|
Lung cancer cells' survival gene seen as drug target
January 02, 2008One of the deadliest forms of cancer appears to carry a specific weakness.
When a key gene called 14-3-3zeta is silenced, lung cancer cells can't survive on their own, researchers have found.
The gene is a potential target for selective anti-cancer drugs, says Haian Fu, PhD, professor of pharmacology, hematology & oncology at Emory University School of Medicine and Emory Winship Cancer Institute.
The research results will be published the week of Dec. 24 in the Proceedings of the National Academy of Sciences (PNAS). The paper's first author is Zenggang Li, PhD, a postdoctoral fellow in Dr. Fu's laboratory.
Lung cancer kills more Americans annually than any other type of malignancy, according to the National Cancer Institute. Yet treatment options are very limited, Dr. Fu says.
"The recent trend towards targeted therapies requires us to understand the altered signaling pathways in the cell that allow cancer to develop," he says. "If you think about genes that are dysregulated in cancer as drivers or passengers, we want to find the drivers and then, aim for these drivers during drug discovery."
Dr. Fu and his collaborator, Fadlo Khuri, MD, deputy director of clinical and translational research at Emory Winship Cancer Institute, chose to focus on the gene 14-3-3zeta because it is activated in many lung tumors. In addition, recent research elsewhere shows that survival of lung cancer patients is worse if the gene is on overdrive in their tumors, Dr. Fu says.
14-3-3 genes are found in mammals, plants and fungi. In the human body, they come in seven flavors, each given a Greek letter. Scientists describe the proteins they encode as adaptors that clamp onto other proteins. The clamping function depends on whether the target protein is phosphorylated, a chemical switch that regulates processes such as cell division, growth, or death.
"We knew that 14-3-3 is important in controlling EGFR (epidermal growth factor receptor) signaling, which is a main pathway driving lung cancer," Dr. Fu says. A couple of recently introduced drugs that were shown to be effective against lung cancer target EGFR, he adds.
In the PNAS study, the authors used a technique called RNA interference to selectively silence the 14-3-3zeta gene. They found that when 14-3-3zeta is turned off, lung cancer cells become less able to form new tumor colonies in a laboratory test.
One of the most important properties of cancer cells is their ability to grow and survive without touching other cells or the polymers that connect them. While the authors found that the cells with 14-3-3zeta turned off do not grow more slowly, the cells are vulnerable to anoikis (Greek for homelessness), a form of cell death that happens when non-cancerous cells that are accustomed to growing in layers find themselves alone.
Further experiments showed that 14-3-3zeta regulates a set of proteins called the Bcl2 family that control programmed cell death, and its absence upsets the balance within the family.
"You can see how control of anoikis means 14-3-3zeta could play a critical role in cancer invasion and metastasis," Dr. Fu says. "The mechanistic question we still haven't answered is: what makes zeta unique so that it can't be replaced by the others."
The finding has implications beyond lung cancer, in that 14-3-3zeta is also activated in other forms of cancer such as breast and oral, he notes.
"Dr. Fu and his team's findings unmask the role of 14-3-3 zeta in the survival advantage of lung cancer cells and their dependence on it," Dr. Khuri says. "Targeting this critical molecule could lead to meaningful therapeutic progress."
Since 14-3-3zeta was identified as a promising target for drugs, Dr. Fu and his co-workers are making use of a robot-driven screening program at the Emory Chemical Biology Discovery Center to sort through thousands of chemicals that may disrupt its interactions specifically.
They hope to identify these compounds rapidly and move them from bench into clinic testing to benefit patients.
Emory University
The research results will be published the week of Dec. 24 in the Proceedings of the National Academy of Sciences (PNAS). The paper's first author is Zenggang Li, PhD, a postdoctoral fellow in Dr. Fu's laboratory.
Lung cancer kills more Americans annually than any other type of malignancy, according to the National Cancer Institute. Yet treatment options are very limited, Dr. Fu says.
"The recent trend towards targeted therapies requires us to understand the altered signaling pathways in the cell that allow cancer to develop," he says. "If you think about genes that are dysregulated in cancer as drivers or passengers, we want to find the drivers and then, aim for these drivers during drug discovery."
Dr. Fu and his collaborator, Fadlo Khuri, MD, deputy director of clinical and translational research at Emory Winship Cancer Institute, chose to focus on the gene 14-3-3zeta because it is activated in many lung tumors. In addition, recent research elsewhere shows that survival of lung cancer patients is worse if the gene is on overdrive in their tumors, Dr. Fu says.
14-3-3 genes are found in mammals, plants and fungi. In the human body, they come in seven flavors, each given a Greek letter. Scientists describe the proteins they encode as adaptors that clamp onto other proteins. The clamping function depends on whether the target protein is phosphorylated, a chemical switch that regulates processes such as cell division, growth, or death.
"We knew that 14-3-3 is important in controlling EGFR (epidermal growth factor receptor) signaling, which is a main pathway driving lung cancer," Dr. Fu says. A couple of recently introduced drugs that were shown to be effective against lung cancer target EGFR, he adds.
In the PNAS study, the authors used a technique called RNA interference to selectively silence the 14-3-3zeta gene. They found that when 14-3-3zeta is turned off, lung cancer cells become less able to form new tumor colonies in a laboratory test.
One of the most important properties of cancer cells is their ability to grow and survive without touching other cells or the polymers that connect them. While the authors found that the cells with 14-3-3zeta turned off do not grow more slowly, the cells are vulnerable to anoikis (Greek for homelessness), a form of cell death that happens when non-cancerous cells that are accustomed to growing in layers find themselves alone.
Further experiments showed that 14-3-3zeta regulates a set of proteins called the Bcl2 family that control programmed cell death, and its absence upsets the balance within the family.
"You can see how control of anoikis means 14-3-3zeta could play a critical role in cancer invasion and metastasis," Dr. Fu says. "The mechanistic question we still haven't answered is: what makes zeta unique so that it can't be replaced by the others."
The finding has implications beyond lung cancer, in that 14-3-3zeta is also activated in other forms of cancer such as breast and oral, he notes.
"Dr. Fu and his team's findings unmask the role of 14-3-3 zeta in the survival advantage of lung cancer cells and their dependence on it," Dr. Khuri says. "Targeting this critical molecule could lead to meaningful therapeutic progress."
Since 14-3-3zeta was identified as a promising target for drugs, Dr. Fu and his co-workers are making use of a robot-driven screening program at the Emory Chemical Biology Discovery Center to sort through thousands of chemicals that may disrupt its interactions specifically.
They hope to identify these compounds rapidly and move them from bench into clinic testing to benefit patients.
Emory University
Lung Cancer News and Current Lung Cancer Events RSSCelebrex shows benefit in first-of-its-kind lung cancer chemoprevention trial
Celecoxib, the anti-inflammatory medication also known by the trade name Celebrex, has proven to be safe and reduces a specific proliferation measurement of precancerous lesions in the lung, according to a study from The University of Texas M. D. Anderson Cancer Center.
Cancer patients' quality of life directly relates to their survival
Patients who feel better live longer, say Mayo Clinic researchers, working with the North Central Cancer Treatment Group (NCCTG), in study results released May 15 as part of the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO).
Tooth loss strongly linked to risk of esophageal, head and neck, and lung cancer
Studying thousands of patients, Japanese researchers have found a strong link between tooth loss and increased risk of three cancers - esophageal, head and neck, and lung. They suggest that preservation of teeth may decrease risk of developing these diseases.
OHSU Cancer Institute researchers pinpoint how smoking causes cancer
Oregon Health & Science University Cancer Institute researchers have pinpointed the protein that can lead to genetic changes that cause lung cancer.
Medical research should include more women participants and examine the role of gender in disease
Are the health needs of women adequately addressed by medical research as it is currently conducted? In the May issue of Mayo Clinic Proceedings, a team of Australian researchers and two cardiologists closely examine this question.
Immune system pathway identified to fight allergens, asthma
For the first time, researchers from the University of Pittsburgh School of Medicine have identified genetic components of dendritic cells that are key to asthma and allergy-related immune response malfunction.
Alcoholism is not just a 'man's disease' anymore
Cross-sectional studies, which collect information at a single point in time, generally find that young Americans report having more lifetime alcohol problems than older Americans, despite having had less time to develop these problems.
Synergistic growth inhibitory effect of herbal extracts against HCC and lung cancer cells
Several herbs with diversified pharmacological properties are known to be rich sources of chemical constituents that may have potential for the treatment of several human cancers. Data from the Department of Preclinical Science, Faculty of Medicine, Thammasat University, demonstrates that the growth inhibitory activity of doxorubicin or cisplatin, as single agents, may be modified in combination with emblic myrobalan or belleric myrobalan extracts and may be synergistically enhanced in some cases.
Researchers light up lungs to help diagnose disease
Researchers at the University of Sheffield have developed innovative technology which illuminates a person's lungs and helps clinicians identify if they are functioning correctly. The new technology could result in earlier diagnosis of emphysema and smoking related damage, as well as other lung conditions and diseases.
New genetic techniques to combat lung cancer
New results on genetic techniques that are helping doctors diagnose and treat lung cancer were released today at the 1st European Lung Cancer Conference jointly organized by the European Society for Medical Oncology (ESMO) and the International Association for the Study of Lung Cancer (IASLC) in Geneva, Switzerland.
More Lung Cancer News Articles
 | Lung Cancer: Myths, Facts, Choices--and Hope by Claudia I. Henschke, Peggy McCarthy, Sarah Wernick |
 | Surviving Cancer by Margie Levine |
 | How to Survive Lung Cancer - A Practical 12-Step Plan by Michael Lloyd |
 | Voices of Lung Cancer: The Healing Companion: Stories for Courage, Comfort and Strength (Voices Of series) |
 | 100 Questions & Answers About Lung Cancer (100 Questions & Answers about . . .) by Karen Parles, Joan H. Schiller |
 | Lung Cancer |
 | What to Eat if You Have Cancer by Daniella Chace, Maureen Keane, John A. Lung |
 | Lung Cancer: Making Sense of Diagnosis, Treatment, and Options by Lorraine Johnston |
 | Lung Cancer: Dana-Farber Cancer Institute Handbook (Dana-Farber Cancer Institute Handbooks) |
 | High-Resolution CT of the Lung by W. Richard Webb, Nestor L Müller, David P Naidich |
| © 2008 BrightSurf.com |