Abstract 4981: The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in in vitro and in vivo models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC

Abstract

Abstract The compound QN-302, a tetra-substituted naphthalene diimide (ND) derivative has been designed to have high affinity for G-quadruplex (G4) nucleic acids. It has single-digit nM anti-proliferative activity in a panel of human pancreatic cancer cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and anti-tumor activity in xenograft, orthotopic and genetic (KPC) models for pancreatic cancer (PDAC). Its mode of action involves the targeting of G4-forming sites in promoter regions of cancer-associated genes, where their prevalence is over-represented compared to other genes. Transcriptome analyses of QN-302 in MIA-PACA2 cells have confirmed genes involved in cancer-associated pathways and carry G4 motifs in their promoters as targets. We have found that expression of the S100P gene, a well-authenticated indicator of PDAC disease and progression, is highly down-regulated in QN-302 treated cells. The S100P gene contains at least five putative G4 motifs, including a classic G4 promoter site just upstream of the transcription start site. We have observed that transcriptome analyses on tumor material from human PDAC patients, and those from poorly differentiated as well as more highly differentiated tumors, have shown that the S100P gene is highly over-expressed (especially in poorly differentiated tumors). We now report on gene expression analysis of S100P using control and treated tumor tissues from a therapeutic study in PDAC MIA-PACA2 xenografts in mice, by means of RT-qPCR and Western blot analyses. The data shows statistically significant dose-dependent decreases in expression of S100P at both the mRNA (to ca 25% of control values) and protein levels (to ca 22% of control values), giving added confidence to the concept that the S100P gene is a therapeutic target in PDAC and may also be useful as a marker of QN-302 response in future clinical use. QN-302 is bio-available at therapeutic doses and is well tolerated at these levels in the animal models. It is being developed for clinical evaluation by Qualigen Therapeutics Inc and is currently at the pre-IND stage. Citation Format: Nicole Williams, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The potent quadruplex-binding compound QN-302 down-regulates the S100P gene in in vitro and in vivo models of pancreatic cancer: a potential therapeutic target and biomarker for PDAC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4981.