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| Researchers find potential new therapeutic target for treating non-small cell lung cancer Posted: 14 Feb 2013 09:00 PM PST Researchers at Moffitt Cancer Center have found a potential targeted therapy for patients with tobacco-associated non-small cell lung cancer. It is based on the newly identified oncogene IKBKE, which helps regulate immune response.
The study appeared in the Feb. 13 online issue of Oncogene. The IKBKE gene is part of a family of enzyme complexes involved in increasing cellular inflammation. IKBKE overexpression has been associated with breast and prostate cancers. However, it had not been linked to environmental carcinogen, such as tobacco smoke, until now. Tobacco smoke is the strongest documented initiator and promoter of lung cancer. The traditional model holds that tobacco components promote carcinogenesis through a process that leads to DNA damage. Recent studies have shown that tobacco smoke can also promote lung cancer through changes in the pathways that regulate cell proliferation and survival. This study explored identifying and understanding one of the signaling pathways in order to find potential drug targets to treat non-small cell lung cancer. In this study, IKBKE was found to be induced by two tobacco carcinogens: nicotine and a nicotine-derived nitrosamine ketone found in tobacco smoke. Their findings suggest that IKBKE is a key molecule related to tobacco-induced lung cancer. “Since IKBKE kinase is induced by tobacco, small molecular inhibitors of IKBKE could have a therapeutic drug potential for lung cancer,” explained lead author Jin Q. Cheng, Ph.D., M.D., senior member of the Molecular Oncology Department at Moffitt. Current treatments for non-small cell lung cancer include surgery, radiotherapy and chemotherapy. However, patients eventually develop resistance to treatment. There is a great need to better understand the molecular mechanism of resistance and develop new gene-targeted therapies that can circumvent resistance, said the authors. In this study, the researchers also reported for the first time that IKBKE is a target of STAT3, a transcription factor that plays a key role in many cellular processes, such as cell growth and programmed cell death. According to the researchers, STAT3 is frequently activated in various types of human cancers and, when activated, STAT3 increases IKBKE overexpression and protein levels. In non-small cell lung cancer, nicotine-induced IKBKE depends on STAT3. The authors noted that the activation stage of STAT3 represents an attractive therapeutic potential because IKBKE is a STAT3 target. While IKBKE induces chemotherapy resistance, knocking down IKBKE sensitizes cancer cells to chemotherapy and reduces cancer cell survival. “Since the IKBKE kinase overexpression is induced by tobacco smoke and IKBKE levels increase in response to nicotine and nicotine-derived nitrosamine ketone, this evidence can be potentially used to develop a non-small cell lung cancer intervention strategy that targets IKBKE,” concluded Cheng. ### The work was supported by National Cancer Institute Grants CA137041 and P50 CA119997 and James & Esther King Biomedical Research Program 1KG02, 1KD04, and 1KN08. About Moffitt Cancer Center Located in Tampa, Moffitt is one of only 41 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s excellence in research, its contributions to clinical trials, prevention and cancer control. Since 1999, Moffitt has been listed in U.S. News & World Report as one of “America’s Best Hospitals” for cancer. With more than 4,200 employees, Moffitt has an economic impact on the state of nearly $2 billion. For more information, visit MOFFITT.org, and follow the Moffitt momentum on Facebook, twitter and YouTube. Media release by Florida Science Communications Contact: Kim Polacek |
| Scientists find promising new approach to preventing progression of breast cancer Posted: 14 Feb 2013 09:00 PM PST Doctors currently struggle to determine whether a breast tumor is likely to shift into an aggressive, life-threatening mode?an issue with profound implications for treatment. Now a group from The Scripps Research Institute (TSRI) has identified a mechanism through which mitochondria, the powerhouses of a cell, control tumor aggressiveness. Based on their findings, the team developed a simple treatment that inhibits cancer progression and prolongs life when tested in mice.
The research team, which describes its results February 15, 2013, in an article published online ahead of print by The Journal of Clinical Investigation, hopes to proceed quickly to human clinical trials to test this new approach using drugs already in use for other conditions. Looking at Clues The TSRI laboratory of Associate Professor Brunhilde H. Felding studies cancer, especially the mechanisms that control metastasis, the spread of cancer from its primary site to distant organs in the body. Past research suggested that mutations affecting mitochondria, which are key to energy production in cells, strongly influence whether a tumor becomes aggressive. But the mechanism was not clear. “We decided to investigate a specific protein complex, called mitochondrial complex I, that critically determines the energy output of cellular respiration,” said the study’s first author, Antonio F. Santidrian, a research associate in Felding’s laboratory. To do this, the group teamed up with Akemi and Takao Yagi at TSRI, who are leading experts in complex I research. Using unique reagents from the Yagi group, the Felding team discovered that the balance of key metabolic cofactors processed by complex I?specifically, nicotinamide adenine dinucleotide (NAD+) and NADH, the form it takes after accepting a key electron in the energy production cycle?was disturbed in aggressive breast cancer cells. Exciting Results To find out if the balance of NAD+ and NADH was critical for tumor cell behavior, the team proceeded to insert a yeast gene into cancer cells that caused a shift toward more NAD+. To the scientists’ amazement, this shift caused the tumor cells to become less aggressive. “It was a really happy moment for me,” said Santidrian. But the more exciting moments, he said, were yet to come. To confirm and extend the initial findings, the team altered genes tied to NAD+ production. The resulting shift again showed that higher NADH levels meant more aggressive tumors, while increased NAD+ had the opposite effect. The next logical step was to find a simple way to enhance the critical NAD+ level therapeutically. So the team explored what would happen if mice with breast cancer were fed water spiked with nicotinamide, a precursor for NAD+ production. The scientists found cancer development was dramatically slowed down, and the mice lived longer “In animal models at various stages, we see that we can actually prevent progression of the disease,” said Felding. Next Steps Now the group is working toward human trials to learn whether nicotinamide or other NAD+ precursors will have similarly impressive results in humans. Since NAD+ precursors are already used for other purposes, such as controlling cholesterol levels, achieving approval for human clinical trials should be simpler than is normally the case. “It is not a totally new treatment that would need to be tested for toxicity and side effects like a new drug,” said Felding. “And we already know the precursors can be easily ingested.” If manipulating the NAD+/NADH ratio in humans has the same effect as in mice, the results could be profound. Such treatment could benefit people at risk of developing aggressive breast cancer, offer complimentary treatment to chemo and radiation therapy to avoid disease recurrence, and maybe even provide a preventive treatment for women with a family history of breast cancer. ### This research was funded by grants from the National Institutes of Health (R01CA112287, R01CA170737, R01CA170140, UL1RR025774 and R01DK053244), the US Department of Defense (W81XWH-08-0468), the California Breast Cancer Research Program (17NB-0058, 16IB-0052, 12NB-0176 and 13NB-0180), and the Susan G. Komen Foundation, as well as a donation from Las Patronas. In addition to Santidrian and Felding, authors of the paper, titled, “Mitochondrial Complex I activity and NAD+/NADH balance regulate breast cancer progression,” were Akemi Matsuno-Yagi, Melissa Ritland, Byoung B. Seo, Sarah E. LeBoeuf, Laurie Gay, and Takao Yagi, all from TSRI. Contact: Mika Ono |
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