bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2020‒08‒02
seventeen papers selected by
Oltea Sampetrean
Keio University


  1. BMC Cancer. 2020 Jul 29. 20(1): 710
    Heuser VD, Kiviniemi A, Lehtinen L, Munthe S, Kristensen BW, Posti JP, Sipilä JOT, Vuorinen V, Carpén O, Gardberg M.
      BACKGROUND: The prognosis of glioblastoma remains poor, related to its diffuse spread within the brain. There is an ongoing search for molecular regulators of this particularly invasive behavior. One approach is to look for actin regulating proteins that might be targeted by future anti-cancer therapy. The formin family of proteins orchestrates rearrangement of the actin cytoskeleton in multiple cellular processes. Recently, the formin proteins mDia1 and mDia2 were shown to be expressed in glioblastoma in vitro, and their function could be modified by small molecule agonists. This finding implies that the formins could be future therapeutic targets in glioblastoma.METHODS: In cell studies, we investigated the changes in expression of the 15 human formins in primary glioblastoma cells and commercially available glioblastoma cell lines during differentiation from spheroids to migrating cells using transcriptomic analysis and qRT-PCR. siRNA mediated knockdown of selected formins was performed to investigate whether their expression affects glioblastoma migration. Using immunohistochemistry, we studied the expression of two formins, FHOD1 and INF2, in tissue samples from 93 IDH-wildtype glioblastomas. Associated clinicopathological parameters and follow-up data were utilized to test whether formin expression correlates with survival or has prognostic value.
    RESULTS: We found that multiple formins were upregulated during migration. Knockdown of individual formins mDia1, mDia2, FHOD1 and INF2 significantly reduced migration in most studied cell lines. Among the studied formins, knockdown of INF2 generated the greatest reduction in motility in vitro. Using immunohistochemistry, we demonstrated expression of formin proteins FHOD1 and INF2 in glioblastoma tissues. Importantly, we found that moderate/high expression of INF2 was associated with significantly impaired prognosis.
    CONCLUSIONS: Formins FHOD1 and INF2 participate in glioblastoma cell migration. Moderate/high expression of INF2 in glioblastoma tissue is associated with worse outcome. Taken together, our in vitro and tissue studies suggest a pivotal role for INF2 in glioblastoma. When specific inhibiting compounds become available, INF2 could be a target in the search for novel glioblastoma therapies.
    Keywords:  Actin; FHOD1; Formin; Glioblastoma; Glioma; INF2; Immunohistochemistry; Knockdown; Migration; Outcome; Spheroid
    DOI:  https://doi.org/10.1186/s12885-020-07211-7
  2. Nat Commun. 2020 Jul 30. 11(1): 3811
    Zhou W, Yao Y, Scott AJ, Wilder-Romans K, Dresser JJ, Werner CK, Sun H, Pratt D, Sajjakulnukit P, Zhao SG, Davis M, Nelson BS, Halbrook CJ, Zhang L, Gatto F, Umemura Y, Walker AK, Kachman M, Sarkaria JN, Xiong J, Morgan MA, Rehemtualla A, Castro MG, Lowenstein P, Chandrasekaran S, Lawrence TS, Lyssiotis CA, Wahl DR.
      Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.
    DOI:  https://doi.org/10.1038/s41467-020-17512-x
  3. JCI Insight. 2020 Jul 28. pii: 134386. [Epub ahead of print]
    Ott M, Tomaszowski KH, Marisetty A, Kong LY, Wei J, Duna M, Blumberg K, Ji X, Jacobs CB, Fuller GN, Langford LA, Huse JT, Long JP, Hu J, Li S, Weinberg JS, Prabhu S, Sawaya R, Ferguson SD, Rao G, Lang FF, Curran MA, Heimberger AB.
      PURPOSE: There is a rapidly evolving portfolio of immune therapeutic modulators, but the relative incidence of immune targets in human gliomas is unknown. In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted followed by preclinical determinations of therapeutic effect in immune competent mice harboring gliomas.METHODS: CD4+ and CD8+ T cells and CD11b+ myeloid cells were isolated from the blood of healthy donors and the blood and tumors of newly diagnosed and recurrent glioma patients and profiled for the expression of immune modulatory targets with an available therapeutic. Preclinical murine models of glioma were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. Immune effector function was analyzed in the setting of glioma induced immune suppression.
    RESULTS: In glioma patients, the adenosine-CD73-CD39 immune suppressive pathway was most frequently expressed, followed by PD-1. CD73 expression was upregulated on immune cells by 2-hydroxygluterate in IDH1 mutant glioma patients. In multiple murine glioma models, including those that express CD73, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells after the engagement of this pathway, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of inhibitors of the adenosine pathway in glioma patients.
    CONCLUSIONS: This study illustrates vetting steps that should be considered prior to clinical trial implementation for immunotherapy resistant cancers including testing an agents ability to restore immunological function in the context of intended use.
    Keywords:  Brain cancer; Cancer immunotherapy; Immunology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.134386
  4. Int J Mol Sci. 2020 Jul 25. pii: E5278. [Epub ahead of print]21(15):
    Vieira de Castro J, Gonçalves CS, Hormigo A, Costa BM.
      The discovery of glioblastoma stem cells (GSCs) in the 2000s revolutionized the cancer research field, raising new questions regarding the putative cell(s) of origin of this tumor type, and partly explaining the highly heterogeneous nature of glioblastoma (GBM). Increasing evidence has suggested that GSCs play critical roles in tumor initiation, progression, and resistance to conventional therapies. The remarkable oncogenic features of GSCs have generated significant interest in better defining and characterizing these cells and determining novel pathways driving GBM that could constitute attractive key therapeutic targets. While exciting breakthroughs have been achieved in the field, the characterization of GSCs is a challenge and the cell of origin of GBM remains controversial. For example, the use of several cell-surface molecular markers to identify and isolate GSCs has been a challenge. It is now widely accepted that none of these markers is, per se, sufficiently robust to distinguish GSCs from normal stem cells. Finding new strategies that are able to more efficiently and specifically target these niches could also prove invaluable against this devastating and therapy-insensitive tumor. In this review paper, we summarize the most relevant findings and discuss emerging concepts and open questions in the field of GSCs, some of which are, to some extent, pertinent to other cancer stem cells.
    Keywords:  GSCs microenvironment; cancer heterogeneity; molecular pathways; stem cell markers; therapy resistance
    DOI:  https://doi.org/10.3390/ijms21155278
  5. Oncogene. 2020 Jul 31.
    Xia Q, Zhang H, Zhang P, Li Y, Xu M, Li X, Li X, Dong L.
      PI3K/Akt/mTOR signaling pathway activity is highly elevated in glioblastoma (GBM). Although rapamycin is known to inhibit this pathway, GBM patients are resistant to rapamycin monotherapy. This may be related to mutations of tumor suppressor phosphatase and tensin homolog (PTEN). Here, we show that higher expression of E3 ligase Smad ubiquitylation regulatory factor 1 (Smurf1) in GBM is correlated with poor prognosis. Smurf1 promotes cell growth and colony formation by accelerating cell cycle and aberrant signaling pathways. In addition, we show that Smurf1 ubiquitylates and degrades PTEN. We further demonstrate that the oncogenic role of Smurf1 is dependent on PTEN. Upregulated Smurf1 impairs PTEN activity, leading to consistent activation of PI3K/Akt/mTOR signaling pathway; and depletion of Smurf1 dramatically inhibits cell proliferation and tumor growth. Moreover, loss of Smurf1 abolishes the aberrant regulation of PTEN, causing negative feedback on PI3K/Akt/mTOR signaling pathway, and thus leading to rescue of tumor sensitivity to rapamycin in an orthotopic GBM model. Taken together, we show that Smurf1 promotes tumor progression via PTEN, and combined treatment of Smurf1 knockdown with mammalian target of rapamycin (mTOR) inhibition reduces tumor progression. These results identify a unique role of Smurf1 in mTOR inhibitor resistance and provide a strong rationale for combined therapy targeting GBM.
    DOI:  https://doi.org/10.1038/s41388-020-01400-1
  6. Radiat Oncol. 2020 Jul 31. 15(1): 184
    Kim N, Kim SH, Kang SG, Moon JH, Cho J, Suh CO, In Yoon H, Chang JH.
      BACKGROUND: To identify the association between somatic ataxia-telangiectasia mutated (ATM) mutations and improved radio-sensitivity, we retrospectively reviewed next-generation sequencing data from patients diagnosed with isocitrate dehydrogenase (IDH)-wildtype high-grade glioma.METHODS: We included 39 individuals with (IDH)-wildtype high-grade glioma (diffuse astrocytoma n = 2, anaplastic astrocytoma n = 10, and glioblastoma n = 27) not subjected to gross tumor resection and undergoing radiation therapy with a median total dose of 60 Gy in 30 fractions. The mutational status of the ATM gene was obtained through next-generation sequencing using a TruSight Tumor 170 cancer panel. Disease progression was defined according to the Response Assessment in Neuro-Oncology (RANO) criteria as well as neurologic and clinical findings.
    RESULTS: Among the 39 samples, ATM mutations (ATM mut(+)) were detected in 26% of cases (n = 10). No significant differences were observed in the characteristics of the patients or tumors. Among the 10 patients in the ATM mut(+) group, there were 6 patients with glioblastoma and 4 patients with anaplastic astrocytoma. Most mutations were missense mutations (n = 8, 80%). With a median follow-up of 16.5 mo (interquartile range, 11.4-19.8), ATM mut(+) exhibited 1-year in-field control of 100% compared with 44.1% in the ATM mut(-) group (p = 0.002). There was no difference in the out-field control rate or overall survival between the two groups (p = 0.861 and p = 0.247, respectively).
    CONCLUSIONS: Our results demonstrated that ATM mutations might be involved in the increased radio-sensitivity with excellent in-field control despite the aggressive nature of IDH-wildtype high-grade glioma. Further studies are necessary to uncover the potential role of ATM as a biomarker and candidate therapeutic target in high-grade gliomas.
    Keywords:  ATM; IDH-wild type high-grade glioma; Next-generation sequencing; Radiation therapy; Radiosensitivity
    DOI:  https://doi.org/10.1186/s13014-020-01619-y
  7. Genome Biol. 2020 Jul 30. 21(1): 181
    Noorani I, de la Rosa J, Choi Y, Strong A, Ponstingl H, Vijayabaskar MS, Lee J, Lee E, Richard-Londt A, Friedrich M, Furlanetto F, Fuente R, Banerjee R, Yang F, Law F, Watts C, Rad R, Vassiliou G, Kim JK, Santarius T, Brandner S, Bradley A.
      BACKGROUND: Glioma is the most common intrinsic brain tumor and also occurs in the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. However, the cooperative partners of EGFR driving gliomagenesis remain poorly understood.RESULTS: We explore EGFR-mutant glioma evolution in conditional mutant mice by whole-exome sequencing, transposon mutagenesis forward genetic screening, and transcriptomics. We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord. We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations. Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3. Transcriptomics confirms transposon-mediated effects on expression of these genes. We validate the clinical relevance of new putative tumor suppressors by showing these are frequently altered in patients' gliomas, with prognostic implications. We discover shared and distinct driver mutations in brain and spinal gliomas and confirm in vivo differential tumor suppressive effects of Pten between these tumors. Functional validation with CRISPR-Cas9-induced mutations in novel genes Tead2, Spred1, and Nav3 demonstrates heightened EGFRvIII-glioma cell proliferation. Chemogenomic analysis of mutated glioma genes reveals potential drug targets, with several investigational drugs showing efficacy in vitro.
    CONCLUSION: Our work elucidates functional driver landscapes of EGFR-mutant gliomas, uncovering potential therapeutic strategies, and provides new tools for functional interrogation of gliomagenesis.
    DOI:  https://doi.org/10.1186/s13059-020-02092-2
  8. Neuro Oncol. 2020 Jul 26. pii: noaa180. [Epub ahead of print]
    Miller JJ, Fink A, Banagis JA, Nagashima H, Subramanian M, Lee CK, Melamed L, Tummala SS, Tateishi K, Wakimoto H, Cahill DP.
      BACKGROUND: IDH-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors.METHODS: The effect of inhibition or activation of Sirtuin activity, using small molecules, CRISPR/Cas9 gene editing and inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines.
    RESULTS: We found that SIRT1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity, when combined with nicotinamide phosphoribosyltransferase inhibition (NAMPTi), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of SIRT1 through either genetic overexpression or pharmacologic SIRT1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth.
    CONCLUSIONS: Activation of SIRT1 can selectively target IDH-mutant tumors. These findings indicate that relatively non-toxic STACs, administered either alone or in combination with NAMPTi, could alter the growth trajectory of IDH-mutant gliomas, while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.
    Keywords:  Glioma; IDH; NAD+; NAMPT; Sirtuin
    DOI:  https://doi.org/10.1093/neuonc/noaa180
  9. Cancer Rep (Hoboken). 2019 Dec;2(6): e1220
    Valdebenito S, D'Amico D, Eugenin E.
      BACKGROUND: Glioblastoma (GBM) is a highly aggressive primary brain tumor. Currently, the suggested line of action is the surgical resection followed by radiotherapy and treatment with the adjuvant temozolomide, a DNA alkylating agent. However, the ability of tumor cells to deeply infiltrate the surrounding tissue makes complete resection quite impossible, and, in consequence, the probability of tumor recurrence is high, and the prognosis is not positive. GBM is highly heterogeneous and adapts to treatment in most individuals. Nevertheless, these mechanisms of adaption are unknown.RECENT FINDINGS: In this review, we will discuss the recent discoveries in molecular and cellular heterogeneity, mechanisms of therapeutic resistance, and new technological approaches to identify new treatments for GBM. The combination of biology and computer resources allow the use of algorithms to apply artificial intelligence and machine learning approaches to identify potential therapeutic pathways and to identify new drug candidates.
    CONCLUSION: These new approaches will generate a better understanding of GBM pathogenesis and will result in novel treatments to reduce or block the devastating consequences of brain cancers.
    Keywords:  artificial intelligence; biomarkers; cancer stem cells; gap junctions; tunneling nanotubes (TNTs)
    DOI:  https://doi.org/10.1002/cnr2.1220
  10. Curr Treat Options Oncol. 2020 Jul 30. 21(9): 76
    Ghiaseddin AP, Shin D, Melnick K, Tran DD.
      OPINION STATEMENT: Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.
    Keywords:  Alternating electric fields; CNS tumors; Glioblastoma; Malignant glioma; Optune®; Tumor treating fields
    DOI:  https://doi.org/10.1007/s11864-020-00773-5
  11. Cancer Cell Int. 2020 ;20 337
    Chen Z, Chen C, Zhou T, Duan C, Wang Q, Zhou X, Zhang X, Wu F, Hua Y, Lin F.
      Background: Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. More than half of GBMs contain mutation(s) of PTEN/PI3K/AKT, making inhibitors targeting the PI3K pathway very attractive for clinical investigation. However, so far, PI3K/AKT/mTOR inhibitors have not achieved satisfactory therapeutic effects in clinical trials of GBM. In this study, we aimed to develop a high-throughput screening method for high-throughput identification of potential targeted agents that synergize with PI3K inhibitors in GBM.Methods: A Sensitivity Index (SI)-based drug combination screening method was established to evaluate the interactions between BKM120, a pan-PI3K inhibitor, and compounds from a library of 606 target-selective inhibitors. Proliferation, colony and 3D spheroid formation assays, western blotting, comet assay, γ-H2AX staining were used to evaluate the anti-glioma effects of the top-ranked candidates. The drug combination effects were analyzed by the Chou-Talalay method.
    Results: Six compounds were successfully identified from the drug screen, including three previously reported compounds that cause synergistic antitumor effects with PI3K/mTOR inhibitors. TH588, an putative MTH1 inhibitor exhibited significant synergy with BKM120 in suppressing the proliferation, colony formation and 3D spheroid formation of GBM cells. Further investigation revealed that both DNA damage and apoptosis were markedly enhanced upon combination treatment with TH588 and BKM120. Finally, activation of PI3K or overexpression of AKT compromised the anti-glioma efficacy of TH588.
    Conclusions: The screening method developed in this study demonstrated its usefulness in the rapid identification of synergistic drug combinations of PI3K inhibitors and targeted agents.
    Keywords:  Glioblastoma; MTH1; PI3K; Sensitivity index; TH588
    DOI:  https://doi.org/10.1186/s12935-020-01427-0
  12. Front Cell Dev Biol. 2020 ;8 538
    Liu HJ, Hu HM, Li GZ, Zhang Y, Wu F, Liu X, Wang KY, Zhang CB, Jiang T.
      Glioma is a fatal brain tumor characterized by rapid proliferation and treatment resistance. Ferroptosis is a newly discovered programmed cell death and plays a crucial role in the occurrence and progression of tumors. In this study, we identified ferroptosis specific markers to reveal the relationship between ferroptosis-related genes and glioma by analyzing whole transcriptome data from Chinese Glioma Genome Atlas, The Cancer Genome Atlas dataset, GSE16011 dataset, and the Repository of Molecular Brain Neoplasia Data dataset. Nineteen ferroptosis-related genes with clinical and pathological features of glioma were identified as highly correlated. Functional assays in glioma cell lines indicated the association of ferroptosis with temozolomide resistance, autophagy, and glioma cell migration. Therefore, the identified ferroptosis-related genes were significantly correlated with glioma progression.
    Keywords:  dataset; ferroptosis; gene signature; glioma; prognosis
    DOI:  https://doi.org/10.3389/fcell.2020.00538
  13. Int J Mol Sci. 2020 Jul 27. pii: E5324. [Epub ahead of print]21(15):
    Vitovcova B, Skarkova V, Rudolf K, Rudolf E.
      Glioblastoma multiforme (GBM) represents approximately 60% of all brain tumors in adults. This malignancy shows a high biological and genetic heterogeneity associated with exceptional aggressiveness, leading to a poor survival of patients. This review provides a summary of the basic biology of GBM cells with emphasis on cell cycle and cytoskeletal apparatus of these cells, in particular microtubules. Their involvement in the important oncosuppressive process called mitotic catastrophe will next be discussed along with select examples of microtubule-targeting agents, which are currently explored in this respect such as benzimidazole carbamate compounds. Select microtubule-targeting agents, in particular benzimidazole carbamates, induce G2/M cell cycle arrest and mitotic catastrophe in tumor cells including GBM, resulting in phenotypically variable cell fates such as mitotic death or mitotic slippage with subsequent cell demise or permanent arrest leading to senescence. Their effect is coupled with low toxicity in normal cells and not developed chemoresistance. Given the lack of efficient cytostatics or modern molecular target-specific compounds in the treatment of GBM, drugs inducing mitotic catastrophe might offer a new, efficient alternative to the existing clinical management of this at present incurable malignancy.
    Keywords:  benzimidazole carbamates; cell death; glioblastoma multiforme; microtubule-targeting agents; mitotic catastrophe
    DOI:  https://doi.org/10.3390/ijms21155324
  14. Cancer Rep (Hoboken). 2019 Dec;2(6): e1185
    Venkatesh VS, Lou E.
      BACKGROUND: The concept of tumour heterogeneity is not novel but is fast becoming a paradigm by which to explain part of the highly recalcitrant nature of aggressive malignant tumours. Glioblastoma is a prime example of such difficult-to-treat, invasive, and incurable malignancies. With the advent of the post-genomic age and increased access to next-generation sequencing technologies, numerous publications have described the presence and extent of intratumoural and intertumoural heterogeneity present in glioblastoma. Moreover, there have been numerous reports more directly correlating the heterogeneity of glioblastoma to its refractory, reoccurring, and inevitably terminal nature. It is therefore prudent to consider the different forms of heterogeneity seen in glioblastoma and how to harness this understanding to better strategize novel therapeutic approaches. One of the most central questions of tumour heterogeneity is how these numerous different cell types (both tumour and non-tumour) in the tumour mass communicate.RECENT FINDINGS: This chapter provides a brief review on the variable heterogeneity of glioblastoma, with a focus on cellular heterogeneity and on modalities of communication that can induce further molecular diversity within the complex and ever-evolving tumour microenvironment. We provide particular emphasis on the emerging role of actin-based cellular conduits called tunnelling nanotubes (TNTs) and tumour microtubes (TMs) and outline the perceived current problems in the field that need to be resolved before pharmacological targeting of TNTs can become a reality.
    CONCLUSIONS: We conclude that TNTs and TMs provide a new and exciting avenue for the therapeutic targeting of glioblastoma and that numerous inroads have already made into TNT and TM biology. However, to target TMs and TNTs, several advances must be made before this aim can become a reality.
    Keywords:  communication; glioblastoma; heterogeneity; tumour communication; tunnelling nanotubes
    DOI:  https://doi.org/10.1002/cnr2.1185
  15. iScience. 2020 Jul 13. pii: S2589-0042(20)30553-8. [Epub ahead of print]23(8): 101365
    Chadwick M, Yang C, Liu L, Gamboa CM, Jara K, Lee H, Sabaawy HE.
      Glioblastoma is the most common and deadly primary brain malignancy. Despite advances in precision medicine oncology (PMO) allowing the identification of molecular vulnerabilities in glioblastoma, treatment options remain limited, and molecular assays guided by genomic and expression profiling to inform patient enrollment in life-saving trials are lacking. Here, we generate four-dimensional (4D) cell-culture arrays for rapid assessment of drug responses in glioblastoma patient-derived models. The arrays are 3D printed with thermo-responsive shape memory polymer (SMP). Upon heating, the SMP arrays self-transform in time from 3D cell-culture inserts into histological cassettes. We assess the utility of these arrays with glioblastoma cells, gliospheres, and patient derived organoid-like (PDO) models and demonstrate their use with glioblastoma PDOs for assessing drug sensitivity, on-target activity, and synergy in drug combinations. When including genomic and drug testing assays, this platform is poised to offer rapid functional drug assessments for future selection of therapies in PMO.
    Keywords:  Cancer; Medical Biotechnology; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.isci.2020.101365
  16. Cell Death Dis. 2020 Jul 30. 11(7): 602
    Zhang J, Jing L, Tan S, Zeng EM, Lin Y, He L, Hu Z, Liu J, Guo Z.
      Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are 'coincidental' treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs deficiency.
    DOI:  https://doi.org/10.1038/s41419-020-02812-3
  17. Clin Cancer Res. 2020 Jul 27. pii: clincanres.1082.2020. [Epub ahead of print]
    Batich KA, Mitchell DA, Healy P, Herndon JE, Sampson JH.
      Despite standard of care for glioblastoma (GBM), including gross total resection, high dose radiation, and dose-limited chemotherapy, this tumor remains one of the most aggressive and therapeutically challenging. The relatively small number of patients with this diagnosis compared to more common solid tumors in clinical trials commits new GBM therapies to testing in small, underpowered, non-randomized settings. Among ~200 registered GBM trials identified between 2005 and 2015, nearly half were single-arm studies with sample sizes not exceeding 50 patients. These constraints have made demonstrating efficacy for novel therapies difficult in GBM and other rare and aggressive cancers. Novel immunotherapies for GBM such as vaccination with dendritic cells (DCs) have yielded mixed results in clinical trials. To address limited numbers, we sequentially conducted three separate clinical trials utilizing Cytomegalovirus (CMV) specific DC vaccines in patients with newly diagnosed GBM whereby each follow-up study had nearly doubled in sample size. Follow-up data from the first blinded, randomized phase II clinical trial (NCT00639639) revealed that nearly one-third of this cohort is without tumor recurrence at five years from diagnosis. A second clinical trial (NCT00639639) resulted in a 36% survival rate at five years from diagnosis. Results of the first two-arm trial (NCT00639639) showed increased migration of the DC vaccine to draining lymph nodes, and this increased migration has been recapitulated in our larger confirmatory clinical study (NCT02366728). We have now observed that nearly one-third of the GBM study patient population receiving CMV-specific DC vaccines results in exceptional long-term survivors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1082