Combined Inhibition of the Vitamin D Receptor and Poly-ADP Ribose Polymerase (PARP) in the Treatment of Cancer

(Ref. No. 381-TY)


Pancreatic cancer is the 4th leading cause of cancer fatality in the United States and has the lowest 5-year survival rate of any major cancer. More than 70% of patients die within the first year after they were diagnosed, as by that time already more than 52% of patients have a distant disease, and 26% have a regional spread. Moreover, only ~15% of patients diagnosed with pancreatic adenocarcinoma can have their tumors surgically removed.

During the development and progression of pancreatic adenocarcinoma, a remarkably complex pattern of genetic mutations was discovered. To prevent mutagenesis, in some cases, the cell homologous recombination apparatus repairs double-stranded DNA breaks and plays an important role in maintaining the integrity of the genome. However, the same mechanism may contribute to chemoresistance. Pancreatic cancer is particularly resistant to the chemo- and radiation therapy. Thus, understanding the mechanisms of chemoresistance and exploring new targets that increase the mortality of cancer cells is important for improving therapeutic efficacy.

Summary of the Invention

When genomic DNA is subjected to sufficient damage, altered gene or group of genes results in cell death. This strategy has been successfully used in chemo- and radiation therapy. For the treatment of pancreatic cancer, inhibitors of PARP-1, a protein that is important for the reparation of single-stranded DNA breaks, are commonly used. However, pancreatic tumor cells are often resistant to PARP-1 inhibitors. Researchers from Fox Chase Cancer Center have discovered a new way to enhance the effect of PARP-1 inhibition with combined depletion of the Vitamin D receptor (VDR) or its pathway. This therapy is suitable for cancer cells that express VDR and its inhibition enhances the susceptibility to inhibition of PARP-1. The therapeutic synergism of this combination has been shown on tumor cells. Therefore, inhibition of homologous recombination-based double stranded DNA break repair via the VDR makes cancer cells more susceptible to PARP inhibition therapy. The future therapeutic strategy may comprise either irradiating the chromosomal DNA, or inducing double-strand DNA breaks by chemical agents.

Bhattacharjee V. et al. A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells.
Cell Cycle. 2014;13(24):3839-56.

Patent Status: Published Patent Application # US 2016/0101111 A1

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