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Abstract 1945: Degradation of ERG transcription factor as a targeted therapy in B-cell and T-cell acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) occurs in children and adults and is one of the most common forms of pediatric cancer. The ideal individualized therapy for B- and T-cell ALL heavily depends on the present molecular drivers. However, even with the success of ALL therapy, only a few strategies target disease-specific molecular lesions. Philadelphia chromosome positive (Ph+) ALL, which harbors the BCR:ABL1 rearrangement, are sensitive to tailored inhibitors. Unfortunately, most ALL cases in both children (97-98%) and adults (70-80%) are Ph-; therefore, agents designed to directly target other molecular lesions are urgently needed. ERG, an ETS-family transcription factor, plays a key role in hematopoietic differentiation, megakaryopoiesis, and megakaryoblastic leukemia associated with Down syndrome. ERG overexpression is predictive of a poor prognosis in acute myeloid leukemia and T-ALL. Transgenic expression of ERG causes T-ALL in mice and knockdown of ERG reduces human T-ALL cell proliferation. We have previously identified a consensus peptide (EIPs) that specifically binds to and leads to the proteosomal degradation of the ERG protein in prostate cancers having the TMPRSS2:ERG gene fusion. Here, we demonstrated that wild type ERG was overexpressed at the mRNA and protein levels in a subset of B- and T-cell ALLs, but not in precursor CD4+, CD8+, or CD19+ cells. Pull-down assay found that streptavidin-linked beads were enriched for ERG proteins. Treatment of EIPs induced proteolytic degradation of ERG protein in Hal-01 cells, and therefore selectively inhibited ERG-driven cell growth and proliferation. More importantly, structure-based optimization created the next generation of ERG degraders (EIPv2). EIPv2 treatment significantly decreased ERG protein in Hal-01 cells starting from 3 hrs and nearly depleted ERG proteins at 48 hrs, resulting in 10-fold more potency than EIPs (IC50=2.3µM vs 25.7µM for EIPv2 and EIPs, respectively). Together, our results validate the development of peptidomimetics for ERG depletion as a targeted therapy for ALL. Unlike small-molecule antagonists, which require continuous dosing that eventually induces drug resistance, most protein degraders have relatively higher and longer pharmacological effects without requiring continuous exposure to high doses. Such an approach can abolish the presence of an oncoprotein, which, in theory, can overcome resistance to target inhibitors. Citation Format: Xiaoju Wang, Caleb Cheng, Yuanyuan Qiao, Lanbo Xiao, Cynthia Wang, Abhijit Parolia, Arul Chinnaiyan. Degradation of ERG transcription factor as a targeted therapy in B-cell and T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1945.