NF-κB and STAT3 in glioblastoma: therapeutic targets coming of age

Gray, G. Kenneth; McFarland, Braden C.; Nozell, Susan E.; Benveniste, Etty N.

doi:10.1586/14737175.2014.964211

Cited by 96 publications

(89 citation statements)

References 131 publications

(138 reference statements)

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Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 99%

“…However, 21% of participants had durable stable disease even if no association between stable disease and molecular biomarkers was seen. There are many other targeted therapeutics affecting various aberrantly activated intracellular signaling pathways of cancer cells that are being examined in the GBM setting, such as inhibitors of poly (ADP-ribose) polymerase (PARP), signal transducer and activator of transcription 3 (STAT3) and others (4,23,(67)(68)(69).However, despite enormous advances in the research of targeted oncological therapy during the past two decades, none of these therapeutics have had proven significant PFS or OS benefit in well-designed phase III clinical trial for patients with newly diagnosed or recurrent GBM as a monotherapy or in combination with standard treatment regimes, which remains truly disappointing. …”

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confidence: 99%

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Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

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Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 99%

mentioning

confidence: 99%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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“…18,31,38,39 NFκB activity is primarily regulated by interaction with inhibitor of kappaB (IkB) proteins 40 with contributions from additional positive and negative upstream regulators. 41 Our findings that NFIA increased NFκB transcription activity, NFκB mRNA, and NFκB protein and that NFκB attenuated shNFIA-induced apoptosis suggest that the pro-GBM effect of NFIA is mediated in part via positive transcriptional regulation of NFκB p65.…”

Section: Discussionmentioning

confidence: 68%

A novel NFIA-NFκB feed-forward loop contributes to glioblastoma cell survival

Lee

Hoxha

Song

2016

NEUONC

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“…Several pathways including phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), ERK/MEK, NOTCH, WNT, forkhead box O3 (FOXO3) A, and STAT pathway hyperactivation have been described for several tumors, such as AML and multiple myeloma [141][142][143][144][145][146][147].…”

Section: Hyperactivation Of Prosurvival Signaling Pathwaysmentioning

confidence: 99%

“…Hyperactivation of other signaling molecules as STAT3 and NF-κB in glioblastoma [141] and WNT/β-catenin signaling pathway have been described in different cancers that are resistant to cancer drugs [143,144,150].…”

Section: Hyperactivation Of Prosurvival Signaling Pathwaysmentioning

confidence: 99%

Mechanisms of tumor cell resistance to the current targeted-therapy agents

et al. 2016

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Resistance to chemotherapy agents is a major challenge infront of cancer patient treatment and researchers. It is known that several factors, such as multidrug resistance proteins and ATP-binding cassette families, are cell membrane transporters that can efflux several substrates such as chemotherapy agents from the cell cytoplasm. To reduce the adverse effects of chemotherapy agents, various targeted-based cancer therapy (TBCT) agents have been developed. TBCT has revolutionized cancer treatment, and several agents have shown more specific effects on tumor cells than chemotherapies. Small molecule inhibitors and monoclonal antibodies are specific agents that mostly target tumor cells but have low side effects on normal cells. Although these agents have been very useful for cancer treatment, however, the presence of natural and acquired resistance has blunted the advantages of targeted therapies. Therefore, development of new options might be necessary. A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities. Therefore, in this review, different mechanisms of tumor cell resistance to chemotherapy drugs and current targeted therapies have been described.

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NF-κB and STAT3 in glioblastoma: therapeutic targets coming of age

Cited by 96 publications

References 131 publications

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

A novel NFIA-NFκB feed-forward loop contributes to glioblastoma cell survival

Mechanisms of tumor cell resistance to the current targeted-therapy agents

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