In search of new strategies against life-threatening tuberculosis infections, a team from the Technical University of Munich (TUM), as well as Harvard University and Texas A&M University in the USA have found a new ally. They discovered a substance that interferes with the mycomembrane formation of the bacterium. It is effective even in low concentrations and when combined with known antibiotics their effectiveness is improved by up to 100-fold. Among the greatest challenges when treating life-threatening tuberculosis infections is the increasing resistance to antibiotics. But the pathogen itself also makes the life of doctors difficult: its dense mycomembrane hampers the effect of many medications. A team of scientists headed by Stephan A. Sieber, Professor of Organic Chemistry at TU Munich, has discovered a substance that perturbs the formation of this membrane significantly. The mycomembrane of the tuberculosis pathogen Mycobacterium tuberculosis consists of a lipid double layer that encapsulates the cell wall, forming an exterior barrier. Structural hallmarks are mycolic acids, branched beta-hydroxy fatty acids with two long hydrocarbon chains. The team hypothesized that similarly structured beta lactones could “mask” themselves as mycolic acid to enter the mycolic acid metabolic pathways and then block the decisive enzymes. In the context of an extensive search, the interdisciplinary team of scientists hit the bullseye with the beta lactone EZ120. It does indeed inhibit the biosynthesis of the mycomembrane and kills mycobacteria effectively. Using enzyme assays and mass spectroscopy investigations, Dr.
Hi, I’m Luke Timmerman, a biotech journalist, and I am carrying my 80-pound training backpack up and down the hills of Seattle for a reason. I’m training to climb Mount Everest, the highest mountain in the world, in 2018. Why do this? Of course, I love mountains. But mostly, I’m doing it to support the top-notch research at the Fred Hutchinson Cancer Research Center. I’m doing it to support my hometown of Seattle, and I’m doing it to support science itself. As a biotech journalist for 15 years, I’ve had the privilege to meet scientists around the world doing amazing work. I see a cancer revolution happening. Immunotherapies are emerging that harness the power of the immune system to attack cancer cells much like the viruses and bacteria we fight off every day. Fast DNA sequencers and other sensitive instruments are making it possible to detect cancer earlier than ever before, when it’s most easily treated. Fred Hutch is at the leading edge of cancer cures. Their pioneering research is helping people with many types of cancer live longer, and lead better lives. We’re seeing just the beginning of what is possible. We can’t let up—especially during this time of so much thrilling progress. So I ask you to please give generously to this important cause at a crucial moment in time. Let’s take this all the way. DONATE TO “THE CLIMB TO FIGHT CANCER AT FRED HUTCH,” (engage.fredhutch.org/site/TR?px=1161441&fr_id=1551&pg=personal) and you’ll help scientist push to the top of the mountain—the cure. Donations are 100 percent tax-deductible, and Fred Hutch sends donors a receipt automatically. (This text was drawn from Luke’s publication, the Timmerman Report, with permission. Luke is the author of the award-winning biography of legendary scientist Leroy Hood, titled simply “Hood.”)
The diminutive size of our aortic valve — just shy of a — belies its essential role in pushing oxygen-rich blood from the heart into the aorta, our body’s largest vessel, and from there to all other organs. Yet for decades, researchers have focused less on damaged valves than on atherosclerosis, the gradual hardening of the blood vessels themselves. Thanks, in part, to pigs at the University of Wisconsin (UW)-Madison’s Arlington Agricultural Research Station, scientists are now catching up on understanding the roots of calcific aortic valve disease (CAVD). “For a long time, people thought CAVD was just the valvular equivalent of atherosclerosis,” says Kristyn Masters (see photo at end), PhD, a Professor of Biomedical Engineering at UW-Madison and Vice Chair of the department. “Today, we know that valve cells are quite unique and distinct from the smooth muscle cells in our blood vessels, which explains why some treatments for atherosclerosis, such as statins, don’t work for CAVD, and why the search for drugs has to start from scratch.” A team led by Dr. Masters has cleared a longstanding hurdle in that search with a study published online on December 27, 2017 in PNAS. The researchers teased apart, for the first time, the early cascade of events that may eventually cause stenosis, a severe narrowing of the aortic valve that reduces blood flow to body tissues and weakens the heart. The only current treatment for stenosis is valve replacement, which typically requires risky and expensive open-heart surgery. “Our study sheds new light on the differences between atherosclerosis and CAVD, especially in terms of bottleneck events that we can target with drugs,” says Dr. Masters, whose work is supported by the National Institutes of Health and the American Heart Association.
A University of Hawai’i Cancer Center researcher has identified how some cancer cells are made to move during metastasis. The research provides a better understanding of how cancer spreads and may create new opportunities for cancer drug development. Metastasis causes the deaths of 90 percent of cancer patients. The spread of cancer by metastasis is driven by a set of mutant proteins called oncogenes, which cause cancer cells to multiply uncontrollably and promote their ability to move. How oncogene activity specifically directs the increased movement and metastasis is highly complex and remains largely unknown. Joe W. Ramos, PhD, Deputy Director of the UH Cancer Center and collaborators focused on investigating how these oncogenes and related signals lead to dysregulation of normal processes within the cell and activate highly mobile and invasive cancer cell behavior. The findings, published online on December 26, 2017 in PNAS, define a mechanism in which the oncogenes turn on a protein called RSK2 that is required for cancer cells to move. The open-access article is titled “RSK2 Drives Cell Motility by Serine Phosphorylation of LARG and Activation of Rho GTPases.” Dr. Ramos and colleagues found that the RSK2 protein forms a signaling hub that includes proteins called LARG and RhoA. They show that turning on this signaling hub activates the movement of the cancer cells. These results significantly advance understanding of how cancer cells are made to move during metastasis and may provide more precise targets for drugs to stop cancer metastasis in patients where there are oncogenic mutations. “These new data are very exciting. Blocking cancer invasion and metastasis remains a central challenge in treating patients.
Evox Therapeutics Ltd (“Evox” or the ‘Company’), a leading exosome therapeutics company, announced on December 19, 2017 that it has entered into a research collaboration with Boehringer Ingelheim to investigate exosome-mediated delivery of RNAs with high medical relevance to targets for specific disease areas of focus to Boehringer Ingelheim. The collaboration is part of Boehringer Ingelheim’s Research Beyond Borders (RBB) initiative that explores emerging science and technologies for and beyond its core therapeutic areas to create new opportunities in disease indications of high medical need. Exosomes are small, cell-derived vesicles. Evox combines its exosome engineering platform with highly specific targeting technology, to enable the development of natural delivery nanoparticles for the treatment of severe diseases. Under the terms of the agreement, Evox and Boehringer Ingelheim will perform comprehensive in vitro and in vivo research with Evox’s exosome technology in return for undisclosed financial considerations. This research may help to pave the way for approaching therapeutic concepts in diseases with high medical need that are currently not amenable to therapeutic intervention. Upon completion of these studies, Boehringer Ingelheim will have the option to negotiate a license agreement to further develop RNA drug candidates using Evox’s exosome-mediated delivery technology. Commenting on the announcement, Dr. Antonin de Fougerolles, Chief Executive Officer of Evox, said: “Evox is pleased to add Boehringer Ingelheim to its growing list of collaborators. The use of exosomes as drug delivery vehicles provides significant advantages over other delivery methods as they can carry therapeutic molecules to difficult-to-reach target tissues.
by Rachel DeRita, PhD candidate (Thomas Jefferson University, Department of Cancer Biology): Cancer immunotherapy is rapidly becoming one of the largest clinical and pre-clinical cancer research fields. You may even hear it talked about at your holiday cocktail party. In particular, the University of Pennsylvania has had a landmark year involving a particular type of immunotherapy, chimeric antigen receptor (CAR) T-cell therapy. This therapy involves taking a patient’s own T-cells and, outside the body, putting them through a cellular “boot camp” and training them to target a specific marker present on the cancer cell, but not normal cells. Those engineered T-cells are then administered back to the patient. Starting on August 30, 2017, the University of Pennsylvania (UPenn) and the Children’s Hospital of Philadelphia (CHOP) officially announced that the pioneering studies done at both institutions led to the first-ever cancer cell and gene therapy approval by the FDA. The approval was given to Novartis for Kymriah(TM) (formerly CTL019) to treat pediatric patients up to the age of 25 for B-cell precursor acute lymphoblastic leukemia (ALL). The T-cells in this therapy are primed and expanded to target cancer cells positive for a protein called CD19 present on the cancerous lymphocytes. Early-stage clinical trials observed more than 90% of patients achieving complete remission, leading to a global trial in 2015 that included 68 children and young adults with advanced ALL all over the world. After a single dose of their own engineered T-cells, a remarkable 83% of patients achieved complete remission. According to the investigators at UPenn’s Perelman School of Medicine and CHOP, in collaboration with Novartis, this marks a milestone for the treatment of younger patients with aggressive blood cancer.
On December 13, 2017, Capricor Therapeutics (NASDAQ: CAPR) announced that the U.S. Patent and Trademark Office has issued U.S. Patent 9,828,603, which includes composition of matter claims covering cardiosphere-derived cell exosomes. This patent, entitled “Exosomes and Micro-ribonucleic Acids for Tissue Regeneration,” is expected to run until at least 2033. Exosomes are nano-sized, membrane-enclosed vesicles that are secreted by cells and contain bioactive molecules, including proteins, RNAs, and microRNAs. They act as messengers to regulate cellular function. Their size, ease of crossing cell membranes, and ability to communicate in native cellular language makes them an exciting class of potential therapeutic agents. CAP-2003 comprises exosomes isolated from the company’s proprietary cardiosphere-derived cells and is being developed as a potential next-generation therapeutic for diseases of fibrosis and inflammation. “The issuance of this patent is an important milestone as Capricor plans to extend the scope of its clinical programs to the development of CAP-2003, which has demonstrated the ability to profoundly modulate the immune response, decrease inflammation, and stimulate cell growth in a variety of disease models,” said Linda Marbán, PhD, Capricor’s President and CEO. “Capricor plans to initially develop CAP-2003 for hypoplastic left heart syndrome, a congenital heart defect that affects about 960 newborns in the U.S. each year and is associated with high rates of mortality and heart failure secondary to the condition.
A new study shows that attaching antibody-like RNA nanoparticles to extracellular microvesicles can deliver effective RNA therapeutics such as small interfering RNA (siRNA) specifically to cancer cells. Researchers used RNA nanotechnology to apply the RNA nanoparticles and control their orientation to produce microscopic, therapy-loaded extracellular microvesicles that successfully targeted three types of cancer in animal models. The findings, reported online on December 11, 2017 in Nature Nanotechnology, could lead to a new generation of anticancer drugs that use siRNA, microRNA, and other RNA-interference technologies. The article is titled “Nanoparticle Orientation to Control RNA Loading and Ligand Display on Extracellular Vesicles for Cancer Regression.” The study was led by researchers at Ohio State’s College of Pharmacy and at the Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James). “Therapies that use siRNA and RNA interference technologies are poised to transform cancer therapy,” says the principal investigator Peixuan Guo (photo), PhD, Sylvan G. Frank Endowed Chair Professor of the College of Pharmacy and a member of the OSUCCC – James Translational Therapeutics Program. “But clinical trials evaluating these agents have failed one after another due to the inability to deliver the agents directly to cancer cells in the human body.” Dr. Guo noted that even when agents did reach and enter cancer cells, they were trapped in internal vesicles called endosomes and rendered ineffective.
Researchers at the Dana-Farber Cancer Institute (DFCI) in Boston have carried out the largest genomic analysis of patients with smoldering multiple myeloma (SMM), a precursor to full-blown blood cancer that doesn’t show outward symptoms. The next-generation sequencing project “will help to explain the biology of the disease and how it unfolds through time from asymptomatic stages to symptomatic ones,” said Mark Bustoros, MD, a postdoctoral fellow in the lab of Irene Ghobrial, MD, at DFCI. “This research also will help us to understand which patients with SMM are at a high risk of progression, and eventually how we can target early stages of the disease, so that we don’t wait to treat them until the cancer cells are spread everywhere in the body and cause major organ damage,” said Dr. Bustoros, who presented results of the study at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta (December 9-12, 2017). The title of his presentation was “Next Generation Sequencing Identifies Smoldering Multiple Myeloma Patients with a High Risk of Disease Progression” (see link below). The scientists, led by Dr. Ghobrial, sequenced 186 bone marrow biopsies from patients with SMM, some of whom progressed to multiple myeloma and some of whom did not. The scientists then matched up the genomic data with standard analyses of risks of progression provided by current non-genetic clinical biomarkers. “We found that mutations were more frequent in the high-risk group of patients with SMM,” Dr. Bustoros said. “We also found that certain mutations that are known to be drivers for cancer progression were more enriched in that group.” Many of the mutations were among genes in the MAPK and NF-kB molecular pathways, while others were MYC gene aberrations that are known to be altered in multiple myeloma.
Although people with multiple myeloma usually respond well to treatment, the blood cancer generally keeps coming back. Following genetic changes in how the disease evolves over time will help tscientists/physicians to understand the disease and, eventually, deliver more effective treatments. Researchers have now successfully demonstrated techniques to track these alterations over time by analyzing cell-free DNA (cfDNA) found in blood, according to Jens Lohr, MD, PhD, a hematologist and oncologist at the Dana-Farber Cancer Institute in Boston. Traditionally, multiple myeloma progress is monitored by painful and invasive bone marrow biopsies, but those biopsies are impractical to perform repeatedly, said Dr. Lohr, who presented study results at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta (December 9-12, 2017). The title of Dr. Lohr’s presentation was “Genomic Discovery and Clonal Tracking in Multiple Myeloma by Cell Free DNA Sequencing” (see link below). “We asked if you could get equivalent genetic information by monitoring cell-free DNA,” he said. “The short answer is yes, in principle, all this information actually is in the blood.” The scientists began by performing whole genome sequencing of 110 blood samples from 75 randomly selected multiple myeloma patients for cfDNA, and used the resulting data to predict the utility of deeper whole exome sequencing of the cfDNA. They also obtained cfDNA, matched normal blood cells, and bone marrow myeloma cells from ten myeloma patients at the same time point, and demonstrated that cfDNA whole exome sequencing robustly identified genetic mutations and these mutations matched up well with those found in sequencing bone marrow cells. The vast majority of clonal mutations and copy number variations in the bone marrow were also identified in cfDNA.