Pancreatic cancer is the 3rd leading cause of cancer fatality in the United States and is slated to take the 2nd spot by 2020. This disease has the lowest 5-year survival rate of any major cancer with over 70% of patients die within the first year. Because of the late stage of diagnosis, more than 52% of patients have a distant disease, and 26% have a regional spread. Thus, only ~15% of patients diagnosed with pancreatic adenocarcinoma can have their tumors surgically removed.
During the development and progression of pancreatic adenocarcinoma, the cancer cells undergo a remarkably complex and diverse pattern of genetic mutations that promote growth and survival. Indeed, the cancer cells rely on their inherent genomic instability to rapidly evolve and adapt to changing environments. This then increases the demand for DNA repair enzymes, many of which act in the homologous recombination repair pathway to repair double-stranded DNA breaks (DSB). As genome instability likely plays an important role in developing chemo- and radio-resistance, exploring new targets that enhance the sensitivity of cancer cells to therapy remains an important strategy for improving the therapeutic efficacy.
Summary of the Invention
Inhibitors of PARP1, one of the key proteins involved in DNA repair, are commonly used to treat cancers that harbor mutations in the homologous recombination proteins BRCA1, 2 and PALB2. Ongoing PARP1 inhibitor studies are focusing on the 10-12% of pancreatic cancer patients that harbor one of these mutant genes. Thus, expanding the utility of PARP1 inhibitors to other pancreatic patients, or those that might have developed resistance to PARP1 inhibitors should be of significant interest. Researchers from Fox Chase Cancer Center have discovered a new way to enhance the effect of PARP1 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 PARP1 by disrupting homologous recombination repair in cells that do not harbor mutations in BRCA1/2 or PALB2. The therapeutic synergism of the combination has been shown on a broad variety of cancers beyond pancreatic cancer. Therefore, inhibition of homologous recombination-based DSB repair via the VDR makes cancer cells more susceptible to PARP inhibition therapy. Additionally, the therapeutic strategy may involve inducing DSB in the tumor cells either by irradiating or using chemical agents.
Relevant Publication: 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. Cell Cycle. 2014;13(24):3839-56.
Patent Status: US 9,889,141 B2 issued in February 2018. Additional patent application is pending.
For Licensing/Partnering information, please contact:
Inna Khartchenko, MS, MBA
Director, Technology Transfer