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Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

ABSTRACT: We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased survival of mice bearing cortical implants of mouse and human G3 MBs that overexpress MYC compared to each agent alone, while having little effect on mouse MBs of the sonic hedgehog subgroup. Our findings strongly suggest that combination therapy with pemetrexed and gemcitabine is a promising treatment for G3 MBs.

SUBMITTER: Morfouace M

PROVIDER: S-EPMC3994669 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

Morfouace Marie M Shelat Anang A Jacus Megan M Freeman Burgess B BB Turner David D Robinson Sarah S Zindy Frederique F Wang Yong-Dong YD Finkelstein David D Ayrault Olivier O Bihannic Laure L Puget Stephanie S Li Xiao-Nan XN Olson James M JM Robinson Giles W GW Guy R Kiplin RK Stewart Clinton F CF Gajjar Amar A Roussel Martine F MF

Cancer cell 20140327 4

We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased s ...[more]

PMID: 24684846

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Project description:BackgroundGemcitabine (GEM) is used as a standard first-line drug to effectively alleviate symptoms and prolong survival time for advanced pancreatic cancer. Most randomized controlled trials (RCTs) show that GEM-based combination therapy is better than GEM alone, while some RCTs have the opposite conclusion. This study aimed to investigate whether GEM-based combination therapy would be superior to GEM alone by a systematic review and meta-analysis.MethodsAccording to the PICOS principles, RCTs (S) focused on comparing GEM-based combination therapy (I) vs. GEM alone (C) for advanced pancreatic cancer (P) were collected from eight electronic databases, outcome variables mainly include survival status and adverse events (AEs) (O). Review Manager 5.4 was used to evaluate the pooled effects of the results among selected articles. Pooled estimate of hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were used as measures of effect sizes. Quality assessment for individual study was performed using the Cochrane tool for risk of bias.ResultsA total of 17 studies including 5,197 patients were selected in this analysis. The pooled results revealed that GEM-based combination therapy significantly improved the overall survival (OS; HR =0.84; 95% CI: 0.79 to 0.90; P<0.00001), progression-free survival (PFS; HR =0.78; 95% CI: 0.72 to 0.84; P<0.00001), overall response rate (ORR; OR =1.92; 95% CI: 1.61 to 2.30; P<0.00001), 1-year survival rate (OR =1.44; 95% CI: 1.02 to 2.03; P=0.04), respectively. Subgroup analysis showed that the efficacy of GEM plus capecitabine (CAP) and GEM plus S-1 was better than that of GEM alone, while GEM plus cisplatin (CIS) did not achieve an improved effect. GEM-based combination therapy can significantly increase the incidence of AEs, such as leukopenia (P<0.001), neutropenia (P<0.001), anemia (P<0.05), nausea (P<0.001), diarrhea (P<0.05), and stomatitis (P<0.001). No publication bias existed in our meta-analysis (P>0.10).DiscussionOur study supported that GEM-based combination therapy was more beneficial to improve patient's survival than GEM alone, while there was no additional benefits in GEM plus CIS. We also found that GEM-based combination therapy increased the incidence of AEs. Clinicians need to choose the appropriate combination therapy according to the specific situation.

Project description:BackgroundGemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non-small-cell lung carcinoma (NSCLC).MethodsWe performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration's risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software.ResultsEleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW".ConclusionsGemcitabine or pemetrexed compared with BSC/observation/placebo significantly improved PFS or OS. Whether pemetrexed + bevacizumab compared with bevacizumab alone significantly improves PFS requires further investigation.

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Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

Publications

Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

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