The latest research shows that continuous inactivation of the p53 tumor suppressor pathway is also required to maintain tumors in later stages of cancer. “This suggests that targeted therapies that act to reactivate tumor suppressors may be an effective new strategy to treat resistant cancers,” said Scott Lowe, Howard Hughes Medical Institute Investigator and Deputy Director of the Cold Spring Harbor Laboratory (CSHL) Cancer Center.
Using three distinct approaches in mouse models, Scott Lowe's group at CSHL, Tyler Jacks' lab at the Massachusetts Institute of Technology (MIT), and Gerald Evans' group at the University of California at San Francisco (UCSF) showed that reactivating or replacing p53 in mouse models of cancer causes tumors to regress.
Cancer is the result of numerous mutations in the genome that affect two major types of genes - tumor suppressors, and oncogenes. Mutations that cause tumor suppressor genes to become inactivated are thought to be responsible for the development and early stages of cancer, while persistent activation of a select few oncogenes, such as Myc and Ras, are known to be required for tumor maintenance in the later, malignant stages of cancer. While cancer therapies that target oncogenes have proven to be very effective in the treatment of cancers in recent years, these therapies often eventually fail as a result of new genetic mutations that cause resistance.
Surprisingly, tumor shrinkage in the Lowe study was seen to be the result of an immune response, most likely triggered by the release of cytokines such as interleukin from non-dividing cells in the tumor. A better understanding of this interaction between the body's natural defense mechanisms and tumor cells may lead to novel cancer treatments that specifically kill cancer cells, while sparing normal tissues.
Wen Xue, Lars Zender, Cornelius Miething, Ross A. Dickins, Eva Hernando, Valery Krizhanovsky, Carlos Cordon-Cardo, and Scott. W. Lowe.CSHL is private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering. For more information, visit www.cshl.edu.