Discovery of Chronotherapeutic Candidate Targets in Pancreatic Cancer

Abstract Our "clock" system regulates diurnal variations (circadian rhythms) in biological processes to synchronize with Earth's 24-hour rotation. This rhythmic pattern presents opportunities for time-dependent treatments of diseases, including cancer, known as chronotherapy. Recent data from our group and others indicates that tumors exhibit temporal gene expression, with variability in rhythmic patterns among individual tumors. Mapping tumor-specific circadian rhythms is crucial to advancing chronotherapy towards clinical application, despite logistical challenges in human organ sampling. Aligned with the PI's current project and the objectives of this RFA, we propose to analyze Common Fund program datasets to develop a robust framework for targeting chronotherapeutic processes against cancer. Pancreatic ductal adenocarcinoma (PDA) will serve as our focus due to the high clinical demand for novel therapeutic strategies given its poor prognosis. Aim 1 involves profiling the cancer-specific molecular rhythmicity of human pancreatic tissue, including tumor and tumor-infiltrating immune cells, utilizing resources such as Genotype-Tissue Expression (GTEx), Gene Expression Omnibus, The Cancer Genome Atlas (TCGA), and COSMIC databases. In Aim 2, we aim to identify potential druggable targets for chronotherapy in PDA, leveraging datasets from the Knockout Mouse Phenotyping Program (KOMP2), Library of Integrated Network- based Cellular Signatures (LINCS), Illuminating the Druggable Genome (IDG), and Drug Bank. We will integrate data, methods, and resources from the parent project as appropriate. These studies will demonstrate a proof-of-concept approach to expand the use of available datasets in identifying chronotherapeutic targets not only in cancer but also in other diseases.