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Published on: August 10, 2017
Connectivity mapping-based identification of pharmacological inhibitor targeting HDAC6 in aggressive pancreatic
Pranita Atri1, Ashu Shah1, Gopalakrishnan Natarajan1
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to limited therapeutic options and expensive/burdensome drug discovery processes. Utilizing genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting may improve pancreatic cancer (PC) patient outcomes. Initially, we mapped CMAP data to gene expression from 106 PC patients, identifying nine negatively connected drugs. These drugs were further narrowed down using a similar analysis for PC cell lines, human tumoroids, and patient-derived xenografts datasets, where ISOX emerged as the most potent agent to target PC. We used human and mouse syngeneic PC cells, human and mouse tumoroids, and in vivo mice to assess the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Global transcriptomic and pathway analysis of the ISOX-LINCS signature identified HDAC 6/cMyc as the target axis for ISOX. Specifically, we discovered that genetic and pharmacological targeting of HDAC 6 affected non-histone protein cMyc acetylation, leading to cMyc instability, thereby disrupting PC growth and metastasis by affecting cancer stemness. Finally, KrasG12D harboring tumoroids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a new drug to treat advanced PC patients without toxicity to normal cells. Our study supports the clinical utility of ISOX along with 5FU in future PC clinical trials.
Insights
This study identifies ISOX as a promising drug for pancreatic cancer (PC) treatment. ISOX targets the HDAC 6/cMyc pathway, showing efficacy in preclinical models and enhancing survival with 5FU.
Area of Science:
- Oncology
- Genomics
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents a significant therapeutic challenge due to limited treatment options and costly drug development.
- Genomic-data-driven approaches like Connectivity Mapping (CMAP) offer potential for identifying novel pancreatic cancer (PC) drug candidates.
- Improving patient outcomes requires innovative strategies to target PC effectively.
Purpose of the Study:
- To identify and validate a novel therapeutic agent for pancreatic cancer (PC) using genomic data.
- To investigate the molecular mechanisms underlying the efficacy of the identified drug candidate.
- To evaluate the therapeutic potential of ISOX, alone and in combination with 5FU, in preclinical models of PC.
Main Methods:
- Utilized Connectivity Mapping (CMAP) analysis on gene expression data from 106 PC patients to identify potential drug candidates.
- Validated drug candidates through analysis of PC cell lines, human tumoroids, and patient-derived xenografts.
- Assessed the efficacy of ISOX and 5FU in inhibiting tumor growth using syngeneic PC cells, tumoroids, and in vivo mouse models.
- Performed global transcriptomic and pathway analysis to elucidate the molecular targets of ISOX.
Main Results:
- Connectivity Mapping identified nine negatively connected drugs, with ISOX emerging as the most potent agent against PC.
- Transcriptomic analysis revealed that ISOX targets the HDAC 6/cMyc axis, leading to cMyc instability and disruption of PC growth and metastasis.
- ISOX demonstrated efficacy in inhibiting tumor growth and metastasis in various preclinical models, including KrasG12D-harboring tumoroids and mice.
- Combined treatment with ISOX and 5FU significantly enhanced survival and controlled metastasis in preclinical models without toxicity to normal cells.
Conclusions:
- ISOX is validated as a novel therapeutic agent for advanced pancreatic cancer (PC) with a favorable safety profile.
- The HDAC 6/cMyc pathway is a critical target for ISOX in disrupting PC progression and stemness.
- ISOX, in combination with 5FU, holds significant clinical potential for future pancreatic cancer (PC) trials.
