Investigating IDH-Mutant Glioma Sensitivity to Statins

Authors:

Ammy Yuan, Yutong Wang, Julie Miller

Date Created:

2025-01-01

Course Title:

Professor:

Not specified

About Paper:

IDH-mutant gliomas are a biologically and clinically distinct oligodendroglioma line TSS2. To validate these findings, dose- subclass of brain tumors defined by mutations in the metabolic response assays were performed in TSS2 and extended to a panel genes IDH1 and IDH2, which lead to accumulation of the of additional IDH-mutant glioma cell lines. Most lines tested oncometabolite D-2-hydroxyglutarate (2-HG) and disruption of exhibited sensitivity to statins, confirming generalizability of the NADPH homeostasis. This altered redox environment renders effect. Additional experiments demonstrated that statins synergize these tumors potentially vulnerable to therapies targeting NADPH- with the CDK4/6 inhibitor abemaciclib, further enhancing their dependent anabolic processes such as cholesterol biosynthesis. antiproliferativeeffects. Futuredirectionsincludeevaluatingstatin Our work examines statins, which inhibit HMG-CoA reductase efficacy in vivo in a mouse model and conducting combination in the mevalonate pathway, reduce intracellular cholesterol, and testing with chemotherapies and inhibitors of alternative metabolic impair oncogenic signaling, making them candidates for targeting pathways. These results support the potential of statins as a these metabolic vulnerabilities. Our preliminary high-throughput metabolic therapy in IDH-mutant gliomas and suggest novel screen identified multiple statins as hits in the IDH-mutant combinatorial treatment strategies. Characterizing p107 and p130 Knockout Cell Lines Evan Zhang, Lukas Noeltner, James A. DeCaprio Harvard College | Currier House | Molecular and Cellular Biology | 2028 The cell cycle is a complex, multi-stage process that is tightly using western blotting and genome sequencing. Cell counting data regulated at a transcriptional level. The transcription factor and parameters derived from it were used to compare the growth complexes RB/E2F and DREAM/MuvB orchestrate cell cycle patterns between the single guide control cells and the knockout gene expression during the appropriate phases. Cyclin-dependent cell lines. This comprehensive characterization reduces the risk kinases (CDKs) phosphorylate the pocket proteins RB, RBL1 of studying effects unique to specific clones. Additionally, the (p107), and RBL2 (p130) upon mitogen stimulation allowing for impact of p107 and p130 loss on density-dependent growth arrest the expression of cell cycle genes. These signaling pathways are was both analyzed through flow cytometry with an EdU/DAPI deregulated in cancer, for instance, due to an increased activity odouble staining, and compared to single guide control cells. After CDK2 and CDK4/6. CDK inhibitors serve as a form of cancer characterizing the three cell lines, I plan to use flow cytometry to treatment, and their effects on RB have been studied extensively. quantify the impacts of CDK2 and CDK4/6 inhibitors on the cell However, little is known about their effects on p107 and p130. lines. Ultimately, the results from studying the growth of double In this study, I explored the contribution of p107 and p130 to knockout cell lines and the effects of CDK inhibitors on them can the function of CDK2 and CDK4/6 inhibitors using three p107-/- improve our understanding of both the role of p107/p130, and the p130-/- CRISPR-dKO RPE-1 cell lines. The absence of p107 and clinical potential of certain CDK inhibitors in treating cancer. p130 within the three double knockout cell lines was confirmed 140 Program for Research in Science and Engineering Bridging Data and Decision-Making: An Intuitive Interface for Large-Scale Disease Transmission Reconstruction Xinyi Christine Zhang, Pardis Sabeti Harvard College | Dunster House | Computer Science | 2027 During an outbreak, computational models of disease transmission such as JUNIPER are complex and lack a straightforward interface provide valuable insights that can inform public health for data analysis, making them difficult for non-specialists to use. interventions. These models integrate genomic and temporal data We introduce an interactive platform built around JUNIPER that to infer infection links between individuals, in other words a bestcombines graph-based models with an intuitive design to visualize estimate of who-infected-whom. JUNIPER (Joint Underlying outbreaks and provide estimates of various parameters related to Network Inference for Phylogenetic and Epidemiological pathogen spread based on user inputs. The platform’s emphasis Reconstructions) is a statistical framework that accounts for viralon quantifying uncertainty in outputs enables users to extract mutationsthataccumulatebothwithinandbetweenhostsovertime epidemiological insights from multiple plausible transmission to inform infection links, while also incorporating cases that may networks. This tool provides a practical avenue to leverage have remained unsampled or undetected during the outbreak. This advanced statistical methods, supporting epidemiologists and enablestransmissionreconstructionsthataremoreaccuratetoreal- public health officials in real-time outbreak surveillance and world disease testing circumstances. However, large-scale models control. Lesion-Driven Pathway Choice in DNA Damage Tolerance: RecO and SSB Modulate TLS and Repriming in Escherichia coli Nicholas Zhang, Seungwoo Chang, Joseph Loparo Harvard College | Dunster House | Neuroscience | 2028 During DNA replication, replication machinery often encounters alleles, including the mutation that ablates the interaction with adverse blocking lesions on the DNA template. Lesions are SSB, and quantify TLS frequency through blue-white colorimetric induced both endogenously and exogenously through various scoring. Ongoing assays are being performed to determine the stresses, including antibiotics, and vary in blocking potency. roles of RecO and SSB in pathway preference, involving more Cells with lesion stalled replication use two competing resolution lesions of varying characteristics. Further research on pathway pathways: low-fidelity translesion synthesis (TLS) and high- choice-regulating protein-protein interaction may uncover new fidelity repriming. Our study examines the role of the interaction strategies to suppress mutagenic TLS, a possible contributor to the between RecO, a recombination factor, and SSB, a replication development of antibiotic resistance. This could pave the way for factor, in facilitating the repriming pathway. We use a cell- novel antimicrobial therapies that minimize the risk of inducing based assay that monitors pathway choices of stalled replication resistance, which is an urgent priority in combating multidrug- between TLS and repriming. In our assay, we incorporate various resistant infections. blocking lesions into E. coli genomes bearing a range of recO Reprogramming of Granulosa Cells via BTP and L1L2 Gene Disruption to In-

Abstract:

IDH-mutant gliomas are a biologically and clinically distinct oligodendroglioma line TSS2. To validate these findings, dose- subclass of brain tumors defined by mutations in the metabolic response assays were performed in TSS2 and extended to a panel genes IDH1 and IDH2, which lead to accumulation of the of additional IDH-mutant glioma cell lines. Most lines tested oncometabolite D-2-hydroxyglutarate (2-HG) and disruption of exhibited sensitivity to statins, confirming generalizability of the NADPH homeostasis. This altered redox environment renders effect. Additional experiments demonstrated that statins synergize these tumors potentially vulnerable to therapies targeting NADPH- with the CDK4/6 inhibitor abemaciclib, further enhancing their dependent anabolic processes such as cholesterol biosynthesis. antiproliferativeeffects. Futuredirectionsincludeevaluatingstatin Our work examines statins, which inhibit HMG-CoA reductase efficacy in vivo in a mouse model and conducting combination in the mevalonate pathway, reduce intracellular cholesterol, and testing with chemotherapies and inhibitors of alternative metabolic impair oncogenic signaling, making them candidates for targeting pathways. These results support the potential of statins as a these metabolic vulnerabilities. Our preliminary high-throughput metabolic therapy in IDH-mutant gliomas and suggest novel screen identified multiple statins as hits in the IDH-mutant combinatorial treatment strategies. Characterizing p107 and p130 Knockout Cell Lines Evan Zhang, Lukas Noeltner, James A. DeCaprio Harvard College | Currier House | Molecular and Cellular Biology | 2028 The cell cycle is a complex, multi-stage process that is tightly using western blotting and genome sequencing. Cell counting data regulated at a transcriptional level. The transcription factor and parameters derived from it were used to compare the growth complexes RB/E2F and DREAM/MuvB orchestrate cell cycle patterns between the single guide control cells and the knockout gene expression during the appropriate phases. Cyclin-dependent cell lines. This comprehensive characterization reduces the risk kinases (CDKs) phosphorylate the pocket proteins RB, RBL1 of studying effects unique to specific clones. Additionally, the (p107), and RBL2 (p130) upon mitogen stimulation allowing for impact of p107 and p130 loss on density-dependent growth arrest the expression of cell cycle genes. These signaling pathways are was both analyzed through flow cytometry with an EdU/DAPI deregulated in cancer, for instance, due to an increased activity odouble staining, and compared to single guide control cells. After CDK2 and CDK4/6. CDK inhibitors serve as a form of cancer characterizing the three cell lines, I plan to use flow cytometry to treatment, and their effects on RB have been studied extensively. quantify the impacts of CDK2 and CDK4/6 inhibitors on the cell However, little is known about their effects on p107 and p130. lines. Ultimately, the results from studying the growth of double In this study, I explored the contribution of p107 and p130 to knockout cell lines and the effects of CDK inhibitors on them can the function of CDK2 and CDK4/6 inhibitors using three p107-/- improve our understanding of both the role of p107/p130, and the p130-/- CRISPR-dKO RPE-1 cell lines. The absence of p107 and clinical potential of certain CDK inhibitors in treating cancer. p130 within the three double knockout cell lines was confirmed 140 Program for Research in Science and Engineering Bridging Data and Decision-Making: An Intuitive Interface for Large-Scale Disease Transmission Reconstruction Xinyi Christine Zhang, Pardis Sabeti Harvard College | Dunster House | Computer Science | 2027 During an outbreak, computational models of disease transmission such as JUNIPER are complex and lack a straightforward interface provide valuable insights that can inform public health for data analysis, making them difficult for non-specialists to use. interventions. These models integrate genomic and temporal data We introduce an interactive platform built around JUNIPER that to infer infection links between individuals, in other words a bestcombines graph-based models with an intuitive design to visualize estimate of who-infected-whom. JUNIPER (Joint Underlying outbreaks and provide estimates of various parameters related to Network Inference for Phylogenetic and Epidemiological pathogen spread based on user inputs. The platform’s emphasis Reconstructions) is a statistical framework that accounts for viralon quantifying uncertainty in outputs enables users to extract mutationsthataccumulatebothwithinandbetweenhostsovertime epidemiological insights from multiple plausible transmission to inform infection links, while also incorporating cases that may networks. This tool provides a practical avenue to leverage have remained unsampled or undetected during the outbreak. This advanced statistical methods, supporting epidemiologists and enablestransmissionreconstructionsthataremoreaccuratetoreal- public health officials in real-time outbreak surveillance and world disease testing circumstances. However, large-scale models control. Lesion-Driven Pathway Choice in DNA Damage Tolerance: RecO and SSB Modulate TLS and Repriming in Escherichia coli Nicholas Zhang, Seungwoo Chang, Joseph Loparo Harvard College | Dunster House | Neuroscience | 2028 During DNA replication, replication machinery often encounters alleles, including the mutation that ablates the interaction with adverse blocking lesions on the DNA template. Lesions are SSB, and quantify TLS frequency through blue-white colorimetric induced both endogenously and exogenously through various scoring. Ongoing assays are being performed to determine the stresses, including antibiotics, and vary in blocking potency. roles of RecO and SSB in pathway preference, involving more Cells with lesion stalled replication use two competing resolution lesions of varying characteristics. Further research on pathway pathways: low-fidelity translesion synthesis (TLS) and high- choice-regulating protein-protein interaction may uncover new fidelity repriming. Our study examines the role of the interaction strategies to suppress mutagenic TLS, a possible contributor to the between RecO, a recombination factor, and SSB, a replication development of antibiotic resistance. This could pave the way for factor, in facilitating the repriming pathway. We use a cell- novel antimicrobial therapies that minimize the risk of inducing based assay that monitors pathway choices of stalled replication resistance, which is an urgent priority in combating multidrug- between TLS and repriming. In our assay, we incorporate various resistant infections. blocking lesions into E. coli genomes bearing a range of recO Reprogramming of Granulosa Cells via BTP and L1L2 Gene Disruption to In-

Source:

Harvard / Harvard College | Leverett House | Mechanical Engineering | 2028 / 2025

Topics:

cell, line, pathway, p107, p130, inhibitor, statin, lesion, idh, effect, model, tls

Co-authors:

@ammyyuan403 , @yutongwang404 , @juliemiller405