Abstract 6859: Targeting scaffold/matrix associated regions in pancreatic ductal adenocarcinoma

Abstract Pancreatic cancer is the tenth most common cancer in the United States and is projected to become the second leading cause of cancer-related death by 2030. Most cases arise in exocrine cells and are driven by genetic mutations, such as KRAS and CDKN2A, as well as modifiable risk factors, including alcohol use, chronic pancreatitis, and obesity. The aggressive nature of pancreatic ductal adenocarcinoma (PDAC), coupled with its complex tumor microenvironment, leads to late-stage diagnoses and a five-year survival rate of 13%. Despite advances in treatment, which include surgical resection, radiotherapy, and chemotherapeutic regimens like gemcitabine and FOLFIRINOX, therapy-related toxicity and chemotherapy resistance remain significant barriers to improved outcomes. One promising therapeutic approach involves exploiting vulnerabilities in the DNA damage response (DDR) pathways unique to cancer cells. While cancer cells rely on an aberrant DDR to sustain unchecked replication, their increased mutational burden renders them particularly susceptible to DNA-targeting therapies. However, existing DNA-targeting treatments are limited by off-target effects, resulting in toxicity and the emergence of resistance. This underscores the need for novel, selective drugs capable of targeting DNA processes specific to cancer cells. We report on a novel carbazole-derived compound that represents a significant advancement in PDAC therapy. Carbazole, a nitrogen-containing heterocyclic molecule, serves as a pharmacophore in therapeutics with diverse applications, including antitumor, antiviral, and anti-inflammatory agents. Our compound demonstrates potent inhibition of PDAC growth and metastasis in both in vitro and in vivo models while sparing normal cells. Our results reveal that our compound blocks PDAC growth and progression by selectively targeting Scaffold/Matrix Associated Regions (S/MARs), which play critical roles in several processes including increasing the rate of transcription initiation, providing support to origin of replication as well as chromatin organization. By disrupting S/MARs and their associated binding proteins, our compound inhibits specific genes that support replication and DNA repair processes. This study will set the stage for a new paradigm of treating PDAC using a carbazole-derivative that is highly potent, has unique mechanism of action and shows minimal toxicity. Furthermore, its potential to complement existing treatments positions it as a promising candidate for PDAC therapy. Citation Format: Jack Prochnau, Daisy Medina, Xena Huang, Panneerdoss Subbarayalu, Deepika Singh, Stanton McHardy, Manjeet Rao. Targeting scaffold/matrix associated regions in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6859.