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Connectivity Mapping-based Identification and Pre-clinical Evaluation of ISOX: A Novel Therapeutic for Pancreatic Cancer

ABSTRACT: Pancreatic Cancer (PC) remains highly lethal due to limited therapeutic options. Here we utilize a genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting. ISOX emerged as a top potential drug from the CMAP pipeline across human PC tissues, cell lines, tumoroids, and patient-derived xenografts datasets. Here, we use PC cells, human and mouse tumoroids, and in vivo mouse models to test the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Transcriptomic and pathway analysis of the ISOX-LINCS signature identified the various pathways as targets for ISOX, suggesting a multiple-target action. Specifically, we discovered that genetic and pharmacological targeting of HDAC6 affected non-histone protein cMYC acetylation leading to cMYC instability, thereby disrupting PC stem cells. Finally, KrasG12D harboring organoids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a novel drug to treat advanced PC patients without toxicity to normal cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE240597 | GEO | 2024/03/13

REPOSITORIES: GEO

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Project description:Purpose: Advanced high-grade gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) are highly aggressive and heterogeneous epithelial malignancies with poor clinical outcomes. No therapeutic predictive biomarkers exist and representative preclinical models to study their biology are missing. Patient-derived (PD) tumoroids may enable fast ex vivo pharmacotyping and provide subsidiary biological information for more personalized therapy strategies in individual patients. Experimental Design: PD tumoroids were established from rare biobanked surgical resections of advanced high-grade GEP-NEN patients. Using targeted in vitro pharmacotyping and next-generation sequencing of patient samples and matching PD tumoroids, we profiled individual patients and compared treatment-induced molecular stress response and in vitro drug sensitivity to the clinical therapy response. Results: We demonstrate high success rates in culturing PD tumoroids of high-grade GEP-NENs within clinically meaningful timespans. PD tumoroids recapitulate biological key features of high-grade GEP-NEN and mimic clinical response to cisplatin and temozolomide in vitro. Moreover, investigating treatment-induced molecular stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A (KDM5A) and interferon-beta (IFNB1) as two vulnerabilities that act synergistically in combination with cisplatin and may present novel therapeutic options in high-grade GEP-NENs. Conclusion: Patient-derived tumoroids from high-grade GEP-NENs represent a relevant model to screen drug sensitivities of individual patients within clinically relevant timespans and provide novel functional insights into drug-induced stress responses. Clinical patient response to standard-of-care chemotherapeutics matches with drug sensitivities of PD tumoroids. Together, our findings provide a functional precision oncology approach for gathering patient-centered subsidiary treatment information that will potentially increase therapeutic opportunities in the framework of personalized medicine.

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Connectivity Mapping-based Identification and Pre-clinical Evaluation of ISOX: A Novel Therapeutic for Pancreatic Cancer

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