scholarly journals Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors

2016 ◽  
Vol 23 (9) ◽  
pp. 759-767 ◽  
Author(s):  
M Cives ◽  
M Ghayouri ◽  
B Morse ◽  
M Brelsford ◽  
M Black ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Proliferative Activity ◽  
Dna Methyltransferase ◽  
Predictive Biomarkers ◽  
Pancreatic Neuroendocrine Tumors ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Response Predictors ◽  
Alternative Lengthening ◽  
Pathway Activation

The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O6-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

scholarly journals MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

2016 ◽  
Vol 23 (8) ◽  
pp. 625-633 ◽  
Author(s):  
J Cros ◽  
O Hentic ◽  
V Rebours ◽  
M Zappa ◽  
N Gille ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Stable Disease ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Tumor Response ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Mgmt Expression

Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). LowO6-methylguanine-DNA methyltransferase (MGMT) expression andMGMTpromoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression andMGMTpromoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0–300) andMGMTpromoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27–84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15–0.81),P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. HighMGMTpromoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29–1.08),P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50–100) seems to be associated with prolonged stable disease.

scholarly journals O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET)

2019 ◽  
Vol 51 (4) ◽  
pp. 595-599 ◽  
Author(s):  
Annie Lemelin ◽  
Marc Barritault ◽  
Valérie Hervieu ◽  
Léa Payen ◽  
Julien Péron ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Dna Methyltransferase ◽  
Phase Ii Study ◽  
Methylguanine Dna Methyltransferase ◽  
Randomized Phase Ii

scholarly journals High incidence of low O6-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease

2009 ◽  
Vol 161 (4) ◽  
pp. 553-559 ◽  
Author(s):  
Akira Takeshita ◽  
Naoko Inoshita ◽  
Manabu Taguchi ◽  
Chikao Okuda ◽  
Noriaki Fukuhara ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Dna Methyltransferase ◽  
Therapeutic Option ◽  
Arterial Embolization ◽  
Cushing's Disease ◽  
High Recurrence Rate ◽  
Cell Adenoma ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Therapeutic Modalities

ContextCrooke's cell adenoma (CCA), characterized by massive Crooke's hyaline change in corticotroph adenoma, causes a rare subtype of Cushing's disease. In contrast to ordinary corticotroph adenomas, CCAs are generally aggressive and present as invasive macroadenomas, which are refractory to both surgery and radiotherapy and have a high-recurrence rate. Moreover, some patients with CCA present with distant or craniospinal metastases. Currently, there are no effective standard therapies for CCA.ObjectiveWe report a patient with Crooke's cell carcinoma who presented with local invasion and liver metastases, which was refractory to conventional therapeutic modalities including transsphenoidal surgery, radiosurgery, medications, and hepatic transcatheter arterial embolization. After all these treatments failed, the patient had monthly temozolomide administrations, resulting in gradual clinical improvement and biochemical data that were consistent with tumor shrinkage. In glioblastoma, low O6-methylguanine DNA methyltransferase (MGMT) expression is associated with epigenetic gene silencing and predicts a better response to temozolomide.MethodsWe thus investigated MGMT expression, immunohistochemically, in seven CCAs (five invasive macroadenomas and two invasive microadenomas) and 17 ordinary-type adenomas (OTAs; three noninvasive macroadenomas, 12 noninvasive microadenomas, and two invasive microadenomas) from patients with Cushing's disease.ResultsIn seven CCAs, all five invasive macroadenomas exhibited low MGMT expression, defined as <5% nuclear MGMT staining. In 17 OTAs, only one adenoma showed low MGMT expression.ConclusionIn Cushing's disease, invasive macroadenomas including CCA usually have low-MGMT expression. Temozolomide thus may be a new therapeutic option for invasive macroadenomas such as CCA particularly when conventional treatments are ineffective.

scholarly journals Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Tetsuya Yamada ◽  
Shohei Tsuji ◽  
Shinsuke Nakamura ◽  
Yusuke Egashira ◽  
Masamitsu Shimazawa ◽  
...  
Keyword(s):  
Cell Lines ◽  
Dna Methyltransferase ◽  
Antitumor Effect ◽  
Metabotropic Glutamate Receptor ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase

OBJECTIVEGlutamatergic signaling significantly promotes proliferation, migration, and invasion in glioblastoma (GBM). Riluzole, a metabotropic glutamate receptor 1 inhibitor, reportedly suppresses GBM growth. However, the effects of combining riluzole with the primary GBM chemotherapeutic agent, temozolomide (TMZ), are unknown. This study aimed to investigate the efficacy of combinatorial therapy with TMZ/riluzole for GBM in vitro and in vivo.METHODSThree GBM cell lines, T98G (human; O6-methylguanine DNA methyltransferase [MGMT] positive), U87MG (human; MGMT negative), and GL261 (murine; MGMT positive), were treated with TMZ, riluzole, or a combination of both. The authors performed cell viability assays, followed by isobologram analysis, to evaluate the effects of combinatorial treatment for each GBM cell line. They tested the effect of riluzole on MGMT, a DNA repair enzyme causing chemoresistance to TMZ, through quantitative real-time reverse transcription polymerase chain reaction in T98G cells. Furthermore, they evaluated the efficacy of combinatorial TMZ/riluzole treatment in an orthotopic mouse allograft model of MGMT-positive GBM using C57BL/6 J mice and GL261 cells.RESULTSRiluzole displayed significant time- and dose-dependent growth-inhibitory effects on all GBM cell lines assessed independently. Riluzole enhanced the antitumor effect of TMZ synergistically in MGMT-positive but not in MGMT-negative GBM cell lines. Riluzole singularly suppressed MGMT expression, and it significantly suppressed TMZ-induced MGMT upregulation (p < 0.01). Furthermore, combinatorial TMZ/riluzole treatment significantly suppressed tumor growth in the intracranial MGMT-positive GBM model (p < 0.05).CONCLUSIONSRiluzole attenuates TMZ-induced MGMT upregulation and enhances the antitumor effect of TMZ in MGMT-positive GBMs. Therefore, combinatorial TMZ/riluzole treatment is a potentially promising novel therapeutic regimen for MGMT-positive GBMs.

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