A protein that protects pancreatic cancer cells from responding to cancer-killing drugs is leading scientists at the University of Minnesota to test a new therapeutic target for one of the most aggressive and difficult to treat forms of cancer. A pair of studies presented at the 2008 Clinical Congress of the American College of Surgeons supports the belief that heat shock factor protein (HSP) may form the basis of a novel treatment for patients with pancreatic cancer. The research continually builds on a proof of principle that this protein is a real and credible mechanism underlying the way pancreatic cancer cells continue to grow, divide, and behave, according to lead researchers Selwyn M. Vickers, MD, FACS, the Jay Phillips Professor of Surgery and Chair, and Ashok K. Saluja, PhD, Vice Chair of Research, both with the department of surgery at the University of Minnesota.

Findings from these studies as well as other studies conducted by Drs. Vickers and Saluja are leading to a phase I clinical trial of triptolide, a drug that inhibits the action of HSP. The trial, which will begin at the end of 2008 or the beginning of 2009, will enroll 12 to 16 patients with advanced pancreatic cancer. "This trial will allow us to move toward the development of an agent which exerts a large part of its effect on inhibiting heat shock factor-1 protein production as a means of treating pancreatic cancer," Dr. Vickers explained.

Triptolide will be the first pancreatic cancer-specific agent tested in nearly a quarter century. "The last drug that was developed directly for the treatment of pancreatic cancer was gemcitabine, and that was about 24 years ago. So having any new drug come to clinical trial that is specifically directed at this tumor and that is based on credible science is a worthwhile venture. The more we can increase the treatment options in the pipeline, the more likely we are to change the paradigm and the regimen nationally and internationally for treatment of the disease," Dr. Vickers said.

The role of HSP-70 in the development of other types of cancer as well as inflammatory condition has been studied by many research groups. Dr. Vickers, Dr. Saluja and their colleagues are one of only a few cancer research laboratories that are investigating HSP and its effect on pancreatic cancer. The University of Minnesota researchers have been examining the relationship between HSP and pancreatic cancer for the last seven years.

HSP acts in both normal and malignant cells. In non-malignant cells, the protein promotes normal function. "Heat shock factor proteins are chaperones that help other critical proteins carry out their jobs. They are usually quiescent, but in times of stress in a cell's environment, their levels increase significantly to keep the cells in a homeostatic environment and protect them from stressors becoming lethal," he explained.

In pancreatic cancer, HSPs act abnormally to protect malignant cells and keep them alive when they should respond and be killed by chemotherapeutic drugs. "Pancreatic cancer cells are resistant to the body's mechanisms of control and resistant to treatment. HSP is over-expressed in pancreatic cancer and therefore it plays a vital role in keeping cancer cells alive and in making pancreatic cancer a disease that is difficult for patients to manage and for doctors to address," Dr. Vickers said.

Triptolide is an anti-inflammatory compound that has long been used as a homeopathic medicine in China and as an anti-inflammatory drug in the US. "As to its role in relation to HSP protein, triptolide has been found to be a fairly strong inhibitor of HSP production. Cells that used to grow into pancreatic tumors in an animal can be treated with the drug, and the growth can be significantly reduced or inhibited. The metastatic potential of the cells also can be inhibited by the drug. This finding gives us a basis for moving forward to test the drug in patients," Dr. Vickers said.

In the first study presented at the Clinical Congress, Dr. Vickers and his colleagues showed that the inhibition of heat shock factor-1 (the source of the heat shock factor protein) caused apoptosis (programmed cell death) of pancreatic cancer cells. In the second study, the same research group demonstrated that triptolide in combination with tumor necrosis factor-related apoptosis-inducing ligand (a molecule that binds to a target on the cell surface to initiate the process of apoptosis) killed three times more cells than either compound alone, and the combination killed cells from all five pancreatic cancer cell lines on which they were tested.

"Triptolide, the foundational piece of this potential treatment for pancreatic cancer, will be tested as a single agent in the phase I trials. But pancreatic tumors in the best of worlds will never succumb totally to a single agent. If we have 10 pancreatic cell lines, six to seven of them will respond to triptolide, but there will be three to four that will have no response. We've asked the question, is there anything we can do to make those three to four cells lines become sensitive to treatment? We found that if we combine the drug with tumor necrosis-related apoptosis-inducing ligand, there is an additional, augmented pathway that works in synergy with triptolide to remove the resistance from treatment from most, if not all, of the pancreatic cell lines we encounter," he concluded.

According to the American Cancer Society, the one-year survival rate for patients with pancreatic cancer is only 20 percent, and the five-year survival rate is 4 percent. This form of cancer is difficult to treat because in nearly 90 percent of cases, the disease has already spread beyond the pancreas by the time it is diagnosed.

Daniel Borja-Cacho, MD; Zwolak Pawel, MD; Yumi Yokoyama, PhD; Jacob S. Ankeny; Mara B. Antonoff, MD; Vikas Dudeja, MD; Rohit Chugh, MD; Rajinder K. Dawra, PhD; Steve Skube; Paul Zwolak, MD, also participated in both University of Minnesota studies.

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