Combinational Targeting EZH2 and PARP1 in Prostate Cancer
Technical Report,01 Sep 2018,31 Aug 2019
Northwestern University Chicago United States
Pagination or Media Count:
Most advanced prostate cancer cells have higher levels of EZH2 and PARP1 proteins compared to that in early stage prostate cancer cells,suggesting the importance of these proteins in prostate cancer progression. We found that PARP1 directly interacts with EZH2. In the proposed project, we will identify precisely how EZH2 and PARP1 interact and how these two proteins regulate each other in prostate cancer. Next, we will study how EZH2 and PARP1 work together to decrease the expression of tumor suppressors genesproteins 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 PARP1. 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. We anticipate that this combination therapy will overcome therapeutic resistance and will substantially benefit the majority of prostate cancer patients, regardless of any DNA repair defects.
- Medicine and Medical Research