Cells in the balance

By Josh Baxt
May 31, 2011
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May is National Cancer Research Month, created by Congress in 2007 to recognize the American Association of Cancer Research (AACR) for its contributions to the field. To honor AACR and highlight some of the important cancer research being done at Sanford-Burnham, throughout May we posted a series of articles on the ongoing work in our National Cancer Institute-designated Cancer Center. The vast majority of this research is made possible by funding from the National Institutes of Health (NIH), which includes the National Cancer Institute (NCI).

Cells contain a complex mixture of opposing forces striving for balance. When these mechanisms work properly, cells are healthy. However, if one side gains the upper hand, balance is lost and disease can result.

Programmed cell death, or apoptosis, is a critical cellular quality control mechanism regulated by small squads of pro- and anti-apoptotic proteins. In healthy cells, these opposing mechanisms maintain the life/death balance. However, they can also go awry in a number of diseases. In particular, cancers often over-express anti-apoptotic proteins, giving them a measure of immortality.

Sanford-Burnham’s NCI-designated Cancer Center has led the way on cell death research. In a recent paper, Dr. Guy Salvesen, who directs the Apoptosis and Cell Death Program, and colleagues showed how an enzyme, caspase-8, can teeter between advancing or defeating apoptosis, depending on factors in the cell. Caspases are critical regulators of apoptosis, and understanding their function could lead to new treatments.

In another promising area of research, Sanford-Burnham CEO Dr. John Reed, President and Cancer Center director Dr. Kristiina Vuori, Dr. Nicholas Cosford and Dr. Stefan Riedl are working to find small molecule chemical compounds that counter inhibitors of apoptosis proteins (IAPs). A crucial advance was made several years ago when Dr. Reed and Dr. Salvesen discovered that these proteins prevent caspases from eliminating sick cells. Now, by inhibiting the inhibitors, the team hopes to restore cellular balance and force diseased cells, including cancer cells, to die.

Discovering and developing therapeutic chemicals requires amazing precision. These compounds bind to the target proteins, inhibiting their function. But IAPs are a family of proteins with similar structures. Finding a chemical that binds selectively to a specific protein, in this case XIAP, can be tricky.

“We have made great strides towards neutralizing IAPs with chemicals in the laboratory,” says Dr. Riedl. “However, we have more work ahead as we improve them so that they have the necessary potency and sufficient longevity to trigger tumor cell death in patients.”

This is where the varied talents of the collaborators produce results. Dr. Riedl studies protein structures. By providing detailed structural information, down to the atoms, his work informs Dr. Cosford’s efforts to optimize chemical compounds. In turn, Dr. Reed and Dr. Vuori will help test the improved compounds in cell and animal models to determine whether they are selectively targeting an XIAP and whether that encourages apoptosis.

“Specific inhibition of XIAP is anticipated to re-establish sensitivity, reduce toxicity, and improve efficacy of cancer treatment,” says Dr. Vuori. “Our multi-disciplinary team is well poised to tackle this important goal.”

Read more about cancer research at Sanford-Burnham:

In Cancer, Context is Everything

Fueling Cancer Cell Growth

Sending Medicine Where it’s Most Needed

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Josh Baxt

Josh was a Sanford-Burnham Communications staff member.

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