The work, a collaboration between the Institute for Molecular Medicine, the Department of Molecular and Medical Pharmacology and the cancer center’s Sarcoma Program, could lead to the development of new therapies that target the cell signaling pathway regulated by PTEN.
A novel mouse model of neurofibromatosis type 1 (NF1) developed at UCLA first illustrated the importance of PTEN tumor suppressor in malignant transformation and this finding was validated in human malignant peripheral nerve sheath tumors, the deadly sarcomas.
The study will be published this week in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.
“The loss of expression of PTEN in the human sarcomas we studied mirrored the loss of PTEN in mice, and we anticipate being able to target this pathway abnormality for the development of new methods of diagnosis and treatment” said Dr. Fritz Eilber, director of the Sarcoma Program and an assistant professor of surgical oncology. “Within the sarcoma world, malignant peripheral nerve sheath tumors are one of the most lethal sub-types, so this is a significant finding and may lead to new and more effective treatments.”
NF1 is one of the most common genetically inherited disorders, with an incidence of about 1 in every 2,500 births, said, Dr. Hong Wu, associate director of the molecular medicine institute, a Jonsson Cancer Center researcher and senior author of the study.
“Patients with NF1 have an about 10 percent lifetime risk of developing this lethal sarcoma sub-type,” Wu said.
The study also showed that Positron Emission Tomography (PET) scanning with the glucose analogue FDG - both in the mice and in humans - is a highly accurate way to distinguish between the benign tumors and the malignant ones, indicating that this non-invasive imaging technology is valuable in assessing therapeutic response to new treatments.
Wu created the mouse model with two of her graduate students, Caroline Gregorian and Jonathan Nakashima, co-first authors of this paper. It was created by altering two cell signaling pathways that are commonly activated in peripheral and central nervous system cancers, the RAS/RAF/MAPK & PTEN/P13K/AKT pathways, known to regulate cell proliferation, survival and differentiation.
“When we began to generate mouse models to mimic different human cancers, we usually did gene-based analysis to see the relevance of a specific gene in the development of the cancer,” Wu said. “But we realize that sometimes targeting the cell signaling pathways that organize and instruct cells to function, both for normal functions of our body and also in abnormal ways in disease, are more important and informative than the individual gene”
The mouse model developed benign neurofibromas, but then progressed to the deadly sub-type of sarcoma. The neurofibromas had half the normal levels of PTEN and the sarcomas had a complete loss of PTEN. Since PTEN is an important factor in suppressing cells from becoming malignant, this could provide an explanation for the sequence of the normal cells transforming into benign neurofibromas that could then transform into cancer.
Wondering if this was also the case in people, Dr. Wu collaborated with Eilber and pathologist Dr. Sarah Dry, director of the Institute of Molecular Medicine’s Pathway Pathology Center, and a multidisciplinary team of physician-scientists to determine if people with this sarcoma sub-type also had little or no PTEN.
“This type of collaboration is the hallmark of the work at the Jonsson Cancer Center and molecular medicine institute - translating discoveries in a basic science lab into discoveries in patients,” Wu said.
Currently, there are no effective treatments to prevent the benign NF1 tumors from transforming into cancer. The genetically engineered mouse model will be used to screen drugs that may be able to target the signaling pathway regulated by PTEN, to block signals that instruct the cells to change from a benign state to a malignant one, providing treatment options for patients with the deadly form of cancer.
“I think these findings will help us provide a better diagnosis that can determine if the neurofibroma is becoming a malignant tumor or not,” Eilber said. “But more importantly, the loss of the PTEN and its associated signaling pathways gives us targets for therapy and it may lay the foundation for treatment in other sarcomas as well.”
Also involved in the research were Dr. Paul Mischel, Dr. Simin Liu, Dr. Phioanh Leia Nghiemphu, Dr. Greg Lawson, Dr. Michael Sofroniew and Dr. Michael Phelps, director of the molecular medicine institute and creator of the PET scanner
The study was funded by the United States Department of Health and Human Services, the National Cancer Institute, the National Institutes of Health, UCLA’s Jonsson Comprehensive Cancer Center, the American Cancer Society, the Brain Tumor Society, the Henry Singleton Brain Cancer Research Program and the James S. McDonnell Foundation.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2009, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 consecutive years.
Kim Irwin | Newswise Science News
Building a brain, cell by cell: Researchers make a mini neuron network (of two)
23.05.2018 | Institute of Industrial Science, The University of Tokyo
Research reveals how order first appears in liquid crystals
23.05.2018 | Brown University
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
23.05.2018 | Life Sciences
23.05.2018 | Life Sciences
23.05.2018 | Physics and Astronomy