Muhammad S. Beg, MD
University of Texas Southwestern Medical Center

Pancreatic ductal adenocarcinoma (PAD) cancer is a terrible and lethal disease, with a 5-year survival rate of < 6%. Fortunately, it has been determined that there may be a way to exploit a stark difference between the cancer cells and the normal cells.

In 85% of the cancerous pancreas tissues removed surgically, an enzyme named NQO1 is present in much larger amounts than that found in healthy pancreatic tissue. The goal of this study is to take advantage of that discrepancy and find a way to damage the cancerous cells while allowing the healthy cells to flourish.

In the healthy pancreatic cells, there are high levels of an enzyme called catalase. In the cancerous pancreatic cells, it is almost nonexistent. Dr. Boothman and his team are working on a regimen that delivers a bioactive drug called beta-lapachone. It attacks the NQO1 cancer cells and is inactivated by catalase.

When the bioactive drug is delivered, it goes to the healthy and cancerous tissue alike. In the healthy cells, the high levels of catalase protects the healthy cells from the chemotherapy. In the cancerous cells, there is almost no catalase so the chemotherapy can attack the NQO1 enzyme at full strength. The damaged cancer cells are then unable to metabolize the sugar they need to survive – thus attacking their Achilles heel and resulting in cellular death.

If successful, this study could greatly improve the 5 year survival rates for this devastating disease. [Awarded 2014]

 

Clinical Summary
Pancreas ductal adenocarcinoma (PDA) cancer is a terrible and lethal disease, with 5-yr survival rates of <6%. The theory is that NAD (P) H: quinone oxidoreductase 1 (NQO1), an enzyme specifically and uniquely elevated in pancreas cancers, can be exploited in a tumor-selective manner for therapy. NQO1 is overexpressed in >85% resected pancreas cancers and Catalase, a hydrogen peroxide (H2O2) scavenging enzyme, is lost in pancreas cancer versus normal pancreas tissue. High NQO1: Catalase ratios in PDA cancers can be exploited using NQO ‘bioactivatable’ drugs, where low expression ratios protect normal tissue. The research team developed a unique NQO1 ‘bioactivatable’ drug, ß-lapachone that specifically kills NQO1+ cancer cells, but is detoxified by Catalase. NQO1 ‘biometabolizes’ ß-lapachone to H2O2, causing massive damage to cancer cell DNA, while normal cells with low NQO1 and high Catalase levels are protected. Massive DNA damage inflicted on pancreas cancer cells causes hyperactivation of PARP1, DNA repair protein, causing dramatic metabolic changes, and hitting cancer cell’s ‘Achilles heel’ - their dependency on using sugar. Exposed NQO1+ cells kill themselves, selectively eliminating cancer, but not normal tissue.