Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma
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 tre...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-021-02135-x |
| _version_ | 1818688859911749632 |
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| author | Raghupathy Vengoji Pranita Atri Muzafar A. Macha Parthasarathy Seshacharyulu Naveenkumar Perumal Kavita Mallya Yutong Liu Lynette M. Smith Satyanarayana Rachagani Sidharth Mahapatra Moorthy P. Ponnusamy Maneesh Jain Surinder K. Batra Nicole Shonka |
| author_facet | Raghupathy Vengoji Pranita Atri Muzafar A. Macha Parthasarathy Seshacharyulu Naveenkumar Perumal Kavita Mallya Yutong Liu Lynette M. Smith Satyanarayana Rachagani Sidharth Mahapatra Moorthy P. Ponnusamy Maneesh Jain Surinder K. Batra Nicole Shonka |
| author_sort | Raghupathy Vengoji |
| collection | DOAJ |
| description | 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 - PTENflox/+; EGFRvIII+; p16Flox/− & GFAP Cre +). PCI-24781 significantly inhibited tumor growth and downregulated DNA repair machinery (BRCA1, CHK1, RAD51, and O6-methylguanine-DNA- methyltransferase (MGMT)), increasing DNA double-strand breaks and causing apoptosis in the GBM cell lines, including an MGMT expressing cell line in vitro. Further, PCI-24781 decreased tumor burden in a PEPG GBM mouse model. Notably, TMZ + PCI increased survival in orthotopic murine models compared to TMZ + vorinostat, a pan-HDAC inhibitor that proved unsuccessful in clinical trials. 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. |
| first_indexed | 2024-12-17T12:00:55Z |
| format | Article |
| id | doaj.art-4e0ce5e978e945f986e962d8700e2ec6 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-17T12:00:55Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-4e0ce5e978e945f986e962d8700e2ec62022-12-21T21:49:51ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-10-0140111710.1186/s13046-021-02135-xDifferential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for GlioblastomaRaghupathy Vengoji0Pranita Atri1Muzafar A. Macha2Parthasarathy Seshacharyulu3Naveenkumar Perumal4Kavita Mallya5Yutong Liu6Lynette M. Smith7Satyanarayana Rachagani8Sidharth Mahapatra9Moorthy P. Ponnusamy10Maneesh Jain11Surinder K. Batra12Nicole Shonka13Department of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Radiology, University of Nebraska Medical CenterDepartment of Biostatistics, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterFred and Pamela Buffett Cancer Center, University of Nebraska Medical CenterAbstract 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 - PTENflox/+; EGFRvIII+; p16Flox/− & GFAP Cre +). PCI-24781 significantly inhibited tumor growth and downregulated DNA repair machinery (BRCA1, CHK1, RAD51, and O6-methylguanine-DNA- methyltransferase (MGMT)), increasing DNA double-strand breaks and causing apoptosis in the GBM cell lines, including an MGMT expressing cell line in vitro. Further, PCI-24781 decreased tumor burden in a PEPG GBM mouse model. Notably, TMZ + PCI increased survival in orthotopic murine models compared to TMZ + vorinostat, a pan-HDAC inhibitor that proved unsuccessful in clinical trials. 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.https://doi.org/10.1186/s13046-021-02135-xConnectivity mapIn silico analysisGlioblastomaHDACBlood-brain barrier |
| spellingShingle | Raghupathy Vengoji Pranita Atri Muzafar A. Macha Parthasarathy Seshacharyulu Naveenkumar Perumal Kavita Mallya Yutong Liu Lynette M. Smith Satyanarayana Rachagani Sidharth Mahapatra Moorthy P. Ponnusamy Maneesh Jain Surinder K. Batra Nicole Shonka Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma Journal of Experimental & Clinical Cancer Research Connectivity map In silico analysis Glioblastoma HDAC Blood-brain barrier |
| title | Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma |
| title_full | Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma |
| title_fullStr | Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma |
| title_full_unstemmed | Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma |
| title_short | Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma |
| title_sort | differential gene expression based connectivity mapping identified novel drug candidate and improved temozolomide efficacy for glioblastoma |
| topic | Connectivity map In silico analysis Glioblastoma HDAC Blood-brain barrier |
| url | https://doi.org/10.1186/s13046-021-02135-x |
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