Antibody Makes Alzheimer’s Protein Detectable in Blood

Antibodies to Tau

Caption: The protein tau (green) aggregates abnormally in a brain cell (blue). Tau spills out of the cell and enters the bloodstream (red). Research shows that antibodies (blue) can capture tau in the blood that reflect its levels in the  brain.
Credit: Sara Moser

Age can bring moments of forgetfulness. It can also bring concern that the forgetfulness might be a sign of early Alzheimer’s disease. For those who decide to have it checked out, doctors are likely to administer brief memory exams to assess the situation, and medical tests to search for causes of memory loss. Brain imaging and spinal taps can also help to look for signs of the disease. But an absolutely definitive diagnosis of Alzheimer’s disease is only possible today by examining a person’s brain postmortem. A need exists for a simple, less-invasive test to diagnose Alzheimer’s disease and similar neurodegenerative conditions in living people, perhaps even before memory loss becomes obvious.

One answer may lie in a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease and other “tauopathy” disorders. In recent years, researchers have been busy designing an antibody to target tau in hopes that this immunotherapy approach might slow or even reverse Alzheimer’s devastating symptoms, with promising early results in mice [1, 2]. Now, an NIH-funded research team that developed one such antibody have found it might also open the door to a simple blood test [3].

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NIH Researchers Recognized for Service to America

Steve Rosenberg

Caption: Steve Rosenberg receiving his Sammie as 2015 Federal Employee of the Year.
Credit: Aaron Clamage/clamagephoto.com

It was a pleasure for me last night to attend the Samuel J. Heyman Service to America Medals, also known as “the Sammies.” This Washington, D.C. event, now in its 12th year as the “Oscars of American government service,” was a big night for NIH. Steven Rosenberg, a highly regarded physician-scientist at NIH’s National Cancer Institute (NCI), took home the evening’s highest honor as the 2015 Federal Employee of the Year.

Also hearing their names called were NCI’s Jean Claude Zenklusen and Carolyn Hutter of NIH’s National Human Genome Research Institute (NHGRI). They received the inaugural People’s Choice Award. It marks the highest vote-getter from the general public, which was invited to choose from among this year’s 30 finalists in eight award categories.

Jean Claude Zenklusen and Carolyn Hutter

Caption: Francis Collins presenting 2015 People’s Choice Award medals to Jean Claude Zenklusen and Carolyn Hutter.
Credit: Aaron Clamage/clamagephoto.com

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Precision Oncology: Creating a Genomic Guide for Melanoma Therapy

Melanoma cell

Caption: Human malignant melanoma cell viewed through a fluorescent, laser-scanning confocal microscope. Invasive structures involved in metastasis appear as greenish-yellow dots, while actin (green) and vinculin (red) are components of the cell’s cytoskeleton.
Credit: Vira V. Artym, National Institute of Dental and Craniofacial Research, NIH

It’s still the case in most medical care systems that cancers are classified mainly by the type of tissue or part of the body in which they arose—lung, brain, breast, colon, pancreas, and so on. But a radical change is underway. Thanks to advances in scientific knowledge and DNA sequencing technology, researchers are identifying the molecular fingerprints of various cancers and using them to divide cancer’s once-broad categories into far more precise types and subtypes. They are also discovering that cancers that arise in totally different parts of the body can sometimes have a lot in common. Not only can molecular analysis refine diagnosis and provide new insights into what’s driving the growth of a specific tumor, it may also point to the treatment strategy with the greatest chance of helping a particular patient.

The latest cancer to undergo such rigorous, comprehensive molecular analysis is malignant melanoma. While melanoma can rarely arise in the eye and a few other parts of the body, this report focused on the more familiar “cutaneous melanoma,” a deadly and increasingly common form of skin cancer [1].  Reporting in the journal Cell [2], The Cancer Genome Atlas (TCGA) Network says it has identified four distinct molecular subtypes of melanoma. In addition, the NIH-funded network identified an immune signature that spans all four subtypes. Together, these achievements establish a much-needed framework that may guide decisions about which targeted drug, immunotherapy, or combination of therapies to try in an individual with melanoma.

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A Surprising Match: Cancer Immunotherapy and Mismatch Repair

Anti-PD-1 Immunotherapy

How Anti-PD-1 Immunotherapy Works. Before immunotherapy (top), the tumor cell’s PD-1 ligand, or PD-L1, molecule (red) binds to a type of white blood cell called a T-cell in a way that enables the tumor cell to evade destruction by the immune system. During immunotherapy (bottom), an anti-PD-1 inhibitor drug (bright green) blocks PD-L1 binding, enabling the T cell to target the tumor cell for destruction.
Credit: NIH

Mismatch repair genes have long been a source of fascination to basic biologists. Normally, these genes serve to fix the small glitches that occur when DNA is copied as cells divide. Most of the original work was done in bacteria, with no expectation of medical relevance. But, as often happens, basic science studies can provide a profoundly important foundation for advances in human health. The relevance of mismatch repair to cancer was dramatically revealed in 1993, when teams led by Bert Vogelstein of Johns Hopkins University School of Medicine, Baltimore, and Richard Kolodner, then of Harvard Medical School, Boston, discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer [1, 2].

That discovery has led to the ability to identify individuals who have inherited misspellings in these mismatch repair genes and are at high risk for colorectal cancer, providing an opportunity to personalize screening by starting colonoscopy at a very early age and, thereby, saving many lives. But now a new consequence of this work has appeared. Vogelstein and his colleagues report that mismatch repair research may help fight cancer in a way that few would have foreseen two decades ago: predicting which cancer patients are most likely to respond to a new class of immunotherapy drugs, called anti-programmed death 1 (PD-1) inhibitors.

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Knocking Out Melanoma: Does This Triple Combo Have What It Takes?

3-Way Knockout of MelanomaIt would be great if we could knock out cancer with a single punch. But the more we learn about cancer’s molecular complexities and the immune system’s response to tumors, the more it appears that we may need a precise combination of blows to defeat a patient’s cancer permanently, with no need for a later rematch. One cancer that provides us with a ringside seat on the powerful potential—and tough challenges—of targeted combination therapy is melanoma, especially the approximately 50% of advanced tumors with a specific “driver” mutation in the BRAF gene [1].

Drugs that target cells carrying BRAF mutations initially provided great hope for melanoma, with many reports of dramatic shrinkage of tumors in patients with advanced disease.  But almost invariably, the disease recurred and was no longer responsive to those same drugs.  A few years ago, researchers thought they’d come up with a solid combination to fight BRAF-mutant melanoma: a one-two punch that paired a BRAF-inhibiting drug with an agent that sensitized the immune system [2]. However, when that combo was tested in humans, the clinical trial had to be stopped early because of serious liver toxicity [3]. Now, in a mouse study published in Science Translational Medicine, NIH-funded researchers at the University of California, Los Angeles (UCLA) provide renewed hope for a safe, effective combination therapy for melanoma—with a strategy that adds a third drug to the mix [4].

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