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Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.
Published in Cancer, it was a clever example of number crunching, using data from the Veteransâ€™ Administration. If you want to know about the anticancer effects of a widely used drug, check whoâ€™s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate â€“ OR a drug that works with a similar mechanism â€“ might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.
However, any examination of valproate should take into account neurologist Kim Meadorâ€™s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.
Thereâ€™s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.
Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.
In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.
With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from â€“ that is, which histone deacetylase in particular is responsible â€“ find a more specific drug, and avoid potential broad side effects.
Posted on April 1, 2014 by
I have a super huge, somewhat tattered, and quite ugly suitcase that sits in my office. Â This suitcase is not packed with clothes or extra large toiletries, but contains a pretty cool microscope, computer, and some shipping foam. Every few weeks I wheel it into the hallway, then into the elevator, and eventually into my car. The suitcase and I end up in Kindergarten-12th grade classrooms where I try to teach children something about science that they would not normally see. Â I try to give them something different, something real, something scientific. I have seen over 3,000 children in about 200 classrooms in rural and urban schools, from pre-K to 12th grade…
We had a post in October about his lab’s research investigating Withania somnifera, a root used in Indian traditional medicine that contains potential tools for stopping breast cancer invasion and metastasis. Marcus’ blog has a collection of microscope movies, which we hope he will keep current.
Posted on March 21, 2014 by
This is a continuation of the post from last week on the early-onset epilepsy patient, whom doctors were able to devise an individualized treatment for. The treatment was based on Emory research on the molecular effects of a mutation in the patientâ€™s GRIN2A gene, discovered through whole exome sequencing.*
For this patient, investigators were able to find the Ray Ban Baratas cause for a previously difficult to diagnose case, and then use a medication usually used for Alzheimerâ€™s disease (memantine) to reduce his seizure frequency.
Last week, I posed the question: how often do we move from a disease-causing mutation to tailored treatment? Read more
Posted on March 3, 2014 by
Peng Jin and collaborators led by Da-Hua Chen from the Institute of Zoology, Chinese Academy of Sciences have a new paper in Stem Cell Reports. They describe a souped-up method for producing iPS cells (induced pluripotent stem cells).
Production of iPS cells in the laboratory is becoming more widespread. Many investigators, including those at Emory, are using the technology to establish â€œdisease in a dishâ€ models and derive iPS cells from patient donations, turning them into tools for personalized medicine research.
Posted on February 27, 2014 by
Just a note for Atlanta-area readers about two interesting lecture series.
One is the Suddath Symposium, a two-day event today and Friday at Georgia Tech focusing on DNA repair in human disease.Â This is an area that Emory is strong in: Gray Crouse, Paul Doetsch, Willian Dynan and Gang Bao are speaking (all on Friday).
Another is a series of talks from Emory investigators on http://www.raybani.com/ complex neurological diseases, being put on by the Department of Cell Biology.Â Four, one a week (originally), all on Wednesdays at 4 pm in Whitehead 400.
Yesterday: Peter Wenner (homeostatic mechanisms/scaling). Feb. 26: Shannon Gourley (stress hormones/distorted decision-making/depression). March 5: Andrew Escayg (sodium channels/inherited epilepsy).Â Kerry Ressler (fear learning/PTSD) was supposed to be last week but that was derailed by ice. So Ressler will speak Â on May 21, according to organizer Victor Faundez, who chose Picasso’s Guernica as the visual theme.
Posted on February 20, 2014 by
Wikipedia says that â€œherding catsâ€ refers to an attempt to control or organize a class of entities that are uncontrollable or chaotic.
Cancer cells certainly qualify as uncontrollable or chaotic, so the metaphor could apply to a recent Nature Materials paper from Georgia Tech and Emoryâ€™s Ravi Bellamkonda â€“ a member of Winship Cancer Institute.
Glioblastoma is the worst of the worst: the most common and the most aggressive form of brain tumor in adults. The tumors are known to invade healthy tissue and migrate along white matter tracts and blood vessels.Â Bellamkonda and his colleagues devised a strategy for luring glioblastoma cells out of the brain by offering the cells attractive nanofibers that the cells will Ray Ban outlet attempt to invade. When the cells arrive, they undergo apoptosis — cellular suicide. He has called this â€œan engineerâ€™s approach to brain cancerâ€ (in a lecture a couple months ago) and â€œthe Pied Piper approach” (in the video below).
(Itâ€™s not the first time Bellamkonda has unfurled dazzling technology against glioblastoma, developed with an Emory collaborator.)
Bellamkondaâ€™s collaborator this time,Â Tobey Macdonald, director of pediatric neuro-oncology at Childrenâ€™s Healthcare of Atlanta, is credited in the paper with coming up with the aspect of the strategy that was based on the molecule cyclopamine. This earlier story from CHOA provides more background on how the collaboration came together.
Cyclopamine is key to the “lure ’em out and kill ’em” strategy. Most high-grade brain tumors overproduce a protein called Sonic Hedgehog, spurring their growth. Cyclopamine is selectively toxic only to cells that are dependent on Sonic Hedgehog. Cyclopamine’s name comes from how it was discovered: through its teratogenic effects on sheep in Idaho that ate corn lily flowers.
Posted on February 17, 2014 by
Brain cancer doesnâ€™t have a purpose or intent. Itâ€™s just a derangement of molecular biology, cells that keep growing when theyâ€™re not supposed to.
But itâ€™s difficult not to think in terms of purpose or intent when looking at what cancers do.Â For example, Winship Cancer Institute scientists Abdessamad (Samad) Zerrouqi, Beata Pyrzynska, Dan Brat and Erwin Van Meir have a recent paper in Cancer Research examining how glioblastoma cells regulate the process of blood clotting.*
Blood clots, often in the legs, are a frequent occurrence in patients fighting glioblastoma, the most common and the most aggressive form of brain cancer.Â Zerrouqi and http://www.gooakley.com/ Van Meir show that a tumor suppressor gene (p14ARF) that is often mutated in glioblastoma stops them from activating blood clotting. Take away the gene and glioblastoma cells activate the clotting process more.
At first glance, a puzzle emerges: why would a cancer â€œwantâ€ to induce blood clots?Â Cancer cells often send out growth factors that stimulate the growth of new blood vesselsÂ (angiogenesis). The cells are growing fast, thus they need their own blood supply. Activating clotting seems contradictory: why build a new highway and then induce a traffic jam?
In a way, tumor cells are acting somewhat Nietzschean, blindly managing their own cheap oakley evolution according to the principle â€œWhatever doesnâ€™t kill me makes me stronger.â€
Blood clots lead to both destruction of the healthy and tumor tissue and hypoxia, a shortage of oxygen that drives more aggressiveness in the tumor. The clots create “micro-necroses” at the leading edge of the tumor that over time probably fuse and create a big central necrosis.
“The paradox is that the tumor kills itself and the normal brain, yet the capacity of doing this is the hallmark of the most malignant form of this tumor,” Van Meir says.
â€œThe advantage of tumoral thrombosis will be selection of cells to progress to higher aggressiveness: infiltrative,Â resistant to death with conventional Oakley Sunglasses cheap therapies, metabolically adapted to low levels of oxygen and nutrients,â€ Zerrouqi says. “At this stage, the tumor seems to have a clear deadly intent.”
A fragment of one of the proteins that cancer cells use to exert the clotting effect, called TFPI2, could be used to antagonize blood clotting Â therapeutically, they write in Cancer Research.Â The findings could also have implications for understanding the effects ofÂ current medications, such as the angiogenesis inhibitor bevacizumab, also known as Avastin.
*A paper by Van Meir and Dan Brat from 2005 is the top Google link under the search term â€œglioblastoma clotting.â€
Posted on January 29, 2014 by
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.
Of course, not every cancer research developmentÂ describedÂ as transformative inÂ the New York TimesÂ lives up to the hype. But the clinical trial results, reportedÂ in the New England Journal of Medicine, are solid enough that the researchers Kolata talks with think they are seeing “a moment in medical history when everything changed.”Â [Winship Cancer Institute’s John Kauh was a co-author on one of the 2012 NEJM papers.]
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
Posted on October 15, 2013 by