This cell-suicide response is thought to be one of the most important defenses against cancer. "Defects in signaling pathways that control apoptosis are thought to be a requirement for the development and maintenance of cancer. However, the specific defects that lead to cancer cell resistance to cell death are poorly understood," said Andrew Thorburn, D. Phil, and principal investigator of the studies.
The Medical Center has received three Department of Defense grants totaling nearly $1.2 million to study both breast cancer and prostate cancer cells to determine what genetic defects may cause cancer cells to develop.
The three studies will evaluate both at what stage cell suicide goes wrong in normal cells thus allowing cancer cells to develop - and how the suicide response could be reactivated in cancer cells.
"If we can identify and understand the defects in apoptosis signaling that cause the differences in cell suicide between normal cells and cancer cells, it may be possible to bypass or correct the defect in cancer cells," said Thorburn.
Most studies on apoptosis are performed in tumor cells derived from patients. However, it is not feasible to use these cells to understand why resistance occurs because all the genetic defects these cells possess are not known.
The researchers at Wake Forest will use normal breast and prostate cells that were converted to cancer cells by the controlled introduction of a few mutant genes. That allows researchers to obtain and study cells at various stages of cancer development and ask how they differ in their ability to activate the suicide response.
"Because we'll obtain resistance to cell suicide in human cells that contain only a few defined genetic defects, we have the opportunity to determine how resistance in cancer occurs," said Thorburn.
This work should provide the first definition of how breast and prostate cancer cells become resistant to a stimulus that causes a normal cell to kill itself. More importantly, it should provide a basis for future efforts to apply an understanding of how apoptosis resistance occurs and to develop new ways to reactivate an apoptosis pathway in cancer cells.
"If we can achieve this goal," said Thorburn, "it may be possible to cause tumor cells to kill themselves and thus provide useful treatments for breast and prostate cancer."