bims-malgli 2022-04-10 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–04–10
eight papers selected by
Oltea Sampetrean, Keio University

Prognostic value of O 6-methylguanine-DNA methyltransferase methylation in isocitrate dehydrogenase mutant gliomas.
Prospective genomically-guided identification of 'early/evolving' and 'undersampled' IDH-wildtype glioblastoma leads to improved clinical outcomes.
GD2-Targeting CAR T Cells Show Promise in H3K27M-Mutated Gliomas.
Evaluation of the efficacy and safety of TAS0313 in adults with recurrent glioblastoma.
PDGF-R inhibition induces glioblastoma cell differentiation via DUSP1/p38MAPK signalling.
A tumor suppressor role for EZH2 in diffuse midline glioma pathogenesis.
Circulating Immune Cell and Outcome Analysis from the Phase 2 Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma.
Hypothetical Generalized Framework for a New Imaging Endpoint of Therapeutic Activity in Early Phase Clinical Trials in Brain Tumors.

Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac030

Prognostic value of O 6-methylguanine-DNA methyltransferase methylation in isocitrate dehydrogenase mutant gliomas.

Keng Lam, Blaine S C Eldred, Bryan Kevan, Sean Pianka, Brittany A Eldred, Serendipity Zapanta Rinonos, William H Yong, Linda M Liau, Phioanh L Nghiemphu, Timothy F Cloughesy, Richard M Green, Albert Lai.

   Background: Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those that are IDH wild-type. Previous studies have shown the prognostic value of O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma multiforme (GBM), which are predominantly IDH wild-type. Little is known of the prognostic value of MGMT methylation status for IDH mutant gliomas.
Methods: We retrospectively identified IDH mutant gliomas patients between 2011 and 2020 that were tested for MGMT promoter methylation. We generated Kaplan-Meier estimator curves and performed Cox proportional hazard models for overall survival (OS) and progression-free survival (PFS) to compare the outcomes of MGMT promoter methylated versus MGMT unmethylated patients.
Results: Of 419 IDH mutant gliomas with MGMT promoter methylation testing, we identified 54 GBMs, 223 astrocytomas, and 142 oligodendrogliomas. 62.3% patients had MGMT methylated tumors while 37.7% were MGMT unmethylated. On Kaplan-Meier analysis, median OS for all MGMT methylated patients was 17.7 years and 14.6 years for unmethylated patients. Median PFS for all MGMT methylated patients was 7.0 years and for unmethylated patients 5.2 years. After univariate subgroup analysis, MGMT methylation is only prognostic for OS and PFS in GBM, and for OS in anaplastic oligodendroglioma and anaplastic oligodendroglioma for OS. In multivariate analysis, MGMT unmethylated GBM patients carry a higher risk of death (HR 7.72, 95% CI 2.10-28.33) and recurrence (HR 3.85, 95% CI 1.35-10.96).
Conclusions: MGMT promoter methylation is associated with better OS and PFS for IDH mutant GBM. MGMT promoter methylation testing for other IDH mutant glioma subtypes may not provide additional information on prognostication.

Keywords:  IDH; MGMT; glioblastoma

DOI:  https://doi.org/10.1093/noajnl/vdac030
Neuro Oncol. 2022 Apr 08. pii: noac089. [Epub ahead of print]

Prospective genomically-guided identification of 'early/evolving' and 'undersampled' IDH-wildtype glioblastoma leads to improved clinical outcomes.

Yalan Zhang, Calixto-Hope G Lucas, Jacob S Young, Ramin A Morshed, Lucie McCoy, Nancy Ann Oberheim Bush, Jennie W Taylor, Mariza Daras, Nicholas A Butowski, Javier E Villanueva-Meyer, Soonmee Cha, Margaret Wrensch, John K Wiencke, Julieann C Lee, Melike Pekmezci, Joanna J Phillips, Arie Perry, Andrew W Bollen, Manish K Aghi, Philip Theodosopoulos, Edward F Chang, Shawn L Hervey-Jumper, Mitchel S Berger, Jennifer L Clarke, Susan M Chang, Annette M Molinaro, David A Solomon.

   BACKGROUND: Genomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma.
METHODS: Clinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of "diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV" per cIMPACT-NOW criteria.
RESULTS: We identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term 'early/evolving' and 'undersampled' glioblastoma, IDH-wildtype. We found that prospective genomically-guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically-matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone.
CONCLUSIONS: These results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.

Keywords:  Precision medicine; genomic profiling; glioblastoma; molecular diagnostics; molecular neuro-oncology

DOI:  https://doi.org/10.1093/neuonc/noac089
Cancer Discov. 2022 Apr 01. 12(4): 882

GD2-Targeting CAR T Cells Show Promise in H3K27M-Mutated Gliomas.

Three out of four patients treated with GD2-targeting CAR T cells showed radiographic and clinical improvement.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-030
Cancer Immunol Immunother. 2022 Apr 04.

Evaluation of the efficacy and safety of TAS0313 in adults with recurrent glioblastoma.

Yoshitaka Narita, Yoshiko Okita, Yoshiki Arakawa.

   BACKGROUND: TAS0313 is a multi-epitope long peptide vaccine targeting several cancer-associated antigens highly expressed in multiple cancer types, including glioblastoma (GBM). This cohort of a Phase 2 part evaluated the efficacy and safety of TAS0313 in patients with GBM.
METHODS: TAS0313 (27 mg) was administered subcutaneously on Days 1, 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). The secondary endpoints were the disease control rate, progression-free survival (PFS) and 6- and 12-month progression-free survival rates (PFR) and safety. Immunological response was assessed as an exploratory endpoint.
RESULTS: The best overall response was partial response in 1 patient, and the ORR (95% CI) was 11.1% (0.3-48.2%) in the per-protocol set (n = 9). A further 3 patients achieved stable disease, for a disease control rate (95% CI) of 44.4% (13.7-78.8%). Median (95% CI) PFS was 1.7 (1.3-NE) months and 6- and 12-month PFRs (95% CI) were 22.2% (3.4-51.3%) each. Common (≥ 20% incidence) treatment-related adverse events (AEs) were injection site reactions (n = 8, 80.0%), followed by pyrexia (n = 7, 70.0%), and malaise, injection site erythema and injection site pruritus (n = 2, 20.0% each). There were no grade 4 or 5 treatment-related AEs. No deaths occurred during the study. In some patients, TAS0313 treatment was confirmed to increase cytotoxic T lymphocyte and immunoglobulin G levels compared with baseline.
CONCLUSION: TAS0313, a multi-epitope long peptide vaccine, demonstrated promising efficacy and acceptable safety in patients with recurrent GBM.
CLINICAL TRIAL REGISTRATION: JapicCTI-183824 (Date of registration: Jan 11, 2018).

Keywords:  Cancer peptide vaccine; Cancer vaccines; Glioblastoma; High-grade glioma; TAS0313

DOI:  https://doi.org/10.1007/s00262-022-03184-7
Oncogene. 2022 Apr 07.

PDGF-R inhibition induces glioblastoma cell differentiation via DUSP1/p38MAPK signalling.

Rosemary Lane, Chiara Cilibrasi, Jianing Chen, Kalpit Shah, Eleonora Messuti, Nektarios K Mazarakis, Justin Stebbing, Giles Critchley, Erwei Song, Thomas Simon, Georgios Giamas.

Glioblastoma (GBM) is the most common and fatal primary brain tumour in adults. Considering that resistance to current therapies leads to limited response in patients, new therapeutic options are urgently needed. In recent years, differentiation therapy has been proposed as an alternative for GBM treatment, with the aim of bringing cancer cells into a post-mitotic/differentiated state, ultimately limiting tumour growth. As an integral component of cancer development and regulation of differentiation processes, kinases are potential targets of differentiation therapies. The present study describes how the screening of a panel of kinase inhibitors (KIs) identified PDGF-Rα/β inhibitor CP-673451 as a potential differentiation agent in GBM. We show that targeting PDGF-Rα/β with CP-673451 in vitro triggers outgrowth of neurite-like processes in GBM cell lines and GBM stem cells (GSCs), suggesting differentiation into neural-like cells, while reducing proliferation and invasion in 3D hyaluronic acid hydrogels. In addition, we report that treatment with CP-673451 improves the anti-tumour effects of temozolomide in vivo using a subcutaneous xenograft mouse model. RNA sequencing and follow-up proteomic analysis revealed that upregulation of phosphatase DUSP1 and consecutive downregulation of phosphorylated-p38MAPK can underlie the pro-differentiation effect of CP-673451 on GBM cells. Overall, the present study identifies a potential novel therapeutic option that could benefit GBM patients in the future, through differentiation of residual GSCs post-surgery, with the aim to limit recurrence and improve quality of life.

DOI: https://doi.org/10.1038/s41388-022-02294-x
Acta Neuropathol Commun. 2022 Apr 08. 10(1): 47

A tumor suppressor role for EZH2 in diffuse midline glioma pathogenesis.

Swati Dhar, Samantha Gadd, Priyam Patel, Jake Vaynshteyn, G Praveen Raju, Rintaro Hashizume, Daniel J Brat, Oren J Becher.

  Pediatric high-grade gliomas, specifically diffuse midline gliomas, account for only 20% of clinical cases but are 100% fatal. A majority of the DMG cases are characterized by the signature K27M mutation in histone H3. The H3K27M mutation opposes the function of enhancer of zeste homolog 2 (EZH2), the methyltransferase enzyme of the polycomb repressor complex 2. However, the role of EZH2 in DMG pathogenesis is unclear. In this study, we demonstrate a tumor suppressor function for EZH2 using Ezh2 loss- and gain-of-function studies in H3WT DMG mouse models. Genetic ablation of Ezh2 increased cell proliferation and tumor grade while expression of an Ezh2 gain-of-function mutation significantly reduced tumor incidence and increased tumor latency. Transcriptomic analysis revealed that Ezh2 deletion upregulates an inflammatory response with upregulation of immunoproteasome genes such as Psmb8, Psmb9, and Psmb10. Ezh2 gain-of-function resulted in enrichment of the oxidative phosphorylation/mitochondrial metabolic pathway namely the isocitrate dehydrogenase Idh1/2/3 genes. Pharmacological inhibition of EZH2 augmented neural progenitor cell proliferation, supporting the tumor suppressive role of EZH2. In vivo 7-day treatment of H3K27M DMG tumor bearing mice with an EZH2 inhibitor, Tazemetostat, did not alter proliferation or significantly impact survival. Together our results suggest that EZH2 has a tumor suppressor function in DMG and warrants caution in clinical translation of EZH2 inhibitors to treat patients with DMG.

Keywords:  Diffuse midline gliomas (DMGs); Ezh2 gain-of-function; Ezh2 loss-of-function; Interferon gamma; Oxidative phosphorylation; Tumor suppressor

DOI:  https://doi.org/10.1186/s40478-022-01336-5
Clin Cancer Res. 2022 Apr 08. pii: clincanres.4064.2021. [Epub ahead of print]

Circulating Immune Cell and Outcome Analysis from the Phase 2 Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma.

Lakshmi Nayak, Nathan Standifer, Jorg Dietrich, Jennifer L Clarke, Gavin P Dunn, Michael Lim, Timothy Cloughesy, Hui K Gan, Elizabeth Flagg, Elizabeth George, Sarah Gaffey, Julia Hayden, Christina Holcroft, Patrick Y Wen, Mary Macri, Andrew J Park, Toni Ricciardi, Aileen Ryan, Paul Schwarzenberger, Ralph Venhaus, Melissa de Los Reyes, Nicholas M Durham, Todd Creasy, Raymond Y Huang, Thomas Kaley, David A Reardon.

BACKGROUND: Programmed death-ligand 1 (PD-L1) is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.
METHODS: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n=40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n=31), or in combination with standard bevacizumab (cohort B2; n=33), or low-dose bevacizumab (cohort B3; n=33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n=22). Primary endpoints were: OS-12 (A); PFS-6 (B, B2, B3); and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS).
RESULTS: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naive cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared to newly diagnosed that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome.
CONCLUSION: Recurrent glioblastoma patients have markedly lower baseline levels of multiple circulating immune cell subsets compared to newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among glioblastoma patients undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-4064
Neuro Oncol. 2022 Apr 05. pii: noac086. [Epub ahead of print]

Hypothetical Generalized Framework for a New Imaging Endpoint of Therapeutic Activity in Early Phase Clinical Trials in Brain Tumors.

Benjamin M Ellingson, Elizabeth R Gerstner, Andrew B Lassman, Caroline Chung, Howard Colman, Patricia E Cole, David Leung, Joshua E Allen, Manmeet S Ahluwalia, Jerrold Boxerman, Matthew Brown, Jonathan Goldin, Edjah Nduom, Islam Hassan, Mark R Gilbert, Ingo K Mellinghoff, Michael Weller, Susan Chang, David Arons, Clair Meehan, Wendy Selig, Kirk Tanner, W K Alfred Yung, Martin van den Bent, Patrick Y Wen, Timothy F Cloughesy.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate impact of new treatments, and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits is strong. Accurately measuring impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later stage development, including those that may not meet currently sought thresholds for "response" and ultimately lead to identification of effective treatments.

DOI: https://doi.org/10.1093/neuonc/noac086