Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma

Zhao, Guisheng; Newbury, Patrick; Ishi, Yukitomo; Chekalin, Eugene; Zeng, Billy; Glicksberg, Benjamin S.; Wen, Anita; Paithankar, Shreya; Sasaki, Takahiro; Suri, Amreena; Nazarian, Javad; Pacold, Michael E.; Brat, Daniel J.; Nicolaides, Theodore; Chen, Bin; Hashizume, Rintaro

doi:10.1186/s40478-022-01463-z

Cited by 11 publications

(10 citation statements)

References 65 publications

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“…These tumors cells preferentially rely on de novo pyrimidine synthesis and methionine consumption [ 25 , 26 ]. Like others [ 41 ], we have found that DMG-H3K27M tumors also rely on de novo guanylate synthesis for survival. However, none of these seminal findings have considered how H3K27M-mediated metabolic changes are related to RT resistance.…”

Section: Discussionsupporting

confidence: 84%

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Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma

Peterson,

Sajjakulnukit,

Scott

et al. 2024

Cancer Metab

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Background Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. Methods We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT. Results DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo. Conclusions Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.

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Section: Discussionsupporting

confidence: 84%

“…3 F and H). Others have observed single agent efficacy of MPA in DMG-H3K27M cells [ 41 ]. While we observed a significant reduction in total neurosphere number at endpoint in DIPGXIII cells at the highest concentration of MPA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma

Peterson,

Sajjakulnukit,

Scott

et al. 2024

Cancer Metab

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“…Previous studies have demonstrated the antitumor effects of TPL on glioblastoma (27). TPL was found to have inhibition of cell viability in Diffuse intrinsic pontine glioma (DIPG) patient-derived cell lines in vitro and in vivo (28). TPL was also reported to have selective cytotoxicity to patient-derived IDH1-mutated glioma cells (29).…”

Section: Discussionmentioning

confidence: 99%

Triptolide inhibits the progression of Glioblastoma U251 cells via targeting PROX1

Yuan

Liao²,

Liao³

et al. 2023

Front. Oncol.

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BackgroundGlioblastoma multiforme (GBM) is the most lethal brain cancer in adults, characterized by rapid growth, extensive invasiveness, and poor prognosis, and there is still a lack of effective treatments. Here, we aimed to explore the role of triptolide (TPL), purified from Tripterygium wilfordii Hook F, on glioblastoma cell growth, apoptosis, proliferation, migration and invasion, as well as potential underlying mechanisms.MethodsThe publicly available clinical data of Brain Lower Grade Glioma (LGG) from The Cancer Genome Atlas (TCGA) had been screened to observe PROX1 expression. The Kaplan-Meier analysis was used to analyze the relationship between PROX1 expression and GBM prognosis. CCK8, cell cycle, EDU, apoptosis, wound healing, and transwell assays were performed to detect the effects of TPL on glioblastoma U251 cell viability, cell cycle, proliferation, apoptosis, migration and invasion, respectively. Further, a soft agar colony assay was used to calculate the growth of glioblastoma cells. The qRT-PCR and western blot were conducted to quantify PROX1 mRNA and protein levels. The transcriptional regulation of TPL was detected by Dual luciferase reporter assay.ResultsWe found that TPL inhibited glioblastoma cell viability, proliferation, cell cycle, migration and invasion, but enhanced apoptosis in a dose-dependent manner. The expression of cell cycle inhibitor, P21, and pro-apoptosis factor, Bax was increased, while invasion-related factors MMP2 and MMP9 were silenced after TPL treatments. Mechanistically, TPL showed transcriptional inhibition of PROX1 appearance. Moreover, ectopic expression of PROX1 partially rescued the effects of TPL on glioblastoma cell viability, proliferation, apoptosis, migration and invasion, and on the expression of cell function-related genes.ConclusionThis study verified that TPL inhibited the progression of glioblastoma cells by transcriptionally depressing the expression of PROX1.

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“…It contains a total of 19,127 samples including 11,715 samples from 130 distinct cancers and 1,950 healthy samples from 5 vital organs (1,148 brain samples from various regions, 376 heart samples either from the left ventricle or atrial appendage, 28 samples from the kidney cortex, 110 liver samples, and 288 lung samples) that were processed from raw sequence data under the same pipeline [9]. Recent studies demonstrated the feasibility of performing integrative analysis of these samples in various tasks [10–12]. For current study, 369 HCC case samples were compared against all healthy control samples (Supplementary Table S1, S2).…”

Section: Methodsmentioning

confidence: 99%

Computational discovery of co-expressed antigens as dual targeting candidates for cancer therapy through bulk, single-cell, and spatial transcriptomics

Chekalin,

Paithankar,

Shankar

et al. 2023

Preprint

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Bispecific antibodies (bsAbs) that bind to two distinct surface antigens on cancer cells are emerging as an appealing therapeutic strategy in cancer immunotherapy. However, considering the vast number of surface proteins, experimental identification of potential antigen pairs that are selectively expressed in cancer cells and not in normal cells is both costly and time-consuming. Recent studies have utilized large bulk RNA-seq databases to propose bispecific targets for various cancers. But, co-expressed pairs derived from bulk RNA-seq do not necessarily indicate true co-expression of both markers in the same cell. Single-cell RNA-seq (scRNA-seq) can circumvent this issue but the issues in dropouts and low-coverage of transcripts impede the large-scale characterization of co-expressed pairs. We present a computational pipeline for bsAbs identification which combines the advantages of bulk and scRNA-seq while minimizing the issues associated with using these approaches separately. We select Hepatocellular Carcinoma (HCC) as a case study to demonstrate the utility of the approach. First, using the bulk RNA-seq samples in the OCTAD database, we identified target pairs that most distinctly differentiate tumors cases from healthy controls. Next, we confirmed our findings on the scRNA-seq database comprising 39,361 healthy cells from vital organs and 18,000 malignant cells from HCC. The top pair was GPC3~MUC13, where both genes are co-expressed on the surface of over 30% of malignant HCCs and have very low expression in other cells. Finally, we leveraged the emerging spatial transcriptomic to validate the co-expressed pair in situ.

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Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma

Cited by 11 publications

References 65 publications

Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma

Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma

Triptolide inhibits the progression of Glioblastoma U251 cells via targeting PROX1

Computational discovery of co-expressed antigens as dual targeting candidates for cancer therapy through bulk, single-cell, and spatial transcriptomics

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