My research program is focused on understanding the oncogenic mechanisms in pediatric cancer by caused by oncogenic fusion transcription factors.
Desmoplastic Small Round Cell Tumor (DSRCT) isa rare but aggressive pediatric cancer, occurring in adolescents and young adults with a predilection for males. The tumor is defined by a recurrent chromosomal translocation that creates a chimeric transcription factor, EWS-WT1, which initiates and drives tumorigenesis. Despite the presence of a tumor-specificEWS-WT1 gene, oncogenic transcription factors (TFs) are considered undruggable due to an inherent difficulty in developing specific inhibitors against TFs. Standard treatment for DSRCT, which comprises of chemotherapy, radiation therapy and surgery, is largely ineffective and prognosis is extremely poor with less than 15% 5-year survival. Therefore, development of rationale-based targeted therapy is urgently needed. Like other pediatric sarcomas, DSRCT has relatively silent genome without any known recurrent mutations outside of the fusion, which makes it even more challenging to develop targeted therapy. We hypothesize that other oncogenic driving alterations must exist in DSRCT which may be generated through epigenetic changes. To better understand DSRCT biology and to identify other oncogenic drivers that are tractable for therapy, my lab is focused on the following two main areas: (1) to identify critical dependencies (other than the fusion driver) that are tractable for therapy and (2) to identify recurrent epigenetic alterations that drive tumorigenesis.
To identify critical dependencies, we have performed integrative transcriptomic analysis on DSRCT cell lines with shRNA-mediated knockdown of EWS-WT1 and 28 primary DSRCT tumors. This analysis identified many potential direct EWS-WT1 target genes. Among them, we identified a number of kinases that are potential drivers of DSRCT. Our recent work showed that SIK1(Salt-inducible kinase 1) and NTRK3 are direct EWS-WT1 targets and silencingSIK1 or NTRK3, either through shRNA or pharmacologically, results in DSRCT cell growth arrest (Hartono et al., Oncogenesis 2022) or cell death (Ogura et al.,2021), respectively. Additionally, we have performed an unbiased CRISPR“ drop-out screen” with human kinome library to identify other kinases as critical dependencies in DSRCT. A clinical trial to evaluate repotrectinib, anNTRK3 inhibitor, with irinotecan and temozolomide (NCT05004116) is currently recruiting patience at MSKCC.
To identify recurrent epigenetic changes, we have performed ATAC-seq and Cut & ag-seq with various histone modifications in three DSRCT cell lines with a goal of identifying genes and pathways that are altered through chromatin and histone modifications. We also plan to perform DNA methylation analysis and ChIP-seq with EWS-WT1 fusion to identify the genomic regions bound by the fusion. We are currently analyzing the ATAC and Cut & Tag data and integrating these data sets with myriad of RNA-seq data we have accumulated with these cell lines to identify recurrent epigenetic alterations that are driving tumorigenesis.
· Education:PhD Microbiology & Immunology, SUNY Downstate Health Sciences University
· ORCID identifier: 0000-0001-6211-3498
· MyNCBI Link: https://www.ncbi.nlm.nih.gov/myncbi/1HEJb00wA97Q1/bibliography/public/
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· Selected Publications:
· Keywords/Tags:
Oncogenic transcription factor, transcriptional regulation, kinase signaling pathway, pediatric cancer,therapeutic targets, EWSR1, WT1
· Link to lab website if they have one
