(Press-News.org) PHILADELPHIA — Inhibitors of indoleamine 2,3-dioxygenase (IDO) are being assessed in clinical trials as a potential treatment for recurrent or refractory solid tumors. Clear genetic rationale for these trials, together with evidence that primary and metastatic lung tumors might be particularly susceptible to the drugs, is now reported in a preclinical study published in Cancer Discovery, a journal of the American Association for Cancer Research.
"Our data provide preclinical genetic validation for the ongoing clinical trials testing IDO inhibitors in cancer patients," said Alexander Muller, Ph.D., associate professor at Lankenau Institute for Medical Research in Wynnewood, Pa. "We also believe that our results indicate that these drugs could have particular impact in patients with lung adenocarcinoma and lung metastases, conditions for which there is an urgent, unmet need for new therapeutic options."
The ongoing clinical trials were initiated based on pharmacological studies that indicated that IDO inhibitors can enhance the effectiveness of other therapies in mouse models of cancer. Genetic evidence to support the concept was lacking. Muller and his colleagues, therefore, set out to determine the effect of disrupting the IDO gene on tumor development in mice.
"It was very important to us to use models of disease as physiologically relevant as possible," he said. "We chose the KRAS-induced lung carcinoma model as our model of primary disease since tumors can be induced selectively in the lung and are driven by mutations in a gene known to be affected in approximately 20 percent of nonsmall cell lung cancers. We modeled metastatic disease using the 4T1 mouse breast cancer cell line, which very efficiently metastasizes to the lung after being engrafted in the mammary glands of mice. This is one of only a few breast cancer models with the capacity to metastasize efficiently to sites affected in human breast cancer patients."
Genetically-induced IDO deficiency reduced lung tumor burden and improved survival in both models.
"This genetic confirmation of the importance of IDO in lung tumor development is essential support for the clinical trials," said Muller. "However, we were also hoping to garner insight into the mechanisms by which IDO impacts tumor development. In this regard, our findings linking IDO to increased vascularization and modification of the inflammatory environment are critical. These data indicate that IDO has a far more expansive role in tumorigenesis than we might have thought."
Analysis of differences between the lungs of IDO-sufficient and -deficient tumor-bearing mice in the KRAS-induced lung carcinoma model revealed that levels of the pro-inflammatory molecule IL-6 were markedly lower in the absence of IDO. Levels of this known tumor-promoting factor were also lower in the model of metastasis when IDO was absent.
Additional work in the model of metastasis indicated that IDO-potentiated IL-6 production and promoted metastasis to the lung by driving the expansion and immunosuppressive function of a population of cells known as myeloid-derived suppressor cells (MDSCs). MDSCs are well-characterized, potent inhibitors of antitumor immune responses.
"It was very satisfying to be able to experimentally close the loop and clearly define a mechanism by which IDO promotes metastatic outgrowth to the lung, at least in the 4T1 breast cancer model," said Muller. "We think that this mechanism might also link with the vascular effects of IDO. IDO promotes tumorigenesis in many different ways, and we are looking to see if we can take clinical advantage of some of these."
Muller has financial interests in the clinical development of IDO inhibitors for the purpose of treating cancer and other diseases.
###
Follow the AACR on Twitter: @aacr #aacr
Follow the AACR on Facebook: http://www.facebook.com/aacr.org
About the AACR
Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR's membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
For more information about the AACR, visit www.AACR.org.
END
CHAMPAIGN, Ill. — A new study answers a question that has baffled researchers for more than 15 years: How does the western corn rootworm – an insect that thrives on corn but dies on soybeans – persist in fields that alternate between corn and soybeans? The answer, researchers say, has to do with enzyme production in the rootworm gut.
Their findings are described in a paper in Ecology and Evolution.
Crop rotation declined in the middle of the 20th century as the use of insecticides and fertilizers expanded in the U.S. Then in the 1950s and '60s, when some insecticides ...
NEW YORK, JULY 15, 2012 – Experts from the Comprehensive Center on Brain Aging at NYU Langone Medical Center will present new research at The 2012 Alzheimer's Association International Conference on Alzheimer's Disease to be held in Vancouver, British Columbia, Canada, July 14 – July 19.
From basic discovery to clinical applications, NYU Langone Medical Center has been at the forefront of the diagnosis and treatment of Alzheimer's disease since the 1970s. The Comprehensive Center on Brain Aging, founded upon the strengths of the Silberstein Alzheimer's Institute, is ...
Muscle contraction and many other movement processes are controlled by the interplay between myosin and actin filaments. Two further proteins, tropomyosin and troponin, regulate how myosin binds to actin. While theoretical models have in fact described exactly how these muscle proteins interact, this interaction has never previously been observed in detail. Stefan Raunser and Elmar Behrmann from the Max Planck Institute of Molecular Physiology in Dortmund have now managed to image the actin-myosin-tropomyosin complex with an unprecedented accuracy of 0.8 nanometres, which ...
STANFORD, Calif. — The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete — the only cells that become a child and through which parents pass on physical traits.
"This represents the culmination of nearly a decade of work in my lab," said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering ...
TORONTO, ON – Humans get most of the blame for climate change, with little attention paid to the contribution of other natural forces. Now, scientists from the University of Toronto and the University of California Santa Cruz are shedding light on one potential cause of the cooling trend of the past 45 million years that has everything to do with the chemistry of the world's oceans.
"Seawater chemistry is characterized by long phases of stability, which are interrupted by short intervals of rapid change," says Professor Ulrich Wortmann in the Department of Earth Sciences ...
ANN ARBOR, Mich.—Why do we age, and what makes some of us live longer than others? For decades, researchers have been trying to answer these questions by elucidating the molecular causes of aging.
One of the most popular theories is that the accumulation of oxygen radicals over time might be the underlying culprit in aging. Oxygen radicals are chemically reactive molecules that can damage cellular components such as lipids, proteins and nucleic acids, resulting in "oxidative stress."
The possible link between oxidative stress and aging has led to the proliferation ...
AMHERST, Mass. – Medical devices save countless lives, and increasingly functions such as data storage and wireless communication allow for individualized patient care and other advances. But after their recent study, an interdisciplinary team of medical researchers and computer scientists warn that federal regulators need to improve how they track security and privacy problems in medical devices.
Researchers from Beth Israel Deaconess Medical Center Harvard Medical School and the University of Massachusetts Amherst analyzed reports from decades of U.S. Food and Drug ...
Certain kinds of viruses such as those that cause the common cold, SARS, hepatitis, and encephalitis, copy themselves using a unique mechanism, according to a team of Penn State University scientists that includes David Boehr, an assistant professor of chemistry and a co-leader of the research team. The discovery sheds light on a previously identified, but never-before-understood region of an enzyme associated with the process of replicating genetic material. The research is an important step toward the improvement of existing vaccines, as well as toward the design of vaccines ...
Korean scientists have used tiny stars, squares and triangles as a toolkit to create live neural circuits in a dish.
They hope the shapes can be used to create a reproducible neural circuit model that could be used for learning and memory studies as well as drug screening applications; the shapes could also be integrated into the latest neural tissue scaffolds to aid the regeneration of neurons at injured sites in the body, such as the spinal cord.
Published today, 20 July, in IOP Publishing's Journal of Neural Engineering, the study, by researchers at the Korea Advanced ...
ANN ARBOR, Mich. — Breast cancer treatments such as Herceptin that target a marker called HER2 have dramatically improved outcomes for women with this type of cancer. But nearly half of these cancers are resistant to Herceptin from the start and almost all of them will eventually become resistant.
Now, researchers at the University of Michigan Comprehensive Cancer Center have discovered one reason why the cancer cells become resistant: They turn on a completely different pathway, one that is involved in inflammation, fueling the cancer independently of HER2.
The pathway ...
