Treatment strategies for several types of cancer have been transformed by the discovery of â€œtargeted therapies,â€ drugs directed specifically against the genetic mutations that drive tumor growth. So far, these strategies have been relatively unsuccessful when it comes to glioblastoma, the most common and most deadly form of brain tumor affecting adults. Glioblastoma was one of the first tumor types to be analyzed in the Cancer Genome Atlas mega-project, but many of the molecular features of glioblastoma have been difficult to exploit.
For example, about 40 percent of glioblastoma tumors ray ban baratas have extra copies of the EGFR (epidermal growth factor receptor) gene. EGFR provides a pedal-to-the-metal growth signal and is known to play a role in driving the growth of lung and colon cancers as well. But drugs targeted against EGFR that have extended patient survival in lung cancer have shown disappointing results with glioblastoma. The reason: the tumor cells can quickly mutate the EGFR gene or switch to reliance on other growth signals.
Keqiang Ye, PhD and colleagues recently described the discovery of a compound that may be valuable in fighting glioblastoma. The Emory researchers devised a scheme to stop tumor cells from using well-known escape routes to avoid EGFR-based drugs. Their results are published in the journal Science Signaling. Postdoctoral fellow Kunyan He, PhD, is the first author.
The compound they identified inhibits the enzyme JAK2, one of the apparent escape Ray Ban outlet routes taken by glioblastoma cells. The compound can pass the blood-brain barrier and inhibit glioblastoma growth while having low toxicity, the researchers report.
Pathologist Keqiang Ye and his colleagues have identified a new potential drug target in Alzheimerâ€™s disease. Itâ€™s called SRPK2 (serine-arginine protein kinase 2).
Keqiang Ye, PhD
Depleting this enzyme from the brain using genetic engineering tools alleviates cognitive impairment in an animal model of Alzheimerâ€™s. The result suggests that drugs Cheap Oakleys that target this enzyme could be valuable in the treatment of Alzheimerâ€™s, although additional studies on human brain samples are necessary to fully confirm the findings, Ye says.
The results were published Tuesday in Journal of Neuroscience. The first author is postdoctoral fellow Yi Hong.
Hong and colleagues found that SRPK2 has elevated activity in a mouse model of Alzheimerâ€™s. It acts on tau, one of the two major toxic clumpy proteins in Alzheimerâ€™s. (beta-amyloid is outside the cell and forms plaques, tau is inside and forms tangles). Previous research on SRPK2 indicated that it had something to do with RNA splicing, so its â€œentanglementâ€ with tau is a surprise.
Over the last few years, pathologist Keqiang Ye and his colleagues have displayed an uncanny talent for finding potentially useful medicinal compounds. Recently another example of this talent appeared in Journal of Biological Chemistry.
Keqiang Ye, PhD
Postdoctoral fellow Qi Qi is first author on the paper. Collaborators include Jeffrey Olson, Liya Wang, Hui Mao, Haian Fu, Suresh Ramalingam and Shi-Yong Sun at Emory and Paul Mischel at UCLA.
Qi and Ye were looking for compounds that could inhibit the growth of an especially aggressive form of brain cancer, glioblastoma with deletion in the tumor suppressor gene PTEN. Tumors with this deletion do not respond to currently available targeted therapies.
The researchers found that acridine yellow G, a fluorescent dye used to stain microscope slides, can inhibit the growth of this tumor:
Oral administration of this compound evidently decreases the tumor volumes in both subcutaneous and intracranial models and elongates the life span of brain tumor inoculated nude mice. It also displays potent antitumor effect against human lung cancers. Moreover, it significantly decreases cell proliferation and enhances apoptosis in tumors…
Optimization of this compound by improving its potency through medicinal chemistry modification might warrant a novel anticancer drug for malignant human cancers.
Ye’s team observed that acridine yellow G appears not to be toxic in rodents. However, the acridine family of compounds tends to intercalate (insert itself) into DNA and can promote DNA damage, so more toxicology studies are needed. Other acridine family compounds such as quinacrine have been used to treat bacterial infections and as antiinflammatory agents, they note.
A paramecium stained with acridine orange, which shows anticancer activity for tumors containing PTEN mutations
Earlier this year, the FDA put limitations on some anti-diabetic drugs because of their cardiovascular risks. The prevalence of diabetes in the United States continues to increase and is now above 8 percent of the population, so the need for effective therapies remains strong.
Keqiang Ye, PhD
Pathologist Keqiang Ye and colleagues have a paper in the Journal of Biological Chemistry describing their identification of a compound that mimics the action of insulin. This could be the starting point for developing new anti-diabetes drugs.
The new research is an extension of the Ye laboratoryâ€™s work on TrkA and TrkB, which are important for the response of neurons to growth factors. Ye and Sung-Wuk Jang, a remarkably productive postdoc who is now an assistant professor at Korea University, developed an assay that allowed them to screen drug libraries for compounds that directly activate TrkA and TrkB. This led them to find a family of growth-factor-mimicking compounds that could treat conditions such as Parkinsonâ€™s disease, depression and stroke.
Since TrkA/B and the insulin receptor are basically the same kind of molecule — receptor tyrosine kinases– and use some of the same cellular circuitry, Ye and Jangâ€™s assay could also be used with the insulin receptor. Kunyan He and Chi-Bun Chan are the first two authors on the new paper. They report that the compound DDN can make cells more sensitive to insulin and improve their ability to take up glucose. They show that DDN (5,8-diacetyloxy-2,3-dichloro-1,4- naphthoquinone) can lower blood sugar, both in standard laboratory mice and in obese mice that serve as a model for type II diabetes.
Ye reports that he and his colleagues are working with medicinal chemists to identify related compounds that may have improved efficacy and potency.
â€œI hope in the near future we may have something that could replace insulin for treating diabetes orally,â€ he says.
Posted on October 7, 2011
Pathologist Keqiang Ye has made a series of discoveries recently, arising from his investigations of substances that can mimic the growth factor BDNF (brain-derived neurotrophic factor).
BDNF is a protein produced by the brain that pushes neurons to withstand stress and make new connections. Some neuroscientists have described BDNF as “Miracle Gro for brain cells.”
â€œBDNF has been studied extensively for its ability to protect neurons vulnerable to degeneration in several diseases, such as ALS, Parkinsonâ€™s and Alzheimerâ€™s disease,â€ Ye says. â€œThe trouble with BDNF is one of delivery. Itâ€™s a protein, so it canâ€™t cross the blood-brain barrier and degrades quickly.â€
Working with Ye, postdoctoral fellow Sung-Wuk Jang identified a compound called 7,8-dihydroxyflavone that can duplicate BDNFâ€™s effects on neurons and can protect them against damage in animal models of seizure, stroke and Parkinsonâ€™s disease. The compoundâ€™s selective effects suggest that it could be the founder of a new class of brain-protecting drugs. The results were published in Proceedings of the National Academy of Sciences.