Challenges in the Treatment of Glioblastoma: Multisystem Mechanisms of Therapeutic Resistance

Noch, Evan; Ramakrishna, Rohan; Magge, Rajiv

doi:10.1016/j.wneu.2018.04.022

Cited by 115 publications

(104 citation statements)

References 155 publications

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“…Our finding that glioblastoma cells leveraged cellular constituents in its microenvironment to protect itself from the deleterious effects of cancer therapeutics is reminiscent of findings reported in breast and ovarian cancer, where the percentage of stromal cells in the clinical specimen prognosticated survival after systemic therapy (78). These findings bear implications in cancer evolution as it relates to therapeutic resistance (79,80). Cancer evolution models built on temporal ordering of clonal or sub-clonal mutations typically do not directly account for contributions from the microenvironment (81).…”

Section: Discussionsupporting

confidence: 63%

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Kaneda²,

et al. 2020

Preprint

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Precision medicine in oncology leverages clinical observations of exceptional response.Towards an understanding of the molecular features that define this response, we applied an integrated, multi-platform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted isoform of PI3K, PI3Kg, by pharmacologic inhibition or genetic inactivation, disrupted this signaling axis by suppressing microglia/macrophage accumulation and associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kg inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kg in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kg inhibition as a glioblastoma therapy. 3 Significance StatementUnderstanding the basis for exceptional responders represents a key pillar in the framework of precision medicine. In this study, we utilized distinct informatics platforms to analyze the expression profiles of clinically annotated tumor specimens derived from patients afflicted with glioblastoma, the most common form of primary brain cancer. These analyses converged on prognostic contributions from glioblastoma-associated microglia/macrophages. Glioblastoma-associated microglia secreted interleukin 11 (IL11) to activate a STAT3-MYC signaling axis in glioblastoma cells, facilitating resistance to the standard-of-care chemotherapy, temozolomide. Microglia recruitment and IL11 secretion were dependent on the myeloid specific phosphoinositide-3-kinase gamma isoform (PI3Kg). Inhibition or genetic inactivation of PI3Kg in murine glioblastoma models recapitulated expression profiles observed in specimens derived from exceptional responders, suggesting potential for clinical translation.

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Section: Discussionsupporting

confidence: 63%

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Kaneda²,

et al. 2020

Preprint

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“…Glioblastoma is one of the most aggressive brain tumors and poorly responsive malignancies to treatment with among the shortest survival rates of all cancers [1]. Patients' 5-year survival rate is less than 5% [2], regardless of novel modalities in surgery, irradiation, and chemotherapy [3,4]. survival rate, being the shortest in the MES subtype, and as cancer invasion was found associated with CCL5/CCR5 axis signaling, we hypothesized that CCR5 and/or CCL5 distribution would be significantly different in GB subtypes.…”

Section: Introductionmentioning

confidence: 99%

CCR5-Mediated Signaling is Involved in Invasion of Glioblastoma Cells in Its Microenvironment

Novak

Krajnc

Hrastar

et al. 2020

IJMS

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The chemokine CCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptor CCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in which CCL5 expression correlates with shorter patient survival. Using immunohistochemistry, we identified CCL5 and CCR5 in a series of glioblastoma samples and cells, including glioblastoma stem cells. CCL5 and CCR5 gene expression were significantly higher in a cohort of 38 glioblastoma samples, compared to low-grade glioma and non-cancerous tissues. The in vitro invasion of patients-derived primary glioblastoma cells and glioblastoma stem cells was dependent on CCL5-induced CCR5 signaling and is strongly inhibited by the small molecule CCR5 antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs release CCR5 ligands. In support of this model, we detected CCL5 and CCR5 in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also found CCR5 expressing macrophages were in close proximity to glioblastoma cells. In conclusion, autocrine and paracrine cross-talk in glioblastoma and, in particular, glioblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to glioblastoma invasion, suggesting the CCL5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc.

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“…Currently, surgical resection followed by radiation and TMZ therapies is the standard of care for GBM patients (55). With these extensive therapies, almost all patients show therapy resistance and recurrence of GBM (56). To address resistance and recurrence, clinicians have adopted antiangiogenic therapies in recurrent GBM.…”

Section: Discussionmentioning

confidence: 99%

Changes in the tumor microenvironment and treatment outcome in glioblastoma: A pilot study

Ali

Borin

Piranlioglu

et al. 2020

Preprint

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37Glioblastoma (GBM) is a hypervascular and aggressive primary malignant tumor of the central 38 nervous system. Recent investigations showed that traditional therapies along with antiangiogenic 39 therapies failed due to the development of post-therapy resistant and recurrent GBM. Our 40 investigations show that there are changes in the cellular and metabolic compositions in the tumor 41 microenvironment (TME). It can be said that tumor cell-directed therapies are ineffective and we 42 need to rethink how to treat GBM. 43 We hypothesize that the composition of TME-associated cells will be different based on the 44 therapy and therapeutic agents, and TME-targeting therapy will be better to decrease recurrence 45 and improve survival. Therefore, the purpose of this study is to determine the changes in the TME 46 in respect of T-cell population, M1 and M2 macrophage polarization status, and MDSC population 47 following different treatments in a syngeneic model of GBM. In addition to these parameters, 48 tumor growth and survival were also studied following different treatments. 49The results showed that changes in the TME-associated cells were dependent on the therapeutic 50 agents and the TME-targeting therapy improved the survival of the GBM bearing animals. 51The current GBM therapies should be revisited to add agents to prevent the accumulation of bone 52 marrow-derived cells in the TME or to prevent the effect of immune-suppressive myeloid cells in 53 causing alternative neovascularization, the revival of glioma stem cells, and recurrence. Instead of 54 concurrent therapy, a sequential strategy would be best to target TME-associated cells. 56Even with current treatment strategies and the addition of expensive immunotherapies or 75 antiangiogenic therapies, the prognosis of glioblastoma (GBM) is dismal (1-3). GBM is a very 76 hypervascular and invasive malignant tumor. So much so that, current treatments consisting of 77 surgery, radiation and chemotherapies with or without adjuvant still show no hope to patients (4-78 6). Interestingly, recent investigations demonstrated that traditional therapies along with newer 79 antiangiogenic therapies are changing the cellular as well as the metabolic compositions of the 80 tumor microenvironment (TME) tremendously (7-11). Therefore, newer treatment strategies 81 targeting TME should be considered along with targeting tumor cells in GBM. 82The TME is composed of tumor cells, stromal cells, cells from the bone marrow, and the 83 extracellular matrix (12). Except for a few cell types, such as normal epithelial cells, myoepithelial 84 cells, dendritic cells, M1 macrophages, N1 neutrophils and CD8 T-cells, most of the stromal and 85 bone marrow-derived cells promote tumor growth and metastasis (10, 11,(13)(14)(15). In fact, platelets 86 have also been shown to promote tumor growth (16)(17)(18)(19). Therefore, it is imperative to include 87 targeting tumor-associated cells in the current standard regimen of therapies for malignant tumors 88 such as GBM. However, the...

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Challenges in the Treatment of Glioblastoma: Multisystem Mechanisms of Therapeutic Resistance

Cited by 115 publications

References 155 publications

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

CCR5-Mediated Signaling is Involved in Invasion of Glioblastoma Cells in Its Microenvironment

Changes in the tumor microenvironment and treatment outcome in glioblastoma: A pilot study

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