Abstract A081: The pan-quadruplex experimental drug QN-302 in pancreatic ductal adenocarcinoma (PDAC): Potential biomarkers for clinical studies

Abstract

Abstract Quadruplexes (G4s) are formed from G-rich elements widely prevalent in the human and other genomes. They comprise repetitive G-tracts of varying length, interspersed with short general sequences, which can fold into higher-order four-stranded G4 structures under appropriate circumstances. Their prevalence is non-random, and they are over-represented in the promoter and untranslated regions of genes involved in replication and replication pathways, especially in cancer-related events and pathways. Promoter G4s have been characterised in, for example, the RAS, MYC, KIT, B-RAF, HIF, VEGF genes. The existence of stable G4 structures within duplex DNA is likely to be transient since they can be effectively unwound by helicases. However, it is now well-established that they can be stabilised by appropriate small molecules, leading to impairment of polymerase precession and transcription factor binding, and then to down-regulation of the expression of the affected gene. This therapeutic strategy has been exploited in the design of a series of potent G4-binding compounds based on the naphthalene diimide framework, culminating in the development of the compound QN-302, which has selectivity to PDAC cell lines with low nM potency. It is also active in several in vivo models of PDAC. Its transcriptional profile shows that it affects multiple G4 promoter genes and thus acts as a pan-G4 agent. QN-302 has been undergoing pre-clinical development by Qualigen Inc and in 2022 was granted Orphan Drug designation for PDAC by the FDA. It is currently being evaluated for clinical development in solid tumors including PDAC. As part of this program, several potential biomarkers are currently being considered. These in large part are suggested by the transcriptome analyses of QN-302 in cells and in vivo. They are established markers of progressive PDAC and thus may be useful for indicating the success of QN-302 therapy in humans. In addition, our orthotopic study of the effects of QN-302 on orthotopically implanted BX-PC3 tumors has indicated that circulating tumor DNA may be a useful indicator of tumor regression by QN-302. Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The pan-quadruplex experimental drug QN-302 in pancreatic ductal adenocarcinoma (PDAC): Potential biomarkers for clinical studies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A081.