bims-malgli 2022-11-27 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–11–27
ten papers selected by
Oltea Sampetrean, Keio University

Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts.
A Cetuximab-CCL5 Fusion Protein-Expressing Oncolytic Virus Has Efficacy in GBM.
Bevacizumab beyond Progression for Newly Diagnosed Glioblastoma (BIOMARK): Phase II Safety, Efficacy and Biomarker Study.
Aberrant L-Fucose accumulation and increased core fucosylation are metabolic liabilities in mesenchymal glioblastoma.
Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity.
Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma.
Methylation Profiling in Diffuse Gliomas: Diagnostic Value and Considerations.
Cytostatic hypothermia and its impact on glioblastoma and survival.
Global hypo-methylation in a proportion of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape.
The conventional dendritic cell 1 subset primes CD8+ T cells and traffics tumor antigen to drive anti-tumor immunity in the brain.

Cancers (Basel). 2022 Nov 09. pii: 5494. [Epub ahead of print]14(22):

Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts.

Matthew McCord, Elizabeth Bartom, Kirsten Burdett, Aneta Baran, Frank D Eckerdt, Irina V Balyasnikova, Kathleen McCortney, Thomas Sears, Shi-Yuan Cheng, Jann N Sarkaria, Roger Stupp, Amy B Heimberger, Atique Ahmed, Charles David James, Craig Horbinski.

  Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma.

Keywords:  CNS cancers; DNA damage and repair; chemotherapy; drug resistance; glioblastomas; gliomas; preclinical models; tumor evolution; xenograft models

DOI:  https://doi.org/10.3390/cancers14225494
Cancer Discov. 2022 Nov 23. OF1

A Cetuximab-CCL5 Fusion Protein-Expressing Oncolytic Virus Has Efficacy in GBM.

The oncolytic virus OV-Cmab-CCL5 induces immune cell infiltration and tumor reduction in glioblastoma.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-207
Cancers (Basel). 2022 Nov 10. pii: 5522. [Epub ahead of print]14(22):

Bevacizumab beyond Progression for Newly Diagnosed Glioblastoma (BIOMARK): Phase II Safety, Efficacy and Biomarker Study.

Motoo Nagane, Koichi Ichimura, Ritsuko Onuki, Daichi Narushima, Mai Honda-Kitahara, Kaishi Satomi, Arata Tomiyama, Yasuhito Arai, Tatsuhiro Shibata, Yoshitaka Narita, Takeo Uzuka, Hideo Nakamura, Mitsutoshi Nakada, Yoshiki Arakawa, Takanori Ohnishi, Akitake Mukasa, Shota Tanaka, Toshihiko Wakabayashi, Tomokazu Aoki, Shigeki Aoki, Soichiro Shibui, Masao Matsutani, Keisuke Ishizawa, Hideaki Yokoo, Hiroyoshi Suzuki, Satoshi Morita, Mamoru Kato, Ryo Nishikawa.

  We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab.

Keywords:  bevacizumab; biomarker; glioblastoma; progression; temozolomide

DOI:  https://doi.org/10.3390/cancers14225522
Cancer Res. 2022 Nov 21. pii: CAN-22-0677. [Epub ahead of print]

Aberrant L-Fucose accumulation and increased core fucosylation are metabolic liabilities in mesenchymal glioblastoma.

Valentina Pieri, Alberto L Gallotti, Denise Drago, Manuela Cominelli, Ilaria Pagano, Valentina Conti, Silvia Valtorta, Angela Coliva, Sara Lago, Daniela Michelatti, Luca Massimino, Federica Ungaro, Laura Perani, Antonello Spinelli, Antonella Castellano, Andrea Falini, Alessio Zippo, Pietro L Poliani, Rosa Maria Moresco, Annapaola Andolfo, Rossella Galli.

Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSCs). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared to proneural (PN) GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)-based glycoproteomic screening indicated that most MES-restricted core fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using pre-clinical minimally-invasive positron emission tomography (PET), implicating this metabolite as a potential subgroup-restricted biomarker. Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0677
Neuro Oncol. 2022 Nov 19. pii: noac253. [Epub ahead of print]

Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity.

Jamie A Dean, Shyam K Tanguturi, Daniel Cagney, Kee-Young Shin, Gilbert Youssef, Ayal Aizer, Rifaquat Rahman, Lubna Hammoudeh, David Reardon, Eudocia Lee, Jorg Dietrich, Kaoru Tamura, Masaru Aoyagi, Lacey Wickersham, Patrick Y Wen, Paul Catalano, Daphne Haas-Kogan, Brian M Alexander, Franziska Michor.

   BACKGROUND: Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model.
METHODS: We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule.
RESULTS: Our statistical modeling predicted that the hazard ratio, when comparing our novel radiation schedule with a standard schedule, would be 0.74. Our mathematical modeling suggested that a practical, near optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy x 7 (1 fraction/day) followed by 1.0 Gy x 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients.
CONCLUSIONS: A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.

Keywords:  cell-state plasticity; clinical trial; glioblastoma; mathematical modeling; radiation oncology

DOI:  https://doi.org/10.1093/neuonc/noac253
J Med Chem. 2022 Nov 21.

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma.

Lakshmi R Bollu, Prashant V Bommi, Paige J Monsen, Lijie Zhai, Kristen L Lauing, April Bell, Miri Kim, Erik Ladomersky, Xinyu Yang, Leonidas C Platanias, Daniela E Matei, Marcelo G Bonini, Hidayatullah G Munshi, Rintaro Hashizume, Jennifer D Wu, Bin Zhang, Charles David James, Peiwen Chen, Masha Kocherginsky, Craig Horbinski, Michael D Cameron, Arabela A Grigorescu, Bakhtiar Yamini, Rimas V Lukas, Gary E Schiltz, Derek A Wainwright.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

DOI: https://doi.org/10.1021/acs.jmedchem.2c00771
Cancers (Basel). 2022 Nov 18. pii: 5679. [Epub ahead of print]14(22):

Methylation Profiling in Diffuse Gliomas: Diagnostic Value and Considerations.

Anna Wenger, Helena Carén.

  Diffuse gliomas cause significant morbidity across all age groups, despite decades of intensive research efforts. Here, we review the differences in diffuse gliomas in adults and children, as well as the World Health Organisation (WHO) 2021 classification of these tumours. We explain how DNA methylation-based classification works and list the methylation-based tumour types and subclasses for adult and paediatric diffuse gliomas. The benefits and utility of methylation-based classification in diffuse gliomas demonstrated to date are described. This entails the identification of novel tumour types/subclasses, patient stratification and targeted treatment/clinical management, and alterations in the clinical diagnosis in favour of the methylation-based over the histopathological diagnosis. Finally, we address several considerations regarding the use of DNA methylation profiling as a diagnostic tool, e.g., the threshold of the classifier, the calibrated score, tumour cell content and intratumour heterogeneity.

Keywords:  MGMT; calibrated score; classification; diffuse gliomas; glioblastoma; heterogeneity; intratumour; methylation

DOI:  https://doi.org/10.3390/cancers14225679
Sci Adv. 2022 Nov 25. 8(47): eabq4882

Cytostatic hypothermia and its impact on glioblastoma and survival.

Syed Faaiz Enam, Cem Y Kilic, Jianxi Huang, Brian J Kang, Reed Chen, Connor S Tribble, Ekaterina Ilich, Martha I Betancur, Stephanie J Blocker, Steven J Owen, Anne F Buckley, Johnathan G Lyon, Ravi V Bellamkonda.

Patients with glioblastoma (GBM) have limited options and require novel approaches to treatment. Here, we studied and deployed nonfreezing "cytostatic" hypothermia to stunt GBM growth. This growth-halting method contrasts with ablative, cryogenic hypothermia that kills both neoplastic and infiltrated healthy tissue. We investigated degrees of hypothermia in vitro and identified a cytostatic window of 20° to 25°C. For some lines, 18 hours/day of cytostatic hypothermia was sufficient to halt division in vitro. Next, we fabricated an experimental tool to test local cytostatic hypothermia in two rodent GBM models. Hypothermia more than doubled median survival, and all rats that successfully received cytostatic hypothermia survived their study period. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia leverages fundamental physics that influences biology broadly. It is a previously unexplored approach that could provide an additional option to patients with GBM by halting tumor growth.

DOI: https://doi.org/10.1126/sciadv.abq4882
Elife. 2022 Nov 22. pii: e77335. [Epub ahead of print]11

Global hypo-methylation in a proportion of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape.

James Boot, Gabriel Rosser, Dailya Kancheva, Claire Vinel, Yau Mun Lim, Nicola Pomella, Xinyu Zhang, Loredana Guglielmi, Denise Sheer, Michael Barnes, Sebastian Brandner, Sven Nelander, Kiavash Movahedi, Silvia Marino.

  We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.

Keywords:  DNA methylation; astrocytes; cancer biology; glioblastoma; human; mouse

DOI:  https://doi.org/10.7554/eLife.77335
Cancer Immunol Res. 2022 Nov 21. pii: CIR-22-0098. [Epub ahead of print]

The conventional dendritic cell 1 subset primes CD8+ T cells and traffics tumor antigen to drive anti-tumor immunity in the brain.

Jay A Bowman-Kirigin, Rupen Desai, Brian T Saunders, Anthony Z Wang, Maximilian O Schaettler, Connor J Liu, Alexandra J Livingstone, Dale K Kobayashi, Vivek Durai, Nicole M Kretzer, Gregory J Zipfel, Eric C Leuthardt, Joshua W Osbun, Michael R Chicoine, Albert H Kim, Kenneth M Murphy, Tanner M Johanns, Bernd H Zinselmeyer, Gavin P Dunn.

The central nervous system (CNS) antigen-presenting cell (APC) that primes anti-tumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDC localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS anti-tumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T-cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes (cLNs) harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided glioblastoma resection. Together, these data elucidate the specialized behavior of cDC1 and suggest cDC1 play a significant role in CNS anti-tumor immunity.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0098