A rapid and aggressive spread into surrounding tissue, resistance to standard chemotherapy and a tendency to recur make pancreatic cancer one of the most challenging diseases to treat. The disease is also difficult to diagnose in its early stage, and patients usually present with incurable disease. It has a high mortality rate, and so far no therapy has been shown to significantly impact survival. Pancreatic cancer is considered an orphan cancer, because of its relatively low incidence and high mortality.

Pancreatic cancer is slightly more common in men than in women. In the U.S., it is the fourth leading cause of cancer-related death in men and the fifth leading cause of cancer-related deaths in women with a death rate estimated by the National Cancer Institute of approximately 96% of patients with the disease.

Pancreatic Cancer: Facts & Figures
The American Cancer Society’s most recent estimates [1] for pancreatic cancer in the United States (2011) show that about 44,030 people (22,050 men and 21,980 women) will be diagnosed with pancreatic cancer. The estimate also shows that about 37,660 people (19,360 men and 18,300 women) will die of pancreatic cancer. Over the past 15 to 25 years, rates of pancreatic cancer have dropped slightly in men and women. Still, pancreatic cancer remains the fourth leading cause of cancer death overall. And while some positive results have been reached in the treatment of this cancer, the progress for patient with pancreatic cancer remains generally poor.

Risk factor
The lifetime risk of developing pancreatic cancer is about 1 in 71 (1.41%). This is about the same for both men and women. However, a person’s risk may be altered by certain risk factors, including smoking (getting pancreatic cancer is 2 to 3 times higher among smokers) and overweight and obesity (obese people are more likely to develop exocrine pancreatic cancer, as are people who don’t get much physical activity).

New treatment options
Results from pre-clinical studies of Triphendiol, a prodrug of the investigational drug candidate NV-143 under development by Marshall Edwards, demonstrates anti-proliferative activity in pancreatic cancer as both a monotherapy and as a chemosensitizer of gemcitabine (Gemzar?, Eli Lilly and Company). The results are published online in the Anti-Cancer Drugs journal website and are scheduled to print in the August 2011 issue of the journal.

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Study results
The studies, conducted in collaboration with lead author Ewan Tytler, Ph.D., at the University of Alabama at Birmingham Medical Center and the Yale University School of Medicine, detail the in vitro activity of triphendiol in pancreatic cancer cells (HPAC and MIAPaCa-2) as well as its in vivo activity in animal models of pancreatic cancer. In addition, both studies show that pre-treatment with Triphendiol enhances the cytotoxic effect of gemcitabine, the standard-of-care chemotherapy currently used to treat advanced pancreatic cancer.

Pretreatment of pancreatic cancer cells
When used in pretreatment of pancreatic cancer cells,triphendiol enhanced the cytotoxic effect of gemcitabine. In xenograft models of pancreatic cancer, the rate of tumor proliferation on mice coadministered with triphendiol and gemcitabine was significantly reduced when compared with the corresponding tumor proliferation rates from the respective monotherapy-control and vehicle-control groups.

Overexpression of IAP
As a monotherapy, triphendiol-inhibited cell proliferation-induced p53-independent G2/M cell cycle arrest and activation of the intrinsic apoptosis pathway. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. Biological studies suggest a mechanism of cytotoxicity that involves mitochondrial depolarization and downregulation of X-linked inhibitor of apoptosis (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) gene family in terms of its ability to inhibit caspases and suppress apoptosis.

Triphendiol exhibits high selectivity, little effect on non-tumor cells and no observable toxicity in animals at therapeutically effective doses. In human studies conducted so far, no adverse events or side effects have been reported when administered to volunteers.

Broad range of anti-cancer activity
Triphendiol is broadly cytostatic and cytotoxic against most forms of human cancer cells in vitro, and has been shown to cause cell cycle arrest and to induce apoptosis in various cancer cell lines. In previous laboratory studies, Triphendiol demonstrated anti-cancer activity against a broad range of tumor cell lines, including breast, colorectal and ovarian. Once administered, Triphendiol is converted in vivo into an active metabolite called NV-143. In addition to being more active than Triphendiol as a single agent, NV-143 appears to be superior in its ability to synergize with chemotherapy in pre-clinical studies.

Investigational New Drug Application
Marshall Edwards has completed the required pre-clinical studies of NV-143 necessary to complete an Investigational New Drug application, which it plans to submit to the U.S. Food and Drug Administration (FDA) next month.

“These studies add to our growing collection of data regarding the activity of our compounds and their potential ability to enhance the effects of current treatments,” said Robert D. Mass, MD, Chief Medical Officer of Marshall Edwards. “These data further support the clinical development strategy for our lead candidate NV-143, the primary metabolite of Triphendiol, in combination with standard-of-care chemotherapy, while expanding the potential drug combinations we can consider in our randomized Phase II clinical trials.”

[1] Cancer Facts and Figures, American Cancer Society

For more information:
– Wang X, McKernan R, Kim KH, Alvero WB, Whiting A, Thompson J, et al. Triphendiol (NV-196), development of a novel therapy for pancreatic cancer. Anticancer Drugs. 2011 Jun 9 [Epub ahead of print]. doi: 10.1097/CAD.0b013e328346f3b4 [Abstract]
– Saif MW, Tytler E, Lansigan F, Brown DM, Husband AJ. Flavonoids, phenoxodiol, and a novel agent, triphendiol, for the treatment of pancreaticobiliary cancers. Expert Opin Investig Drugs. 2009 Apr;18(4):469-79.
– Triphendiol (NV-196) induces apoptosis and sensitizes pancreatic cancer cells to gemcitabine. American Association for Cancer Research (AACR 2008), April 12-16, San Diego, CA. Abstract# 8989.

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