Fatty liver disease has been a hot area for drug development recently. In Science Translational Medicine: blocking the recycling of bile acids can stop fat accumulation in the liver. Paper describes mice fed a high-fat, high-sugar diet, but clinical study Read more
Scientists at Winship Cancer Institute, Emory University have identified compounds that stop two elusive anticancer targets from working together. In addition to striking two birds with one stone, this research could expand the envelope of what is considered “druggable.”
Many of the proteins and genes that have critical roles in cancer cell growth and survival have been conventionally thought of as undruggable. That’s because they’re inside the cell and aren’t enzymes, for which chemists have well-developed sabotage strategies.
In a twist, the potential anticancer drugs described in Cancer Celldisable an interaction between a notorious cancer-driving protein, MDM2, and a RNA encoding a radiation-resistance factor, XIAP.
The compounds could be effective against several types of cancer, says senior author Muxiang Zhou, MD, professor of pediatrics (hematology/oncology) at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center.
In the paper, the compounds show activity against leukemia and neuroblastoma cells in culture and in mice, but a fraction of many other cancers, such as breast cancers (15 percent) and sarcoma (20 percent), show high levels of MDM2 and should be susceptible to them.
Scientists have devised a triple-stage â€œcluster bombâ€ system for delivering the chemotherapy drug cisplatin, via tiny nanoparticles designed to break up when they reach a tumor.
Details of the particlesâ€™ design and their potency against cancer in mice are described this week inÂ PNASÂ Early Edition.Â They have not been tested in humans, although similarÂ waysÂ ofÂ packaging cisplatinÂ have been in clinical trials.Â
What makes these particles distinctive is that they start out relatively large — 100 nanometers wide â€“ to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge â€œbombletsâ€ just 5 nanometers in size.
The PNAS paper is the result of a collaboration between a team led by professor Jun Wang, PhD at the University of Science and Technology of China, and researchers led by professor Shuming Nie, PhD inÂ the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Nie is a member of the Discovery and Developmental Therapeutics research program at Winship Cancer Institute of Emory University. The lead authors are graduate student Hong-Jun Li and postdoctoral fellows Jinzhi Du, PhD and Xiao-Jiao Du, PhD.
â€œThe negative side effects of cisplatin are a long-standing limitation for conventional chemotherapy,â€ says Jinzhi Du. â€œIn our study, the delivery system was able to improve tumor penetration to reach more cancer cells, as well as release the drugs specifically inside cancer cells through their size-transition property.â€
The researchers showed that their nanoparticles could enhance cisplatin drug accumulation in tumor tissues. When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery could restrainÂ the toxic side effects of cisplatin during cancer treatment. Read more
Koroshetz explained that neuroscience research is spread out among NINDS (National Institute for Neurological Disorders and Stroke), NIMH (National Institute of Mental Health), NIDA (National Institute for Drug Abuse) and several others, while cancer research is concentrated at the National Cancer Institute. [Hereâ€™s some official category tracking that the NIH does â€“ his breakdown checks out.]
Koroshetz highlighted a project from Dieter Jaeger and Garret Stanley that is part of the White Houseâ€™s BRAIN Initiative focused on mapping brain circuits and connectivity. He also noted NINDSâ€™s efforts in promoting translational research, since pharmaceutical companies were frustrated by repeated failures in the 1990s with difficult areas such as stroke, and the R35 mechanism for funding â€œoutstanding investigatorsâ€ for up to eight years continuously.
Earlier today, weÂ posted a notice on Eurekalert for a Sunday, December 13 presentation by graduate student Jessica Konen at theÂ American Society for Cell Biology meeting in San Diego.
Her research, performed with Adam Marcus at Winship Cancer Institute, was the topic of a video that recently won first prize in a contest sponsored by the Association of American Medical Colleges. ThisÂ was our video team’s first use of theÂ “fast hand on whiteboard” effect, and a lot of fun to make. The video’s strength growsÂ out of the footageÂ Konen and Marcus have of cancer cells migrating in culture. Check it out, if you haven’t already.
PosterÂ presentations at the 2015 ASCB meeting can be found by searching this PDF. A few Emory-centric highlights:
What do cancer cells have in common with horseshoe crabs and Mr. Spock from Star Trek?
They all depend upon copper. Horseshoe crabs have blue blood because they use copper to transport oxygen in their blood instead of iron (hemocyanin vs hemoglobin). Vulcansâ€™ blood was supposed to be green, for the same reason.
Horseshoe crabs and Vulcans use copper to transport oxygen in their blood. Cancer cells seem to need the metal more than otherÂ cells.
To be sure, all our cells need copper. Many human enzymes use the metal to catalyze important reactions, but cancer cells seem to need it more than healthy cells. Manipulating the bodyâ€™s flow of copper is emerging as an anticancer drug strategy.
A team of scientists from University of Chicago, Emory and Shanghai have developed compounds that interfere with copper transport inside cells. These compounds inhibit the growth of several types of cancer cells, with minimal effects on the growth of non-cancerous cells, the researchers report in Nature Chemistry.
â€œWeâ€™re taking a tactic that’s different fromÂ other approaches. These compounds actually cause copper to accumulate inside cells,â€ says co-senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. Read more
Parietin, shown to have anticancer activity in the laboratory, is a dominant pigment in Caloplaca lichens. Note: this study did not assess the effects of eating lichens or rhubarb. Photo courtesy of www.aphotofungi.com
Parietin, also known as physcion, could slow the growth of and kill human leukemia cells obtained directly from patients, without obvious toxicity to human blood cells, the authors report. The pigment could also inhibit the growth of human cancer cell lines, derived from lung and head and neck tumors, when grafted into mice.
A team of researchers led by Jing Chen, PhD, discovered the properties of parietin because they were looking for inhibitors for the metabolic enzyme 6PGD (6-phosphogluconate dehydrogenase). 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. Researchers have already found 6PGD enzyme activity increased in several types of cancer cells.
â€œThis is part of the Warburg effect, the distortion of cancer cellsâ€™ metabolism,â€ says Chen, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. â€œWe found that 6PGD is an important metabolic branch point in several types of cancer cells.â€ Read more
Evolutionary theory says mutations are blind and occur randomly. But in theÂ controversialÂ phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.
Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.
“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.
Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.
Retromutagenesis resolves the puzzle: if cells arenâ€™t growing because theyâ€™re under stress, which means their DNA isnâ€™t being copied, how do the new mutants appear?
The answer: a mutation appears in the RNA first. Read more
Several drugs now used to treat cancer and autoimmune diseases are actually repurposed tools derived from the immune system. One of the ways these “therapeutic antibodies” work is to grab onto malignant or inflammatory cells and escort them to their doom.
Emory researchers have found that in a mouse model of chronic viral infection, a kind of traffic pileup inside the body limits how effective therapeutic antibodies can be.
The results, published this week inÂ Immunity, have implications for biotechnology researchers who continue to refine antibodies for therapeutic purposes, as well as bolster our understanding of how chronic viral infections impair the immune system.
Researchers led by Rafi Ahmed, PhD, director of the Emory Vaccine Center, were studying mice infected by LCMV (lymphocytic choriomeningitis virus). They injected several antibodies with the goal of removing various types of immune cells from the mice. Â One end of the antibody molecule is supposed to bind the target cell, while another acts as a flag for other cells to get rid of the target cell.
However, during a chronic LCMV infection, the mouseâ€™s immune system is producing its own antibodies against the virus, which form complexes with viral proteins. These immune complexes prevented the injected antibodies from having the effect the scientists wanted, which was to deplete their target cells.
Excessive amounts of immune complexes appear to be â€œcloggingâ€ the Fc gamma receptors that immune cells would use to grab the antibodies bound to the target cell, says postdoctoral fellow Andreas Wieland, PhD, first author of theÂ ImmunityÂ paper. That these immune complexes form was not news; but how much they interfere with other antibodies was, Wieland says. Fc gamma receptors were already known to be important for antibodies to be effective against influenza and HIV. Read more
Gina Kolata has a section front story in Tuesday’s New York Times exploring the potential of a relatively new class of anticancer drugs. The drugs break through “shields” built by cancers to ward off the threat posed by the patient’s immune system. Many are based on blocking PD-1, an immune regulatory molecule whose importance in chronic infections was first defined by Emory’s Rafi Ahmed.
Let’s take a moment to examine some of the roots of this story.Â Rafi Ahmed didnâ€™t set out to study cancer. For the last two decades, he and his colleagues have been studying T cells, parts of the immune system that are critical for responding to infections. Read more
Biochemist Paul Doetschâ€™s recent appearance in a Science magazine feature on laboratory leadership led to a conversation with him about the challenges of graduate school.
He emphasized that scientific research is a team sport, and brilliance on the part of the lab head may not yield fruit without a productive relationship with the people in the lab. Doetsch suggested talking with Lydia Morris, a graduate student in the Genetics and Molecular Biology graduate program. Morris has been working in Doetsch’s lab for several years and is about to complete her degree. She has been examining the in vivo distribution of DNA repair proteins.
In this video, Morris and Doetsch talk about the differences between turn-the-crank and blue-sky projects, and the importance of backup projects, communications, high expectations and perseverance.