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Breaking oncogene's hold on cancer cell provides new treatment direction

Date:
January 11, 2012
Source:
Baylor College of Medicine
Summary:
Just as people's bodies and minds can become addicted to substances their cancers can become addicted to certain genes that insure their continued growth and dominance. Researchers have now developed ways to exploit the addictions of cancers to kill them without harming normal tissues.

Just as people's bodies and minds can become addicted to substances such as drugs, caffeine, alcohol, their cancers can become addicted to certain genes that ensure their continued growth and dominance.

Researchers at Baylor College of Medicine and Harvard Medical School have developed ways to exploit the addictions of cancers to kill them without harming normal tissues. A report on their work recently appeared online in the journal Science.

Many cancers are driven by the overexpression of oncogenes. These oncogenes are two-faced. On one hand, they promote processes that allow the cells to become immortal and to grow unchecked. On the other hand, the expression of these oncogenes creates additional anti-growth cellular stresses, conflicts that the cancer cell must subvert in order to survive.

Myc gene

One classical example of an oncogene that creates such a delicate balance is c-myc. In patients, hyper-activation of c-myc is associated with the most aggressive cancer types, with 20-40 percent of all cancers having an activated myc gene.

"For 30 years, scientists have tried to attack the oncogene myc," said Dr. Thomas Westbrook, assistant professor of molecular and human genetics and biochemistry and molecular biology at BCM and a senior author of the report. "However, it has not been amenable to the drugs we have. Now we have to take advantage of the stresses the oncogene puts on the cancer cell and determine if we can ramp those up to kill the tumor."

"Tumor cells experience considerable mitotic stress," said Westbrook. Regular chemotherapy takes advantage of this, but the drugs kill dividing cancer and normal cells. Experts think that special programs within the cancer cell allow it to cope with the stress as it grows and divides (mitosis).

"The fundamental question we asked was how are the stresses in cancer cells different from those in normal cells?" said Westbrook. "We want to exploit that idea and see if we can exacerbate that stress.

SUMO-activating enzyme

To identify genes involved in coping with this stress, Westbrook and his colleague Dr. Stephen Elledge of Harvard Medical School used a special RNA interference screen to disrupt the function of each gene in the genome and identify the genes required to allow the cancer cell to tolerate the stress of the myc oncogene.

One of the core biochemical processes they uncovered was SUMOylation, a three-step process. Westbrook, Elledge, and colleagues showed that SUMO-activating enzyme, the first step in the process, is required for myc-driven cancers to go through cell division. Thus, inhibiting SAE could be a therapeutic strategy for myc-cancers.

To test this, they turned off the SAE enzyme in a form of myc-driven breast cancer.

"The tumors stopped growing and many of them melted away," said Westbrook. Today, many of the mice are still alive and healthy. If they did not turn off production of the enzyme, the tumors grew and eventually killed the animals.

"If you inhibit this enzyme in a non-myc driven breast cancer, nothing happens," said Westbrook. "If you inhibit it in normal cells of many kinds, nothing happens."

That means that turning off SAE2 exacerbates the stress on cancer cells but not normal cells and thus be a great way to kill cancers without many of the side effects of traditional chemotherapies.

Particular importance for TNBC

The findings in this report have particular importance for an aggressive form of breast cancer called triple negative breast cancer (TNBC). This subtype is often driven by myc, and there are currently no effective treatments for these patients.

"This may provide that target," said Westbrook. The therapeutic value is that a drug targeting SAE will cause the cancer cell to no longer tolerate myc but will not be detrimental to normal cells.

In addition, myc drives many others kinds of cancers and he anticipates that inhibiting this enzyme in these tumors may have the same effect.

Others who took part in this work include Jessica D. Kessler, Tingting Sun, Kristen L. Meerbrey, Earlene M. Schmitt, Samuel O. Skinner, Mitchell Rao, Peng Yu, Rocio Dominguez-Vidana, Ronald J. Bernardi, Tiffany Hsu, Ido Golding, C. Kent Osborne, Chad J. Creighton, Susan G. Hilsenbeck, Rachel Schiff, Chad A. Shaw, all of BCM; ,Kristopher T. Kahle, Michael R. Schlabach, Qikai Xu, Mamie Z. Li, Anthony C. Liang and Nicole L. Solimini, all of Harvard and Brigham and Women's Hospital; Bing Yu and Ji Luo, both of the National Cancer Institute and Zachary C. Hartman of the University of Texas MD Anderson Cancer Center.

Funding for this work came from the National Institutes of Health, the U.S. Department of Defense, the Human Frontier Science Program, the Welch Foundation, the National Science Foundation, the Susan G. Komen for the Cure, the National Cancer Institute, the U.S. Army Innovator Award, the Howard Hughes Medical Institute, the V Foundation for Cancer Research and the Mary Kay Ash Foundation for Cancer Research.


Story Source:

The above story is based on materials provided by Baylor College of Medicine. Note: Materials may be edited for content and length.


Journal Reference:

  1. J. D. Kessler, K. T. Kahle, T. Sun, K. L. Meerbrey, M. R. Schlabach, E. M. Schmitt, S. O. Skinner, Q. Xu, M. Z. Li, Z. C. Hartman, M. Rao, P. Yu, R. Dominguez-Vidana, A. C. Liang, N. L. Solimini, R. J. Bernardi, B. Yu, T. Hsu, I. Golding, J. Luo, C. K. Osborne, C. J. Creighton, S. G. Hilsenbeck, R. Schiff, C. A. Shaw, S. J. Elledge, T. F. Westbrook. A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis. Science, 2011; DOI: 10.1126/science.1212728

Cite This Page:

Baylor College of Medicine. "Breaking oncogene's hold on cancer cell provides new treatment direction." ScienceDaily. ScienceDaily, 11 January 2012. <www.sciencedaily.com/releases/2011/12/111208141935.htm>.
Baylor College of Medicine. (2012, January 11). Breaking oncogene's hold on cancer cell provides new treatment direction. ScienceDaily. Retrieved September 20, 2014 from www.sciencedaily.com/releases/2011/12/111208141935.htm
Baylor College of Medicine. "Breaking oncogene's hold on cancer cell provides new treatment direction." ScienceDaily. www.sciencedaily.com/releases/2011/12/111208141935.htm (accessed September 20, 2014).

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