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Velcrin molecular glues induce apoptosis in glioblastomas with high PDE3A and SLFN12 expression
Elisa Aquilanti1,2,3, Silvia Goldoni4, Andrew Baker5
1Cancer Program, Broad Institute, Cambridge, Massachusetts, USA.
Background:
Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNALeu(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the cancer cell line encyclopedia, including glioblastoma cell lines. We therefore aim to characterize velcrins as novel therapeutic agents in glioblastoma.
Materials And Methods:
PDE3A and SLFN12 expression levels were measured in glioblastoma cell lines, the Cancer Genome Atlas (TCGA) tumor samples, and tumor neurospheres. Velcrin-treated cells were assayed for viability, induction of apoptosis, cell cycle phases, and global changes in translation. Transcriptional profiling of the cells was obtained. Xenograft-harboring mice treated with velcrins were also monitored for survival.
Results:
We identified several velcrin-sensitive glioblastoma cell lines and 4 velcrin-sensitive glioblastoma patient-derived models. We determined that BAY 2666605 crosses the blood-brain barrier and elicits full tumor regression in an orthotopic xenograft model of GB1 cells. We also determined that the velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma PDX models.
Conclusions:
Velcrins have antitumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.
Insights
Velcrins, a new class of molecular glues, show promise in treating glioblastoma. These compounds effectively kill glioblastoma cells and reduce tumor size in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Velcrins are molecular glues that induce apoptosis by forming a complex between RNase SLFN12 and phosphodiesterase PDE3A.
- This complex formation activates SLFN12, leading to tRNA cleavage and programmed cell death.
- Velcrins, including BAY 2666605, demonstrated activity against various solid tumors, including glioblastoma.
Purpose of the Study:
- To investigate velcrins as novel therapeutic agents for glioblastoma.
- To characterize the efficacy and mechanism of action of velcrins in glioblastoma models.
Main Methods:
- Assessed PDE3A and SLFN12 expression in glioblastoma cell lines, TCGA samples, and neurospheres.
- Evaluated velcrin-treated cells for viability, apoptosis, cell cycle, and translation.
- Conducted transcriptional profiling and monitored survival in velcrin-treated xenograft mouse models.
Main Results:
- Identified velcrin-sensitive glioblastoma cell lines and patient-derived models.
- Demonstrated that BAY 2666605 crosses the blood-brain barrier and achieves complete tumor regression in an orthotopic xenograft model.
- Showed that velcrins BAY 2666605 and BRD3800 induce tumor regression in subcutaneous glioblastoma patient-derived xenograft models.
Conclusions:
- Velcrins exhibit significant antitumor activity in preclinical glioblastoma models.
- These findings support further investigation of velcrins as potential glioblastoma therapeutics.
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