Ann Richmond, Ph.D., and colleagues at Vanderbilt-Ingram Cancer Center report that a signaling molecule, known as IKKâ, is essential for melanoma tumor development in a mouse model of the disease. The results, published June 7 in the Journal of Clinical Investigation, also point to ways of targeting therapies that inhibit IKKâ toward the patients most likely to benefit from them based on their genetic profile.
Melanoma is the deadliest form of skin cancer and incredibly difficult to treat successfully once the tumor has spread beyond the skin.
Prior studies have shown that the NF-êB signaling pathway – centered on the protein NF-êB, which regulates gene expression – is abnormally activated in tumor cells; the pathway is turned "on" constantly, even at times it should be turned "off." This activation often results from abnormal activation of another enzyme in the pathway, IKKâ.
Just how NF-êB contributes to tumor progression has been unclear. And with drugs that inhibit this pathway entering clinical trials, a clearer picture of its function in tumor progression is needed.
To better understand the role of this pathway – in particular, of IKKâ's role – Richmond's lab developed a mouse model that mimics the genetic alterations involved in melanoma development in humans.
Jinming Yang, Ph.D., a staff scientist in Richmond's lab, led the effort to generate these mice, which lack the tumor suppressor INK4a/ARF (commonly lost in melanomas) and have the Ras/Raf pathway activated (which is activated in about 70 percent of melanoma lesions).
The researchers then added the ability to "turn off" IKKâ only in melanocytes, the pigment-producing skin cells in which melanomas initiate, simply by treating the mice with an antibiotic.
Mice with normal IKKâ activity developed "loads and loads of melanoma tumors all over their bodies…on the tail, the ear, and anywhere melanocytes are," said Richmond, an Ingram Professor of Cancer Biology at Vanderbilt University Medical Center and a senior career research scientist with the Department of Veterans Affairs.
But mice in which IKKâ was "turned off" developed no melanoma tumors.
They also found that treating mice with normal IKKâ activity with small molecule inhibitors of the enzyme could inhibit the growth of melanoma lesions.
"This shows for the first time that you have to have IKKâ for Ras-induced melanoma, suggesting that there's a way to specifically target melanoma lesions," she said.
However, the experiments identified an important caveat: blocking IKKâ only seemed to protect against melanoma formation when another tumor suppressor, p53, is expressed.
Since mutations that disrupt p53 are sometimes found in melanomas, this suggests that therapies targeting IKKâ or the NF-êB pathway in general would need to be limited to tumors with normal p53.
Richmond cautions, "With NF-êB inhibitors entering clinical trials at this time, it is imperative that these data be taken into consideration for patient selection or evaluation of response in these trials."
Richmond is collaborating with Vanderbilt-Ingram Cancer Center investigators Mark Kelley, M.D., and Jeffrey Sosman, M.D., to identify, in human tumor samples, which tumors would respond to targeted inhibitors of the Ras/Raf and NF-êB pathways.
Such information could aid in diagnosis and "be used to deliver personalized medicine" to melanoma patients in the future, she said.
"We're passionate about (IKKâ inhibitors) possibly going forward, maybe not as a single agent, but in combination (treatments). As we are able to better predict which patients will respond to which drugs, there's real hope there."
Richmond is also a professor of Medicine in the Division of Dermatology. Other authors on the study include: Ryan Splittgerber, Ph.D., Fiona Yull, D.Phil., Sara Kantrow, Gregory Ayers from Vanderbilt, and Michael Karin, Ph.D., from the University of California San Diego. The research was supported by the Department of Veterans Affairs, the National Institutes of Health, the Skin Disease Research Center and the Vanderbilt-Ingram Cancer Center.
Dagny Stuart | EurekAlert!
Nanoparticles as a Solution against Antibiotic Resistance?
15.12.2017 | Friedrich-Schiller-Universität Jena
Plasmonic biosensors enable development of new easy-to-use health tests
14.12.2017 | Aalto University
DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.
Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...
MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.
Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
15.12.2017 | Power and Electrical Engineering
15.12.2017 | Materials Sciences
15.12.2017 | Life Sciences