bims-malgli 2021-11-07 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2021–11–07
eightteen papers selected by
Oltea Sampetrean, Keio University

Telomeric Parameters Improve Glioma Diagnosis and Liquid Biopsy Approaches.
Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response.
The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis.
External Controls to Improve on Glioblastoma Clinical Trials.
Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.
Association Between Oral Microbiota and Human Brain Glioma Grade: A Case-Control Study.
Large Animal Models of Glioma: Current Status and Future Prospects.
Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells.
Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.
Glutamine Imaging: A New Avenue for Glioma Management.
Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: Phase I/II clinical trial data.
Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers.
Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma.
Loss of FBXW7 correlates with increased IDH1 expression in glioma and enhances IDH1-mutant cancer cell sensitivity to radiation.
A Phase 2 Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma.
PD-1 independent of PD-L1 ligation promotes glioblastoma growth through the NFκB pathway.
DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology.
DIPG harbour alterations targetable by MEK inhibitors, with acquired resistance mechanisms overcome by combinatorial inhibition.

Cancer Discov. 2021 Nov 05.

Telomeric Parameters Improve Glioma Diagnosis and Liquid Biopsy Approaches.

Detection of telomeric maintenance mechanisms enabled classification of both typical and atypical glioma.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-158
J Exp Clin Cancer Res. 2021 Nov 05. 40(1): 347

Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response.

Silvia Matteoni, Paola Matarrese, Barbara Ascione, Lucia Ricci-Vitiani, Roberto Pallini, Veronica Villani, Andrea Pace, Marco G Paggi, Claudia Abbruzzese.

   BACKGROUND: Glioblastoma (GBM; grade IV glioma) is characterized by a very short overall survival time and extremely low 5-year survival rates. We intend to promote experimental and clinical research on rationale and scientifically driven drug repurposing. This may represent a safe and often inexpensive way to propose novel pharmacological approaches to GBM. Our precedent work describes the role of chlorpromazine (CPZ) in hindering malignant features of GBM. Here, we investigate in greater detail the molecular mechanisms at the basis of the effect of CPZ on GBM cells.
METHODS: We employed proteomics platforms, i.e., activity-based protein profiling plus mass spectrometry, to identify potential cellular targets of the drug. Then, by means of established molecular and cellular biology techniques, we assessed the effects of this drug on GBM cell metabolic and survival pathways.
RESULTS: The experimental output indicated as putative targets of CPZ several of factors implicated in endoplasmic reticulum (ER) stress, with consequent unfolded protein response (UPR). Such a perturbation culminated in a noticeable reactive oxygen species generation and intense autophagic response that resulted in cytotoxic and abortive effects for six GBM cell lines, three of which growing as neurospheres, while it appeared cytoprotective for the RPE-1 human non-cancer neuro-ectodermal cell line.
CONCLUSIONS: This discrepancy could be central in explaining the lethal effects of the drug on GBM cells and the relatively scarce cytotoxicity toward normal tissues attributed to this compound. The data presented here offer support to the multicenter phase II clinical trial we have undertaken, which consists of the addition of CPZ to first-line treatment of GBM patients carrying a hypo- or un-methylated MGMT gene, i.e. those characterized by intrinsic resistance to temozolomide.

Keywords:  Autophagy; Cell death; Chlorpromazine; Drug repurposing; Endoplasmic reticulum stress; Glioblastoma; Mitotic catastrophe; Unfolded protein response

DOI:  https://doi.org/10.1186/s13046-021-02144-w
Sci Rep. 2021 Nov 02. 11(1): 21504

The immune checkpoint VISTA exhibits high expression levels in human gliomas and associates with a poor prognosis.

Amina Ghouzlani, Abdelhakim Lakhdar, Soumaya Rafii, Mehdi Karkouri, Abdallah Badou.

In human gliomas, anti-tumor T cell responses are inhibited through induction of local and systemic immunosuppression. Immune checkpoint blockade is proving to be a success in several types of cancers. However, many studies reported that the treatment of glioblastoma patients with anti-CTLA-4 or anti-PD-1 has no survival benefit compared to standard chemotherapy. This study aimed to investigate the expression and role of VISTA, a newly described immune checkpoint regulator, in human gliomas. mRNA expression was assessed in a total of 87 samples from glioma patients. 57 glioma tissues were taken at different grades. 20 peripheral blood mononuclear cells (PBMC) samples were taken before surgery and ten after surgery, all from the same set of patients. As for the control, ten specimens of PBMC were taken from healthy donors. Protein expression using immunohistochemistry was performed for 30 patients. The Cancer Genome Atlas (TCGA) data set, was also used to investigate VISTA expression through analysis of RNA-seq data of 667 glioma patients. In the Moroccan cohort, VISTA gene expression was significantly upregulated in glioma tissues related to PBMC of healthy donors. This high expression was specific to patient tissues since VISTA expression in PBMC was low when assessed either before or after surgery. Besides, VISTA exhibited higher expression levels in grade III/IV relative to grade I/II glioma patients. Interestingly, VISTA correlated positively with PD-1 expression. PD-1 also showed elevated expressions in higher glioma grades. The TCGA cohort corroborated these observations. Indeed, VISTA was also found to be strongly expressed in high grades. It was positively correlated with other critical immune checkpoints. Finally, increased VISTA transcript levels were associated with weak overall survival of glioma patients. Our study highlighted a correlation between high levels of VISTA expression and poor prognosis in glioma patients. VISTA might be involved in glioma progression and could be considered as a possible new therapeutic target, especially in advanced gliomas.

DOI: https://doi.org/10.1038/s41598-021-00835-0
Neuro Oncol. 2021 Oct 29. pii: noab251. [Epub ahead of print]

External Controls to Improve on Glioblastoma Clinical Trials.

Annette M Molinaro.

DOI: https://doi.org/10.1093/neuonc/noab251
Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01434-0. [Epub ahead of print]37(5): 109957

Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.

Junfeng Bi, Atif Khan, Jun Tang, Aaron M Armando, Sihan Wu, Wei Zhang, Ryan C Gimple, Alex Reed, Hui Jing, Tomoyuki Koga, Ivy Tsz-Lo Wong, Yuchao Gu, Shunichiro Miki, Huijun Yang, Briana Prager, Ellis J Curtis, Derek A Wainwright, Frank B Furnari, Jeremy N Rich, Timothy F Cloughesy, Harley I Kornblum, Oswald Quehenberger, Andrey Rzhetsky, Benjamin F Cravatt, Paul S Mischel.

  The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.

Keywords:  EGFR signaling; Membrane lipids; SMPD1; combination therapy; electronic medical records; fluoxetine; glioblastoma; real-world evidence; sphingolipid metabolism

DOI:  https://doi.org/10.1016/j.celrep.2021.109957
Front Microbiol. 2021 ;12 746568

Association Between Oral Microbiota and Human Brain Glioma Grade: A Case-Control Study.

Yuqi Wen, Le Feng, Haorun Wang, Hu Zhou, Qianqian Li, Wenyan Zhang, Ming Wang, Yeming Li, Xingzhao Luan, Zengliang Jiang, Ligang Chen, Jie Zhou.

  Gliomas are the most prevalent form of primary malignant brain tumor, which currently have no effective treatments. Evidence from human studies has indicated that oral microbiota is closely related to cancers; however, whether oral microbiota plays a role in glioma malignancy remains unclear. The present study aimed to investigate the association between oral microbiota and grade of glioma and examine the relationship between malignancy-related oral microbial features and the isocitrate dehydrogenase 1 (IDH1) mutation in glioma. High-grade glioma (HGG; n=23) patients, low-grade glioma (LGG; n=12) patients, and healthy control (HCs; n=24) participants were recruited for this case-control study. Saliva samples were collected and analyzed for 16S ribosomal RNA (rRNA) sequencing. We found that the shift in oral microbiota β-diversity was associated with high-grade glioma (p=0.01). The phylum Patescibacteria was inversely associated with glioma grade (LGG and HC: p=0.035; HGG and HC: p<0.01). The genera Capnocytophaga (LGG and HC: p=0.043; HGG and HC: p<0.01) and Leptotrichia (LGG and HC: p=0.044; HGG and HC: p<0.01) were inversely associated with glioma grades. The genera Bergeyella and Capnocytophaga were significantly more positively correlated with the IDH1 mutation in gliomas when compared with the IDH1-wild-type group. We further identified five oral microbial features (Capnocytophaga Porphyromonas, Haemophilus, Leptotrichia, and TM7x) that accurately discriminated HGG from LGG (area under the curve [AUC]: 0.63, 95% confidence interval [CI]: 0.44-0.83) and HCs (AUC: 0.79, 95% CI: 0.68-0.92). The functional prediction analysis of oral bacterial communities showed that genes involved in cell adhesion molecules (p<0.001), extracellular matrix molecule-receptor interaction (p<0.001), focal adhesion (p<0.001), and regulation of actin cytoskeleton (p<0.001) were associated with glioma grades, and some microbial gene functions involving lipid metabolism and the adenosine 5'-monophosphate-activated protein kinase signaling pathway were significantly more enriched in IDH1 mutant gliomas than compared with the IDH1-wild-type gliomas. In conclusion, our work revealed oral microbiota features and gene functions that were associated with glioma malignancy and the IDH1 mutation in glioma.

Keywords:  glioma; human cohort; isocitrate dehydrogenase 1 mutation; malignant grade; oral microbiota

DOI:  https://doi.org/10.3389/fmicb.2021.746568
Anticancer Res. 2021 Nov;41(11): 5343-5353

Large Animal Models of Glioma: Current Status and Future Prospects.

William H Hicks, Cylaina E Bird, Mark N Pernik, Ali S Haider, Aksharkumar Dobariya, Kalil G Abdullah, Salah G Aoun, R Timothy Bentley, Aaron A Cohen-Gadol, Robert M Bachoo, Bruce E Mickey, Juan M Pascual, Tarek Y El Ahmadieh.

  Enhanced understanding of the molecular features of glioma has led to an expansion of murine glioma models and successful preclinical studies. However, clinical trials continue to have a high cost, extended production time, and low proportion of success. Studies in large-animal models of various cancer types have emerged to bridge the translational gap between in vitro and in vivo animal studies and human clinical trials. The anatomy and physiology of large animals are of more direct relevance to human disease, allowing for more rigorous testing of treatments such as surgical resection and adjuvant therapy in glioma. The recent generation of multiple porcine glioma models supports their use in high-throughput preclinical studies. The demonstration of spontaneous glioblastoma formation in canines further provides a unique avenue for the study of de novo glioma. The aim of this review was to outline the current status of large animal models of glioma and their value as a transitional step between rodent models and human clinical trials.

Keywords:  Glioma; dog; glioblastoma; large animal; non-human primate; pig; review

DOI:  https://doi.org/10.21873/anticanres.15347
Proc Natl Acad Sci U S A. 2021 Nov 09. pii: e2107507118. [Epub ahead of print]118(45):

Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells.

Jiao Wang, Sandra Toregrosa-Allen, Bennett D Elzey, Sagar Utturkar, Nadia Atallah Lanman, Victor Bernal-Crespo, Matthew M Behymer, Gregory T Knipp, Yeonhee Yun, Michael C Veronesi, Anthony L Sinn, Karen E Pollok, Randy R Brutkiewicz, Kathryn S Nevel, Sandro Matosevic.

  Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site-specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell-based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.

Keywords:  CD73; autophagy; glioblastoma; immunotherapy; natural killer cells

DOI:  https://doi.org/10.1073/pnas.2107507118
Neuro Oncol. 2021 Oct 28. pii: noab247. [Epub ahead of print]

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.

Lily J Andrews, Zak A Thornton, Saanwalshah S Saincher, Ian Y Yao, Sarah Dawson, Luke A McGuinness, Hayley E Jones, Sarah Jefferies, Susan C Short, Hung-Yuan Cheng, Alexandra McAleenan, Julian P T Higgins, Kathreena M Kurian.

BACKGROUND: Detailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development.
METHODS: Our systematic review analysed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response.
RESULTS: Based on 13,682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45-89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48-64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23-54%], ganglioglioma (GG): 40% [33-46%], and anaplastic ganglioglioma (aGG): 46% [18-76%]. Prevalence in astroblastoma was 24% [8-43%], desmoplastic infantile astrocytoma (DIA): 16% [0-57%], subependymal giant cell astrocytoma (SEGA): 8% [0-37%], dysembryoplastic neuroepithelial tumour (DNET): 3% [0-11%], diffuse astrocytoma (DA): 3% [0-9%], and pilocytic astrocytoma (PA): 3% [2-5%].We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. 129 paediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 paediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. 39 adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. 97 adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively.
CONCLUSIONS: BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG and lower in astroblastoma, DIA, SEGA, DNET, DA and PA. Our data provides the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.

DOI: https://doi.org/10.1093/neuonc/noab247
AJNR Am J Neuroradiol. 2021 Nov 04.

Glutamine Imaging: A New Avenue for Glioma Management.

S Ekici, J A Nye, S G Neill, J W Allen, H-K Shu, C C Fleischer.

The glutamine pathway is emerging as an important marker of cancer prognosis and a target for new treatments. In gliomas, the most common type of brain tumors, metabolic reprogramming leads to abnormal consumption of glutamine as an energy source, and increased glutamine concentrations are associated with treatment resistance and proliferation. A key challenge in the development of glutamine-based biomarkers and therapies is the limited number of in vivo tools to noninvasively assess local glutamine metabolism and monitor its changes. In this review, we describe the importance of glutamine metabolism in gliomas and review the current landscape of translational and emerging imaging techniques to measure glutamine in the brain. These techniques include MRS, PET, SPECT, and preclinical methods such as fluorescence and mass spectrometry imaging. Finally, we discuss the roadblocks that must be overcome before incorporating glutamine into a personalized approach for glioma management.

DOI: https://doi.org/10.3174/ajnr.A7333
Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab142

Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: Phase I/II clinical trial data.

Daniela A Bota, Warren Mason, Santosh Kesari, Rajiv Magge, Benjamin Winograd, Ileana Elias, Steven D Reich, Nancy Levin, Mohit Trikha, Annick Desjardins.

   Background: This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood-brain barrier.
Methods: Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5-0.8 mg/m2) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8-1.0 mg/m2) for the combination.
Results: In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m2 and bevacizumab showed a nonoverlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months.
Conclusions: The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood-brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

Keywords:  clinical trials; glioblastoma; marizomib

DOI:  https://doi.org/10.1093/noajnl/vdab142
Neuro Oncol. 2021 11 02. 23(23 Suppl 5): S4-S15

Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers.

Aleena K S Arakaki, Frank Szulzewsky, Mark R Gilbert, Taranjit S Gujral, Eric C Holland.

  Patients with rare central nervous system (CNS) tumors typically have a poor prognosis and limited therapeutic options. Historically, these cancers have been difficult to study due to small number of patients. Recent technological advances have identified molecular drivers of some of these rare cancers which we can now use to generate representative preclinical models of these diseases. In this review, we outline the advantages and disadvantages of different models, emphasizing the utility of various in vitro and ex vivo models for target discovery and mechanistic inquiry and multiple in vivo models for therapeutic validation. We also highlight recent literature on preclinical model generation and screening approaches for ependymomas, histone mutated high-grade gliomas, and atypical teratoid rhabdoid tumors, all of which are rare CNS cancers that have recently established genetic or epigenetic drivers. These preclinical models are critical to advancing targeted therapeutics for these rare CNS cancers that currently rely on conventional treatments.

Keywords:  atypical teratoid rhabdoid tumors; diffuse midline glioma; ependymoma; preclinical cancer models; rare cancers

DOI:  https://doi.org/10.1093/neuonc/noab183
Nat Commun. 2021 Nov 03. 12(1): 6321

Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma.

Tatenda Mahlokozera, Bhuvic Patel, Hao Chen, Patrick Desouza, Xuan Qu, Diane D Mao, Daniel Hafez, Wei Yang, Rukayat Taiwo, Mounica Paturu, Afshin Salehi, Amit D Gujar, Gavin P Dunn, Nima Mosammaparast, Allegra A Petti, Hiroko Yano, Albert H Kim.

The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance.

DOI: https://doi.org/10.1038/s41467-021-26653-6
Cancer Res. 2021 Nov 04. pii: canres.0384.2021. [Epub ahead of print]

Loss of FBXW7 correlates with increased IDH1 expression in glioma and enhances IDH1-mutant cancer cell sensitivity to radiation.

Zhuo Yang, Nan Hu, Weiwei Wang, Weihua Hu, Shaolong Zhou, Jianxiang Shi, Minghe Li, Zhou Jing, Chao Chen, Xuyang Zhang, Ruyi Yang, Xudong Fu, Xinjun Wang.

F-box and WD repeat domain containing 7 (FBXW7) is a substrate receptor of the ubiquitin ligase SKP1-Cullin1-F-box complex and a potent tumor suppressor that prevents unregulated cell growth and tumorigenesis. However, little is known about FBXW7-mediated control of cell metabolism and related functions in cancer therapy. Here, we report that FBXW7 expression inversely correlates with the expression levels of the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in glioma patients and public glioma datasets. Deletion of FBXW7 significantly increased both wild type (WT) and mutant IDH1 expression, which was mediated by blocking degradation of sterol regulatory element binding protein 1 (SREBP1). The upregulation of neomorphic mutant IDH1 by FBXW7 deletion stimulated production of the oncometabolite 2-hydroxyglutarate (2-HG) at the expense of increasing pentose phosphate pathway (PPP) activity and NADPH consumption, limiting the buffering ability against radiation-induced oxidative stress. Additionally, FBXW7 knockout and IDH1 mutations induced non-homologous end joining (NHEJ) and homologous recombination (HR) defects, respectively. In vitro and in vivo, loss of FBXW7 dramatically enhanced the efficacy of radiation treatment in IDH1 mutant cancer cells. Taken together, this work identifies FBXW7 deficiency as a potential biomarker representing both DNA repair and metabolic vulnerabilities that sensitizes IDH1 mutant cancers to radiotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0384
Clin Cancer Res. 2021 Nov 02. pii: clincanres.2225.2021. [Epub ahead of print]

A Phase 2 Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma.

Andrew B Lassman, Patrick Y Wen, Martin J van den Bent, Scott R Plotkin, Annemiek M E Walenkamp, Adam L Green, Kai Li, Christopher J Walker, Hua Chang, Sharon Tamir, Leah Henegar, Yao Shen, Mariano J Alvarez, Andrea Califano, Yosef Landesman, Michael G Kauffman, Sharon Sacham, Morten Mau-Sørensen.

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematological tumors. We assessed intra-tumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma.
PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status{greater than or equal to}60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) pre-operatively (Arm A; N=8 patients). Patients not undergoing surgery received 50mg/m2 (Arm B, N=24), or 60mg (Arm C, N=14) twice weekly, or 80mg once weekly (Arm D; N=30). Primary endpoint was six-month progression-free survival rate (PFS6).
RESULTS: Median selinexor concentrations in resected tumors from patients receiving pre-surgical selinexor was 105.4nM (range 39.7-291nM). In Arms B, C, and D, respectively, the PFS6 was 10% (95%CI, 2.79-35.9), 7.7% (95%CI, 1.17-50.6), and 17% (95%CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% (Arm B, 8.3% (95%CI, 1.0-27.0); C:7.7% (95%CI, 0.2-36.0); D:10% (95%CI, 2.1-26.5)), with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; one (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%) and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC=0.88).
CONCLUSION: At 80mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2225
Sci Adv. 2021 Nov 05. 7(45): eabh2148

PD-1 independent of PD-L1 ligation promotes glioblastoma growth through the NFκB pathway.

Reza Mirzaei, Ashley Gordon, Franz J Zemp, Mehul Kumar, Susobhan Sarkar, H Artee Luchman, Anita C Bellail, Chunhai Hao, Douglas J Mahoney, Jeff F Dunn, Pinaki Bose, V Wee Yong.

[Figure: see text].

DOI: https://doi.org/10.1126/sciadv.abh2148
Neuro Oncol. 2021 11 02. 23(23 Suppl 5): S16-S29

DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology.

Drew Pratt, Felix Sahm, Kenneth Aldape.

  Recent years have witnessed a shift to more objective and biologically-driven methods for central nervous system (CNS) tumor classification. The 2016 world health organization (WHO) classification update ("blue book") introduced molecular diagnostic criteria into the definitions of specific entities as a response to the plethora of evidence that key molecular alterations define distinct tumor types and are clinically meaningful. While in the past such diagnostic alterations included specific mutations, copy number changes, or gene fusions, the emergence of DNA methylation arrays in recent years has similarly resulted in improved diagnostic precision, increased reliability, and has provided an effective framework for the discovery of new tumor types. In many instances, there is an intimate relationship between these mutations/fusions and DNA methylation signatures. The adoption of methylation data into neuro-oncology nosology has been greatly aided by the availability of technology compatible with clinical diagnostics, along with the development of a freely accessible machine learning-based classifier. In this review, we highlight the utility of DNA methylation profiling in CNS tumor classification with a focus on recently described novel and rare tumor types, as well as its contribution to refining existing types.

Keywords:  DNA methylation; brain tumor; neuro-oncology

DOI:  https://doi.org/10.1093/neuonc/noab143
Cancer Discov. 2021 Nov 04. pii: candisc.0930.2020. [Epub ahead of print]

DIPG harbour alterations targetable by MEK inhibitors, with acquired resistance mechanisms overcome by combinatorial inhibition.

Elisa Izquierdo, Diana M Carvalho, Alan Mackay, Sara Temelso, Jessica Kr Boult, Giulia Pericoli, Elisabet Fernandez, Molina Das, Valeria Molinari, Yura Grabovska, Rebecca F Rogers, Maria Antonietta Ajmone-Cat, Paula Z Proszek, Mark Stubbs, Sarita Depani, Patricia O'Hare, Lu Yu, Georgia Roumelioti, Jyoti S Choudhary, Matthew Clarke, Amy R Fairchild, Thomas S Jacques, Richard G Grundy, Lisa Howell, Susan Picton, Jenny Adamski, Shaun Wilson, Juliet C Gray, Bassel Zebian, Lynley V Marshall, Fernando Carceller, Jacques Grill, Maria Vinci, Simon P Robinson, Michael Hubank, Darren Hargrave, Chris Jones.

The survival of children with DIPG remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly-established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harbouring MAPK pathway alterations, however treatment of PDX models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 with sustained pathway up-regulation. These cells showed hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and combinatorial treatments for meaningful clinical translation.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0930