Abstract B021: Investigating the cyclin A/B RxL inhibitor CID-078 in pediatric cancers with RB1 loss and high E2F1

Abstract The cyclin-dependent kinase (CDK)-RB-E2F axis forms the core transcriptional machinery driving cell cycle progression. Alterations in RB1 or other key components occur in many cancers, leading to increased oncogenic E2F activity. E2F down regulation at the end of S phase relies on the interaction between the cyclin’s conserved hydrophobic patch (HP) and the RxL motif found on E2F and other cyclin/CDK substrates. Disrupting this cyclin A/E2F RxL interaction leads to hyperactivation of E2F and synthetic lethality in E2F-driven tumors. The cyclin A/B RxL inhibitor CID-078 is a novel, orally bioavailable, passively cell-permeable, potent and selective macrocycle that functions by disrupting the RxL binding of E2F and Myt1 to the HP on cyclin A2-CDK2 and cyclin B1-CDK1, respectively, inducing cell cycle arrest at G2/M phase leading to cellular apoptosis. In preclinical studies, CID-078 has induced tumor regression in multiple E2F-high cancer models. A subset of pediatric cancers exhibits aberrant up-regulation of E2F1 with or without RB1-alterations. Therefore, CID-078 presents as a novel therapeutic option in pediatric cancers. The ZERO Childhood Cancer Precision Medicine Program (ZERO) performs comprehensive molecular profiling (whole genome sequencing, RNA-sequencing and methylation analysis) on all children (≤18 years) with cancer in Australia regardless of disease type. Utilizing data from over 2800 tumor samples, we identified tumors with RB1 alterations, increased E2F1 expression or CDKN2A/B loss, key biomarkers of interest for CID-078 sensitivity. In ZERO we detected RB1 alterations 5% of pediatric tumors, 14% of pediatric tumors exhibited increased expression of E2F1 and 11% had CDKN2A/B loss. These biomarkers were identified across diverse cancer types including, retinoblastoma, osteosarcoma (OS), rhabdomyosarcoma, Ewing’s sarcoma (EWS), neuroblastoma, high-grade glioma, medulloblastoma, Burkitt Lymphoma and acute lymphoblastic leukemia.In vitro activity of CID-078 was tested against a range of patient-derived cell lines from ZERO tumor samples representing a range of pediatric cancer subtypes and categorized based on RB1 alterations, high E2F1 expression and/or CDKN2A/B loss. The metabolic activity of CID-078 treated cells was measured, by CellTiter-Glo® assay. The AUC (area under the curve), IC50 (half-maximal inhibitory concentration), LC50 (lethal concentration 50) and GI50 (growth inhibitory power) of CID-078 were calculated. Here, we will present the initial correlation data between CID-078 sensitivity and RB1, E2F1, and CDKN2A/B biomarker status. These evaluations may enable predictive biomarker mapping across the entire ZERO cohort and inform strategies for real-time patient identification and stratification in future pediatric studies of CID-078. Ultimately, this work will inform the relative contributions of biomarkers and tumor type/histology to CID-078 activity and potentially support optimized enrollment of patients with pediatric cancer on future clinical trials. Citation Format: Chelsea Mayoh, Jinhan Xie, Gabor Tax, Li-Pen Ben Tsao, Li-Fen Liu, Emmy G Fleuren, Catherine E Gleason, Lisa M Kopp, Michael C Cox, Emily VA Mould. Investigating the cyclin A/B RxL inhibitor CID-078 in pediatric cancers with RB1 loss and high E2F1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B021.