Combinational Targeting EZH2 and PARP1 in Prostate Cancer
Abstract
Prostate cancer is the leading cause of cancer-related deaths in American men. It is estimated that each year more than 180,000 new prostate cancer patients will be diagnosed, and approximately 26,000 patients in the United States will die, primarily due to metastasis. This occurs despite advances in early detection and treatment. The available treatment options are limited, not very effective, and associated with severe side effects. Furthermore, prostate cancer patients can develop resistance to the currently available therapeutics. Therefore, this proposal will address the overarching challenge of developing effective treatments and address mechanisms of therapeutic resistance for men with metastatic prostate cancer. Similar to other genetic diseases, prostate cancer develops in a background of dysregulated gene expression and is affected by environmental factors. These environmental factors can lead to epigenetic modifications, which affect the interactions between DNA and protein components of chromosomes, called histones, in which DNA winds around, thus regulating gene expression. The protein enzyme enhancer of zest homolog 2 (EZH2) specifically modifies the histone H3 protein at its lysine 27, thereby tightly winding DNA and silencing gene expression. Our previous work showed that EZH2 is upregulated in advanced prostate carcinomas and metastatic prostate cancer and that prostate cancer patients who have higher expression levels of EZH2 have shorter survival times than prostate cancer patients with low or no expression of EZH2. We also found that high expression levels of EZH2 induce chromosome instability by repressing many important proteins that are responsible for repair of DNA damage. DNA damage and improper DNA repair can lead to the initiation and progression of many cancers, including prostate cancer. One family of proteins mediating DNA repair is poly ADP-ribose polymerase (PARP)-1, and its inhibition can make cancer cells more susceptible to death. Recently, pharmacological inhibitors of PARPs have been clinically tested for the treatment of prostate cancer; however, these drugs are only effective in a subset of patients with DNA repair defects. Furthermore, patients can develop therapeutic resistance to PARP inhibitors. Therefore, treatment with PARP inhibitors alone may not be effective for every patient, suggesting the importance of other biological mechanisms in regulating the development and progression of prostate cancer. Most advanced prostate cancer cells have higher levels of EZH2 and PARPl proteins compared to that in early-stage prostate cancer cells, suggesting the importance of these proteins in prostate cancer progression. We found that PARPl directly interacts with EZH2. In the proposed project, we will identify precisely how EZH2 and PARPl interact and how these two proteins regulate each other in prostate cancer. Next, we will study how EZH2 and PARPl work together to decrease the expression of tumor suppressors (genes/proteins that inhibit tumor growth) and increase genetic instability in advanced prostate cancer. Understanding these mechanisms will lead to the future design of new inhibitors of EZH2 and PARPl. Furthermore, our preliminary data strongly suggest that PARP inhibition-resistant tumors have higher levels of EZH2 compared to PARP inhibition-sensitive tumors and that inhibiting EZH2 alone enhances the enzymatic activities of PARPs, thus overcoming the therapeutic effectiveness of PARP inhibition. Therefore, our work provides a novel rationale to target both PARPs and EZH2, and we predict that the inhibition of both PARPs and EZH2 will kill more cancer cells than inhibiting either PARPs or EZH2 alone. Although pharmacological inhibitors of EZH2 and PARP have been clinically proven to be safe, the combination of these drugs has never been tested and does pose some risks. To decrease the risk to patients, we will preclinically test, in this proposal, the sa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710357
Entities
People
- Qi Cao
Organizations
- Houston Methodist Research Institute
- United States Army