Molecularly targeted therapy for malignant glioma

Sathornsumetee, Sith; Reardon, David A.; Desjardins, Annick; Quinn, Jennifer A.; Vredenburgh, James J.; Rich, Jeremy

doi:10.1002/cncr.22741

Cited by 288 publications

(234 citation statements)

References 90 publications

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“…glioblastoma | NAMPT | NAD + | self-renewal | radiation resistance T he prognosis for glioblastoma, the most common malignant intrinsic brain tumor in adults, remains poor despite aggressive multidisciplinary therapy, including maximal safe surgical resection, radiation therapy, and temozolomide (1,2). The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3,4).…”

mentioning

confidence: 99%

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD + ). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD + -dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD + metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.T he prognosis for glioblastoma, the most common malignant intrinsic brain tumor in adults, remains poor despite aggressive multidisciplinary therapy, including maximal safe surgical resection, radiation therapy, and temozolomide (1, 2). The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3, 4). Nicotinamide adenine dinucleotide (NAD + ) has a well-known role in cellular metabolism and is an important cofactor for signaling pathways that regulate aging, inflammation, diabetes mellitus, axonal injury, and cancer (5, 6). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD + synthesis, produces NAD + precursor nicotinamide mononucleotide (NMN) to drive NAD + -dependent processes. Interestingly, NAMPT expression is extremely low in the mammalian brain compared with other organs (7,8). However, NAMPT is highly expressed in several cancers, and features of cancer cells, including proliferation, invasion, and tumor growth, exhibit a dependence on NAD + (9-11). In noncancer cells, NAD + plays a critical role in transcriptional control, providing a metabolic basis for epigenetic reprogramming (12-16). Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13-15). Additionally, NAD + can control transcription by altering DNA methylation in neurons (12). However, in glioblastoma, little is known about NAD + -dependent transcriptional events and whether these even...

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mentioning

confidence: 99%

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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“…However, the percentage was similar to that reported from Hongkong (33%), reflexing that the incidence rates of glioblastomas and other gliomas may be affected by socioeconomic status and genetic susceptibility. 3,53 Thus, our case group may be representative of Han Chinese. Another limitation of our study was potential for spurious associations as a result of hidden population stratification.…”

Section: Discussionmentioning

confidence: 99%

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital‐based case‐control study

Zhou

Liu

Zhang

et al. 2009

Intl Journal of Cancer

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In mammalian cells, X-ray repair cross-complementing group3 (XRCC3) plays an important role in the DNA double-strand breaks (DSBs) repair by homologous recombination. Genetic polymorphisms in the XRCC3 gene may potentially affect the repair of DSBs and thus confer susceptibility to gliomas. In this study, we used a haplotype-based approach to investigate whether 4 tagging single nucleotide polymorphisms of the XRCC3 gene are associated with risk of gliomas in 771 glioma patients and 752 cancerfree controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the unconditional logistic regression, and haplotype associations were estimated using Haplo.Stat. After adjustment for age and sex, the variant G allele of rs861530 and T allele of rs3212092 were significantly associated with an increased risk of gliomas (AG/GG versus AA: adjusted OR 5 1.44, 95% CI 5 1.15-1.80, p 5 0.001 and CT/TT versus CC: adjusted OR 5 1.66, 95% CI 5 1.12-2.46, p 5 0.013, respectively). Consistent with these results, XRCC3 haplotype ''GGCC'' containing rs861530 G allele and haplotype ''AGTC'' containing rs3212092 T allele were also significantly associated with an elevated risk of gliomas compared with the common haplotype ''AGCC'' (adjusted OR 5 1.35, 95% CI 5 1.14-1.58, p 5 0.000 and adjusted OR 5 1.67, 95% CI 5 1.11-2.52, p 5 0.015, respectively). Our results suggest that common genetic variants in the XRCC3 gene may modulate glioma risk. ' 2009 UICC

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“…One of the most promising developments in chemotherapy has been to substitute cytotoxic agents that inhibit non-specific targets in cellular pathways that contribute to carcinogenesis and resistance (25,26). It has been reported that IM inhibits the growth of glioma cells in preclinical models, but its poor brain distribution by P-gp limits its efficacy in patients (34).…”

Section: Discussionmentioning

confidence: 99%

“…One of the most recent novel developments in chemotherapy has been to move away from cytotoxic agents that inhibit non-specific targets in cellular pathways that contribute to carcinogenesis and resistance (25,26). The present study investigated the therapeutic potential of the selective mitochondria inhibitor, CIMP, used in combination with IM for the treatment of malignant C6 glioma cells used as monolayers and spheroid cultures.…”

Section: Introductionmentioning

confidence: 99%

Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma

Bılır¹,

Ergüven²,

Öktem³

et al. 2008

Int J Oncol

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Abstract. Rat C6 glioma is a chemo-resistant experimental brain tumor that is difficult to treat with various drug combinations. Previous studies suggested that imatinib mesylate (Gleevec) is effective in pre-clinical trials for glioblastoma. Also, chlorimipramine (Anafranil) is an anti-depressant drug in use in the clinic and shown to have anti-neoplastic activity. We hypothesized that treatment of resistant C6 glioma with combination of imatinib and chlorimipramine may potentiate cytotoxicity and reverse resistance. C6 glioma was examined both as monolayer and as spheroid cultures. Several experimental designs were examined all of which showed synergistic activity albeit at different time kinetics. Combination treatment resulted in inhibition of cell growth and enhanced cell death as determined by dye exclusion. Further, the combination treatment resulted in significant induction of apoptosis as determined by Annexin V-FITC and PI. Also, there was inhibition of DNA synthesis and cAMP. Altogether, these findings supported the antiproliferative and cytotoxic effects of the combination treatment. Morphological studies were also performed using transmission and scanning electron microscopy. Significant synergistic apoptosis was detected by the combination treatment in both the monolayers and spheroid cultures. There was also a synergistic effect in autophagy by the combination. Several altered morphological features were noted by both the individual compound and enhanced by the combination treatment. The present findings support our hypothesis and demonstrate the potentiation of cytotoxicity by the com-bination of imatinib and chlorimipramine in C6 glioma. Further, the findings suggest the potential clinical application of the combination in the treatment of drugresistant glioma.

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Molecularly targeted therapy for malignant glioma

Cited by 288 publications

References 90 publications

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital‐based case‐control study

Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma

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Molecularly targeted therapy for malignant glioma

Cited by 288 publications

References 90 publications

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital‐based case‐control study

Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma

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An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma