Chemo-mediated transcriptional reprogramming in ovarian cancer

Abstract
High-grade serous carcinoma (HGSC) is the most aggressive OC subtype that accounts for 80% of OC-related
deaths. Rapid emergence of platinum (Pt)-resistance is the main reason for this mortality. Despite initial
response to surgery plus chemotherapy, tumors relapse and rapidly become chemoresistant in 80% of patients.
Although few genetic mutations have been associated with chemoresistance, in a large fraction of tumors, drivers
of the chemoresistance's rapid emergence are unknown. Here we propose that non-genetic mechanisms play
an important part in regulating cellular transition to a resistant state in high grade serous ovarian cancer. We
will tackle the emergence of Pt resistance from a global transcriptional reprogramming point of view. Our
published and preliminary findings support the hypothesis that Pt resistance emerges from therapy-induced
population-level epigenomic and transcriptional reprogramming. Through integrative analysis of epigenomes
and transcriptomes of multiple naïve and cisplatin-resistant isogenic cells, we identified resistant-state specific
super-enhancers and their target transcription factor networks (TFN). The first aim employs cutting edge
genomic mapping and manipulation technologies including single cell-level CRISPR-perturbations followed by
transcriptome profiling to identify which TFs and TF-combinations are necessary to reprogram naïve cells into
the resistant state. The second aim investigates a novel combinatorial target to achieve synthetic lethality with
carboplatin in HGSOC. The findings from this proposal will provide new mechanistic insight into the role of key
transcription factor network that govern platinum resistance in ovarian cancer.

Grant Number: 4R01CA267544-04
NIH Institute/Center: NIH
Principal Investigator: Mazhar Adli