Overcoming fusion oncoprotein dependence through CIC-DUX4 target gene inhibition in undifferentiated sarcoma
The CIC-DUX4 fusion oncoprotein is an understudied molecular entity that characterizes a rare but lethal subset of undifferentiated round cell sarcomas. CIC-DUX4 patients have dismal clinical outcomes due to 1) an incomplete understanding of how the CIC-DUX4 fusion oncoprotein drives tumor progression and survival; 2) no CIC-DUX4 focused clinical trial options; and 3) the un-informed therapeutic approaches that leverage “salvage” chemotherapy options from other round cell sarcomas to treat CIC-DUX4 sarcoma. To overcome these challenges, we have recently integrated “Omics” (RNA-seq and ChIP-seq) profiing with a deep mechanistic dissection of the CIC-DUX4 fusion oncoprotein and identified key target genes that drive tumor progression and survival. One critical CIC-DUX4 transcriptional target is the CCNE-CDK2 complex, which promotes CIC-DUX4 sarcoma growth and survival. Our proposed work will leverage these mechanistic insights to develop a more rational therapeutic strategy using clinically advanced CDK2 inhibitors to specifically target the CCNE-CDK2 complex in multiple patient-derived CIC-DUX4 sarcoma models.
Objective/Hypothesis: We hypothesize that the CCNE-CDK2 complex is a therapeutic vulnerability in CIC-DUX4 sarcomas that can be rationally targeted with clinically advanced CDK2 inhibitor therapies as an innovative, mechanism-based approach to improve outcomes for CIC-DUX4 patients.
Aim 1: Targeting the CCNE-CDK2 complex to block CIC-DUX4 regulated sarcomagenesis in rare patient-derived models.
Aim 2: To globally define the physical and functional CIC-DUX4 DNA-binding landscape in undifferentiated sarcoma.
Study Design/Methods: In aim 1, we will leverage our rare, clinically annotated CIC-DUX4 patient-derived models to test the preclinical efficacy of pharmacologic CDK2 inhibition. We will treat the world’s largest CIC-DUX4 patient-derived biobank (PDXs and PDCLs) with clinically advanced CDK2 inhibitors, Dinaciclib and Fadraciclib (CYC065) as a prelude to a clinical trial. We will develop CDK2 inhibitor drug resistant CIC-DUX4 models in parallel to further understand the mechanisms that drive CDK2 inhibitor resistance. In aim 2, we will define the CIC-DUX4 cistrome through comprehensive ChIP-Seq analysis of CIC-DUX4 DNA-binding and histone modifications to uncover new therapeutic vulnerabilities.
Innovation: This proposal is innovative because the current clinical management of CIC-DUX4 sarcoma borrows “salvage” chemotherapy from other morphologically similar sarcomas. This approach is ineffective and leads to dismal outcomes for CIC-DUX4 patients. We will leverage mechanistically-informed studies to more rationally target CIC-DUX4 sarcomas through pharmacologic interception of the CCNE-CDK2 complex, offering a paradigm shifting precision-based strategy to treat CIC-DUX4 patients.
Impact: There is no standard therapy for CIC-DUX4 sarcoma, which remains universally lethal in the metastatic setting