March 2013 Archives

By Sarah Adai

136257_Shen_X.jpgActin is a protein that has been long known to work by linking itself into chains to form filaments. Providing rigidity to the cell, actin filaments are involved in a host of processes including muscle contraction, cell mobility and cell division. The protein does this job outside of the nucleus, in the cytoplasm.

When actin was first discovered in the cell's nucleus several decades ago, it was dismissed as a contaminant. But since then a growing list of studies have supported a nuclear role for the protein, and scientists have been stumped as to what exactly it's doing there.

At long last, one of actin's key nuclear functions was uncovered. The study was published this week in the Journal Nature Structural & Molecular Biology.

Senior author of the study Xuetong "Snow" Shen, Ph.D., associate professor in The University of Texas MD Anderson Cancer Center Department of Molecular Carcinogenesis, developed a unique model system to nail down actin's function in the nucleus: the actin-containing INO80 chromatin remodeling complex in yeast cells.

"Our model system opened up a new opportunity to look in depth at the function of nuclear actin as it relates to gene regulation, genome stability, and ultimately cancer," Snow said.

The authors found that a mutant form of actin impairs the ability of INO80 to function correctly, implicating nuclear actin in the process of chromatin remodeling - a mechanism that helps regulate the expression of genes.

Cancer studies have increasingly focused on chromatin -- the intertwined proteins and DNA that are packaged into chromosomes -- because of its ability to regulate genes important for either activating or inhibiting tumorigenesis.

Surprisingly, Shen's lab found that actin inside the INO80 complex is arranged in such a way that it can't link up with itself to form filaments. Instead, the protein functions singly, as a monomer.

"Our study challenges the dogma that actin functions through polymerization, revealing a novel and likely a fundamental mechanism for monomeric nuclear actin," Shen said.


News Release:

New drugs are too slow getting to children with cancer

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By Michael Rytting and Sara Farris


101594_Rytting_M.jpgRecently, the U.S. Food and Drug Administration (FDA) approved the use of Gleevec in combination with chemotherapy to treat newly diagnosed children with Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL).


While this is good news, it comes more than 10 years after it was approved in adults and about 8 years after I treated my first pediatric patient with chemotherapy plus Gleevec followed by a stem cell transplant. This young patient came here from the Philippines with Ph+ ALL, and I was able to treat her 'off-label' since Gleevec had already been approved in adults and was well-tolerated. Today she is cured of cancer.


Historically, high-risk Ph+ ALL patients received chemotherapy and a stem cell transplant. However, in 2009, a study in the Journal of Clinical Oncology showed that the addition of Gleevec to chemotherapy increased the 3-year survival without relapse from 35% to 80.5%. In retrospect, perhaps my patient might not have needed the transplant (and its associated risks) to be cured of her cancer.


For the most part, this latest approval doesn't really change the therapy for children with this disease. In fact, we have already moved forward with enrolling patients on similar therapies in clinical trials that involve newer variations of Gleevec. The new drugs may be more effective or have fewer toxicities.


For years, scientists have crafted vaccines designed to treat cancer, rather than to prevent it, by priming the immune system to track down and kill tumors.

They identify antigens - distinctive targets - on tumors, combine them with substances (adjuvants) to enhance immune response, and then inject the vaccine to treat a given cancer.

A frustrating pattern emerged, says Willem Overwijk, Ph.D. associate professor in MD Anderson's Department of Melanoma Medical Oncology.  In both mouse experiments and human clinical trials, the vaccines created abundant T cells specialized to find the antigen and destroy cells that have it.

These T cells were easily observed in the bloodstream, yet there was little or no effect on tumors in the vast majority of cases.

Overwijk and colleagues decided to focus their attention on potential problems in the vaccine itself.  What they found, reported this week in Nature Medicine, could profoundly alter vaccine design and effectiveness.

"We discovered that only a few T cells actually get to the tumor, while many more are stuck or double back to the vaccination site," Overwijk says.



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