Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in the United States. Thus, there is an urgent need to develop new therapeutic approaches for this disease. EOC is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies be personalized by targeting distinct molecular subsets of EOC. CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. Notably, EOC is among the cancer types that show the highest CARM1 amplification rates in The Cancer Genome Atlas (TCGA) database. The role of CARM1 in EOC has never been investigated. The ultimate goal of the current proposal is to develop novel approaches to treat and eradicate CARM1-associated EOC. Our unbiased screen show that CARM1-expressing EOC cells are selectively sensitive to the inhibition of EZH2, another epigenetic regulator. Genome-wide profiling suggests that the observed selectivity correlates with upregulation of EZH2 target genes in a CARM1-dependent manner. Inactivation of subunits of the SWI/SNF chromatin- remodeling complex is synthetically lethal with inhibition of EZH2. Interestingly, BAF155, a core subunit of the SWI/SNF complex, is a substrate of CARM1. Indeed, our preliminary data support a model that CARM1 renders cells functionally dependent on EZH2 activity by methylating BAF155. CARM1 expression is typically mutually exclusive with BRCA1/2 mutations in EOC. PARP inhibitor Olaparib is approved by FDA for recurrent BRCA1/2-mutated EOC. Thus, sensitizing BRCA1/2 wildtype EOC to PARP inhibition remains an unmet clinical need. Notably, our preliminary data suggest a synergy between EZH2 inhibitor and PARP inhibitor in a CARM1-dependent manner. Further, EZH2 inhibition enhances CD8+ effector T cell trafficking into tumors by upregulating Th1-type chemokines. This raises the possibility of combining EZH2 inhibitor with immuno-checkpoint blockade such as anti-PD-L1 therapy in CARM-expressing EOCs. Thus, our central hypothesis is that CARM1-expressing EOC can be treated and ultimately eradicated by targeting EZH2 in combination with PARP inhibitor or immune-checkpoint blockade such as anti-PD-L1 therapy.
Two specific aims are proposed:
Aim 1 : To investigate the mechanistic basis underlying the selectivity of EZH2 inhibition against CARM1;
and Aim 2 : To develop novel therapeutic strategies for CARM1-expressing EOC. The proposed studies are highly innovative because they challenge current research/clinical paradigms, and explore new intervention strategies for CARM1-associated EOC. The research proposed is of high impact because it has the potential to establish the first effective combinational therapeutic strategy for CARM1-associated EOC. Since amplification and overexpression of CARM1 occurs in several other major cancer types, the mechanistic insights gained from the current studies will also have broad implications.
Theproposedresearchisrelevanttopublichealthbecauseitwillnotonlyrevealcriticalmolecular insightsintohowtheoncogenicproteincodinggeneCARM1contributestoovariancancer,butitwillalso provideascientificrationalefordevelopingurgentlyneedednewtherapeuticstrategiesforthis devastatingdiseasebasedonCARM1expressionstatus.Thesestudieswillalsoserveasaprototypefor moreepigenetictherapeuticstrategiesforcancerswithCARM1upregulation,awell-recognizedfeature ofseveralmajorcancertypes.Therefore,theproposedresearchisrelevanttothepartoftheNIH?s missionthatpertainstodevelopingfundamentalknowledgethatwillreducetheburdenofhumanillness.
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