bims-malgli 2023-04-09 papers

Issue of 2023‒04‒09
seven papers selected by
Oltea Sampetrean
Keio University

J Clin Oncol. 2023 Apr 07. JCO2201579

Evaluation of Standard Response Assessment in Neuro-Oncology, Modified Response Assessment in Neuro-Oncology, and Immunotherapy Response Assessment in Neuro-Oncology in Newly Diagnosed and Recurrent Glioblastoma.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update.MATERIALS AND METHODS: Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated.
RESULTS: Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO.
CONCLUSION: RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

DOI: https://doi.org/10.1200/JCO.22.01579

Cancer Discov. 2023 Apr 03. pii: CD-23-0004. [Epub ahead of print]

A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.

Michael McNicholas, Antonella De Cola, Zahedeh Bashardanesh, Amelia Foss, Cameron B Lloyd, Steven Hebert, Damien Faury, Augusto Faria Andrade, Nada Jabado, Claudia L Kleinman, Manav Pathania.

Pediatric high-grade gliomas (pHGGs) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomical locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities- H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1 and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0004

Proc Natl Acad Sci U S A. 2023 Apr 11. 120(15): e2209435120

The moonlighting function of glycolytic enzyme enolase-1 promotes choline phospholipid metabolism and tumor cell proliferation.

Qingxia Ma, Hongfei Jiang, Leina Ma, Gaoxiang Zhao, Qianqian Xu, Dong Guo, Ningning He, Hao Liu, Zhaoyuan Meng, Juanjuan Liu, Lei Zhu, Qian Lin, Xiaolin Wu, Min Li, Shudi Luo, Jing Fang, Zhimin Lu.

Aberrantly upregulated choline phospholipid metabolism is a novel emerging hallmark of cancer, and choline kinase α (CHKα), a key enzyme for phosphatidylcholine production, is overexpressed in many types of human cancer through undefined mechanisms. Here, we demonstrate that the expression levels of the glycolytic enzyme enolase-1 (ENO1) are positively correlated with CHKα expression levels in human glioblastoma specimens and that ENO1 tightly governs CHKα expression via posttranslational regulation. Mechanistically, we reveal that both ENO1 and the ubiquitin E3 ligase TRIM25 are associated with CHKα. Highly expressed ENO1 in tumor cells binds to I199/F200 of CHKα, thereby abrogating the interaction between CHKα and TRIM25. This abrogation leads to the inhibition of TRIM25-mediated polyubiquitylation of CHKα at K195, increased stability of CHKα, enhanced choline metabolism in glioblastoma cells, and accelerated brain tumor growth. In addition, the expression levels of both ENO1 and CHKα are associated with poor prognosis in glioblastoma patients. These findings highlight a critical moonlighting function of ENO1 in choline phospholipid metabolism and provide unprecedented insight into the integrated regulation of cancer metabolism by crosstalk between glycolytic and lipidic enzymes.

Keywords: CHKα; TRIM25; enolase

DOI: https://doi.org/10.1073/pnas.2209435120

Antioxid Redox Signal. 2023 Apr 05.

Glioblastomas: Hijacking Metabolism to Build a Flexible Shield for Therapy Resistance.

Justine Bailleul, Erina Vlashi.

Significance: Glioblastomas (GBMs) are among the most lethal tumors despite the almost exclusive localization to the brain. This is largely due to therapeutic resistance. Radiation and chemotherapy significantly increase the survival for GBM patients, however, GBMs always recur, and the median overall survival is just over a year. Proposed reasons for such intractable resistance to therapy are numerous and include tumor metabolism, in particular, the ability of tumor cells to reconfigure metabolic fluxes on demand (metabolic plasticity). Understanding how the hard-wired, oncogene-driven metabolic tendencies of GBMs intersect with flexible, context-induced metabolic rewiring promises to reveal novel approaches for combating therapy resistance. Recent Advances: Personalized genome-scale metabolic flux models have recently provided evidence that metabolic flexibility promotes radiation resistance in cancer and identified tumor redox metabolism as a major predictor for resistance to radiation therapy (RT). It was demonstrated that radioresistant tumors, including GBM, reroute metabolic fluxes to boost the levels of reducing factors of the cell, thus enhancing clearance of reactive oxygen species that are generated during RT and promoting survival. Critical Issues: The current body of knowledge from published studies strongly supports the notion that robust metabolic plasticity can act as a (flexible) shield against the cytotoxic effects of standard GBM therapies, thus driving therapy resistance. The limited understanding of the critical drivers of such metabolic plasticity hampers the rational design of effective combination therapies. Future Directions: Identifying and targeting regulators of metabolic plasticity, rather than specific metabolic pathways, in combination with standard-of-care treatments have the potential to improve therapeutic outcomes in GBM.

Keywords: glioblastoma; metabolism; plasticity; redox

DOI: https://doi.org/10.1089/ars.2022.0088

Nat Commun. 2023 Apr 03. 14(1): 1839

Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma.

Zhihong Chen, Nishant Soni, Gonzalo Pinero, Bruno Giotti, Devon J Eddins, Katherine E Lindblad, James L Ross, Montserrat Puigdelloses Vallcorba, Tanvi Joshi, Angelo Angione, Wes Thomason, Aislinn Keane, Nadejda M Tsankova, David H Gutmann, Sergio A Lira, Amaia Lujambio, Eliver E B Ghosn, Alexander M Tsankov, Dolores Hambardzumyan.

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no effect on Nf1-silenced GBM model. Single-cell RNA sequencing reveals that intratumoral neutrophils promote proneural-to-mesenchymal transition and increase hypoxia in PDGFB-driven GBM. We further demonstrate neutrophil-derived TNF-a directly drives mesenchymal transition in PDGFB-driven primary GBM cells. Genetic or pharmacological inhibiting neutrophils in HCC or monocyte-deficient PDGFB-driven and Nf1-silenced GBM models extend the survival of tumor-bearing mice. Our findings demonstrate tumor-type and genotype dependent infiltration and function of monocytes and neutrophils and highlight the importance of targeting them simultaneously for cancer treatments.

DOI: https://doi.org/10.1038/s41467-023-37361-8