaches in Huntington’s Disease and Parkinson’s Disease

Research led by a Monash University (Australia) scientist has identified a highly conserved mechanism in worms and humans that controls the removal of toxic protein aggregates – hallmarks of neurodegenerative diseases. Insights from their study may provide a novel therapeutic approach for diseases such as Huntington's and Parkinson's. Associate Professor Roger Pocock, from the Monash Biomedicine Discovery Institute (BDI), and colleagues from the University of Cambridge led by Professor David Rubinsztein, found that microRNAs are important in controlling protein aggregates, proteins that have amassed due to a malfunction in the process of ‘folding’ that determines their shape. The scientists’ findings were published online on December 9, 2019 in eLIFE. The open-access article is titled “Interferon-β-Induced miR-1 Alleviates Toxic Protein Accumulation by Controlling Autophagy.” MicroRNAs, short strands of genetic material, are tiny but powerful molecules that regulate many different genes simultaneously. The scientists sought to identify particular microRNAs that are important for regulating protein aggregates and homed in on miR-1, which is found in low levels in patients with neurodegenerative diseases such as Parkinson’s disease. “The sequence of miR-1 is 100 per cent conserved; it’s the same sequence in the Caenorhabditis elegans worm as in humans even though they are separated by 600 million years of evolution,” Associate Professor Pocock said. “We deleted miR-1 in the worm and looked at the effect in a preclinical model of Huntington’s and found that when you don’t have this microRNA there’s more aggregation,” he said. “This suggested miR-1 was important to remove Huntington’s aggregates.”

Scientists Find Way to Supercharge Protein Production; Discovery Promises to Aid Production of Protein-Based Drugs, Vaccines, Other Biomaterials

Medicines such as insulin for diabetes and clotting factors for hemophilia are hard to synthesize in the lab. Such drugs are based on therapeutic proteins, so scientists have engineered bacteria into tiny protein-making factories. But even with the help of bacteria or other cells, the process of producing proteins for medical or commercial applications is laborious and costly. Now, researchers at the Washington University School of Medicine in St. Louis have discovered a way to supercharge protein production up to a thousand-fold. The findings, published online on December 18, 2019 in Nature Communications, could help increase production and drive down costs of making certain protein-based drugs, vaccines, and diagnostics, as well as proteins used in the food, agriculture, biomaterials, bioenergy, and chemical industries. The open-access article is titled “A Short Translational Ramp Determines the Efficiency of Protein Synthesis.” “The process of producing proteins for medical or commercial applications can be complex, expensive, and time-consuming,” said Sergej Djuranovic, PhD, an Associate Professor of Cell Biology and Physiology and the study’s senior author. “If you can make each bacterium produce 10 times as much protein, you only need one-tenth the volume of bacteria to get the job done, which would cut costs tremendously. This technique works with all kinds of proteins because it’s a basic feature of the universal protein-synthesizing machinery.” Proteins are built from chains of amino acids hundreds of links long. Dr. Djuranovic and first author Manasvi Verma, an undergraduate researcher in Dr. Djuranovic’s lab, stumbled on the importance of the first few amino acids when an experiment for a different study failed to work as expected.

Scientists Discover New Mechanism in Childhood Kidney Cancer (Wilms’ Tumor); Findings on Possible Role of ENL Chromatin Reader Protein May Point to New Treatment Approaches

As an embryo develops, its cells must learn what to do with the thousands of genes they've been equipped with. That's why each cell comes with a detailed gene-expression manual outlining exactly which genes should be switched on, to what extent, and when. To execute their respective manuals, the cells employ so-called chromatin reader proteins that identify which gene is up for expression. Now, a new study has found that a problem in this gene-regulatory process may cause normal cells to turn malignant and produce Wilms’ tumor, the most common kidney cancer in children. The findings, which were published online on December 18, 2019, in Nature, open up new treatment possibilities for the disease, which is currently treated by surgery and chemotherapy. The article is titled “Impaired Cell Fate Through Gain-of-Function Mutations in a Chromatin Reader.” The findings also raise intriguing questions about other cancer types. The researchers found that the implicated reader protein causes problems by acquiring a new property and being too active. "We have never seen this type of mechanism before," says Liling Wan, PhD, a former postdoctoral associate in the Rockefeller Univeersity lab of Dr. C. David Allis, and now an Assistant Professor at the University of Pennsylvania. "It raises the question whether this type of molecular mechanism is also hijacked in other cancer types." A few years ago, Dr. Wan discovered that a reader protein called ENL is involved in blood cancer leukemia by activating the cancer-causing genes. Her attention was turned to Wilms' tumor recently, when it was discovered that some people with Wilms' tumor carry mutations in the gene that codes for ENL.