According to the National Cancer Institute, more than a third of all human cancers, including a high percentage of pancreas, lung and colon cancers are driven by mutations in a family of genes known as Ras. Ras has long been considered to be a target that does not respond to cancer treating drugs, but recent research suggests new possibilities. Investigators at Rutgers Cancer Institute of New Jersey have demonstrated that targeting a metabolic dependency downstream of Ras could provide therapeutic benefit to patients with Ras-driven lung cancers.
Activation of oncogenic Ras promotes tumor growth but also activates the cellular self-cannibalization process of autophagy that recycles intracellular components to help sustain that growth. In research published in the current online edition of Cancer Discovery (doi: 10.1158/2159-8290.CD-14-0363), senior author Eileen White, associate director for basic science at the Cancer Institute of New Jersey, and colleagues tested the consequence of removing the autophagy gene known as ATG7 from laboratory models with non-small-cell lung cancer. Their goal was to establish if systemic genetic inactivation of autophagy would have selective anti-tumor activity against Ras-driven lung cancers while sparing most normal tissues. If so, then this would provide evidence that therapeutically targeting autophagy would be a new approach to treat these cancers.
Their research showed that systemic loss of ATG7 caused loss of fat tissue and sensitivity to fasting, but few other damaging consequences to normal tissue in the short-term. In contrast to most normal tissues, switching off autophagy by deleting ATG7 was dramatically destructive to established non-small-cell lung cancers. This demonstrated that non-small-cell lung cancer selectively requires autophagy for tumor development and that therapeutically targeting autophagy may be an alternative to targeting Ras.
One of the challenges in administering cancer therapy is that the treatment designed to destroy the disease can also have a negative effect on healthy, normal tissue. "The anti-tumor activity seen in our study occurred prior to the destruction of normal tissue. This suggests that the action of selectively and deliberately blocking the autophagy process may have therapeutic benefit for non-small-cell lung cancer and other Ras-driven cancers," notes Dr. White, who is also a distinguished professor of molecular biology and biochemistry at Rutgers School of Arts and Sciences.
White and colleagues will work with other collaborators at the Cancer Institute to develop early-phase patient clinical trials based on the findings from this study in the near future.
- G. Karsli-Uzunbas, J. Y. Guo, S. Price, X. Teng, S. V. Laddha, S. Khor, N. Y. Kalaany, T. Jacks, C. S. Chan, J. D. Rabinowitz, E. White. Autophagy is Required for Glucose Homeostasis and Lung Tumor Maintenance. Cancer Discovery, 2014; DOI: 10.1158/2159-8290.CD-14-0363
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