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Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC. However, the number of possible combinations of pharmacological agents is too large to be explored experimentally. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as the game changers especially in combined therapy settings. In this work, we explored a possibility of using drug-sensitivity data together with the basal gene expression of pancreatic cell lines to predict combinatorial options available for HDACi. Developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC identified the sphingolipid signaling pathway with associated downstream effectors as a promising novel targets for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.

 

Comments:

It seems like you've provided a comprehensive overview of a research project focused on pancreatic ductal adenocarcinoma (PDAC) and the development of novel pharmacological approaches, particularly involving the use of histone deacetylase inhibitors (HDACi) in combination therapy. The work appears to involve a bioinformatics screening protocol for predicting synergistic drug combinations in PDAC.

Here's a breakdown of the key points from your description:

1. **Background on PDAC:** You've highlighted PDAC as an aggressive and lethal malignancy, emphasizing the need for novel approaches due to the development of chemoresistance.

2. **Rationale for Combination Therapy:** Acknowledging the vast number of potential drug combinations, you stress the importance of systematically tailored combination therapy to improve treatment outcomes.

3. **Role of Epigenetic Drugs:** Given the numerous epigenetic alterations in PDAC, you propose that epigenetic drugs, particularly HDACi, could be pivotal in combined therapy settings.

4. **Bioinformatics Screening Protocol:** You describe the development of a bioinformatics screening protocol that utilizes drug-sensitivity data and basal gene expression of pancreatic cell lines. This protocol aims to predict synergistic drug combinations involving HDACi.

5. **Identified Target Pathway:** The screening protocol led to the identification of the sphingolipid signaling pathway, along with its downstream effectors, as promising novel targets for future multi-target therapeutics or combined therapy with HDACi.

6. **Experimental Validation:** The research involves experimental validation, and you mention the characterization of novel synergisms between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, as well as between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.

This summary provides a clear outline of the rationale, methods, and key findings of the research project. It demonstrates a multidisciplinary approach, incorporating bioinformatics and experimental validation, which is crucial for advancing our understanding of PDAC and developing effective treatment strategies.