Scientists at Cold Spring Harbor Laboratory (CSHL) today report a discovery that they hope will lead to the development of a powerful new way of treating an aggressive form of breast cancer.
The breast cancer subtype in question is commonly called "HER2-positive"; it's a subset of the disease affecting about one patient in four, in which tumor cells overexpress a signaling protein called HER2.
The blockbuster drug Herceptin is a treatment of choice for many women with HER2-positive breast cancer, but in most cases, resistance to the treatment develops within several years. The prognosis for HER2-positive breast cancer patients is worse than for those with other subtypes of the illness.
In a paper appearing online today in Nature Chemical Biology, a multi-institution team led by CSHL Professor Nicholas Tonks reports that it has found a means of inhibiting another protein, called PTP1B, whose expression is also upregulated in HER2-positive breast cancer. PTP1B has been shown to play a critical role in the development of tumors in which HER2 signaling is aberrant.
When they treated mice modeling HER2-positive breast cancer with a PTP1B inhibitor called MSI-1436 (also called trodusquemine), Tonks and colleagues inhibited signaling by HER2 proteins.
"The result was an extensive inhibition of tumor growth and prevention of metastasis to the lung in HER2-positive animal models of breast cancer," notes Navasona Krishnan, Ph.D., a postdoctoral investigator in the Tonks lab who performed many of the experiments and is lead author on the paper reporting the results.
Dr. Tonks discovered PTP1B some 25 years ago. It is an enzyme – one in a "superfamily" of 105 called protein tyrosine phosphatases (PTPs) -- that perform the essential biochemical task of removing phosphate groups from amino acids called tyrosines in other proteins. Adding and removing phosphate groups is one of the means by which signals are sent among proteins.
PTP1B for many years has been a target of interest among drug developers. It is well known to be a negative regulator of insulin – an antagonist of insulin signaling -- and of signaling by leptin, the hormone that helps regulate appetite. Drugs that can block or inhibit the action of PTP1B have great potential in controlling diabetes and obesity. Yet properties of the molecule -- involving both its charged active binding site and its shape – have stymied potential developers of inhibitory drugs.
The new paper by Tonks and collaborators importantly reveals an alternative binding site, called an allosteric site, that does not present the biochemical difficulties that the active, or "catalytic," binding site does. This allosteric site is a target of the candidate drug trodusquemine.
Later this year early-stage human trials will begin for the drug, a collaboration of CSHL and North Shore-Long Island Jewish Hospital. Dr. Tonks and CSHL have interests in a joint venture called DepYmed Inc., in partnership with Ohr Pharmaceutical (NasdaqCM: OHRP). The venture seeks to develop trodusquemine and related analogs.
Funders for the research discussed in this release include: the National Institutes of Health, Cold Spring Harbor Laboratory Cancer Center, American Diabetes Association, Brown University Research Seed Fund, and Agence Nationale de Researche.
"Targeting the disordered C terminus of PTP1B with an allosteric inhibitor" appears online ahead of print Sunday, May 18, 2014 in Nature Chemical Biology. The authors are: Navasona Krishnan, Dorothy Koveal, Daniel H. Miller, Bin Xue, Sai Dipikaa Akshinthala, Jaka Kragelj, Malene Ringkjobing Jensen, Carla-Maria Gauss, Rebecca Page, Martin Blackledge, Senthil K. Musthuswamy, Wolfgang Peti and Nicholas K. Tonks. the paper can be obtained at: http://www.nature.com/nchembio/journal/vaop/ncurrent/index.html
About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for the impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 600 researchers and technicians strong and its Meetings & Courses program hosts more than 12,000 scientists from around the world each year to its Long Island campus and its China center. For more information, visit http://www.cshl.edu.
Peter Tarr | Eurek Alert!
Custom-tailored strategy against glioblastomas
26.09.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn
New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology
The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.
“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...
With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.
Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...
For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.
Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...
At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.
In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...
Every three years, the plastics industry gathers at K, the international trade fair for plastics and rubber in Düsseldorf. The Fraunhofer Institute for Laser Technology ILT will also be attending again and presenting many innovative technologies, such as for joining plastics and metals using ultrashort pulse lasers. From October 19 to 26, you can find the Fraunhofer ILT at the joint Fraunhofer booth SC01 in Hall 7.
K is the world’s largest trade fair for the plastics and rubber industry. As in previous years, the organizers are expecting 3,000 exhibitors and more than...
23.09.2016 | Event News
20.09.2016 | Event News
16.09.2016 | Event News
26.09.2016 | Materials Sciences
26.09.2016 | Materials Sciences
26.09.2016 | Materials Sciences