2-Aryl-Pyridylazoles for the Treatment of Solid Tumors Such as Pancreatic Cancer

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Researchers
Daniel Von Hoff
Director, Clinical Translational Research Division
Yeng Jeng Shaw
Research Associate, Pharmacology & Toxicology
Laurence Hurley
Professor, Pharmacology & Toxicology
Meredith Henderson
Graduate Associate, Research, Cancer Center Division
Haiyong Han
Associate Investigator
Gary Flynn
UA Associate, Pharmacology & Toxicology
Robert Dorr
Professor, Pharmacology
Managed By
Kaitlyn Norman

Title: Potential Treatment of Solid Tumors such as Pancreatic Cancer


Technology: University of Arizona researchers have identified two potent small molecules that target a common mutation found in pancreatic cancer cells with high specificity and induce cell death. These compounds are genotype specific for the DPC4 mutation associated with cancer phenotypes and, compared to available treatments, are significantly more potent and have less harmful side effects in normal cells. The anti-tumor agents have been tested in three pancreatic cell lines and have demonstrated a 16- fold selectivity difference against DPC4 deficient cells.

Pancreatic cancer is the fourth leading cause of all cancer deaths, due largely to the rapid progression of the disease, the lack of diagnostic tools or effective therapeutics. The response rate of gemcitabine, at present the most effective drug for advanced pancreatic cancer, is approximately 10%.

The search for cancer therapeutics is largely focused on gain-of-function mutations, a strategy reported to be inappropriate for pancreatic cancer. Loss-of- function mutations such as DPC4, a tumor suppressor gene that is turned off in 55% of pancreatic cancers, has been successfully exploited to distinguish between normal cells and tumor cells. The investigators identified the highly selective and lethal molecules that target DPC4 using a cell-based pharmacological synthetic lethal screening approach (Wang, et al., Proc. AACR 44:1258, 2003) developed at the University.

Stage of Development: The structures of both compounds have been determined and each has been successfully tested for specificity in three pancreatic cell lines.

Highlights:
*Potential for development of a therapeutic.
*Potent and specific compounds with reduced side effects to normal cells.
*Applications for other cancers with DPC4 deletions such as colorectal and lung.
*Targets mutations that are more appropriate for pancreatic cancer.