DigitalCommons@UNMC

Title

Differential Gene Expression-Based Connectivity Mapping Identified Novel Drug Candidate and Improved Temozolomide Efficacy for Glioblastoma

Authors

Raghupathy Vengoji, University of Nebraska Medical CenterFollow
Pranita Atri, University of Nebraska Medical CenterFollow
Muzafar A. Macha, Islamic University of Science and Technology
Parthasarathy Seshacharyulu, University of Nebraska Medical CenterFollow
Naveenkumar Perumal, University of Nebraska Medical CenterFollow
Kavita Mallya, University of Nebraska Medical CenterFollow
Yutong Liu, University of Nebraska Medical CenterFollow
Lynette M. Smith, University of Nebraska-LincolnFollow
Satyanarayana Rachagani, University of Nebraska Medical CenterFollow
Sidharth Mahapatra, University of Nebraska Medical CenterFollow
Moorthy P. Ponnusamy, University of Nebraska Medical CenterFollow
Maneesh Jain, University of Nebraska Medical CenterFollow
Surinder K. Batra, University of Nebraska Medical CenterFollow
Nicole Shonka, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Journal of Experimental & Clinical Cancer Research

Publication Date

2021

Volume

40

Abstract

BACKGROUND: Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment.

METHODS: We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM's specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability.

RESULTS: We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTEN

CONCLUSION: PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation.

ISSN

1756-9966

DOI Link

10.1186/s13046-021-02135-x

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Vengoji, Raghupathy; Atri, Pranita; Macha, Muzafar A.; Seshacharyulu, Parthasarathy; Perumal, Naveenkumar; Mallya, Kavita; Liu, Yutong; Smith, Lynette M.; Rachagani, Satyanarayana; Mahapatra, Sidharth; Ponnusamy, Moorthy P.; Jain, Maneesh; Batra, Surinder K.; and Shonka, Nicole, "Differential Gene Expression-Based Connectivity Mapping Identified Novel Drug Candidate and Improved Temozolomide Efficacy for Glioblastoma" (2021). Journal Articles: Biochemistry & Molecular Biology. 144.
https://digitalcommons.unmc.edu/com_bio_articles/144