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Pemetrexed Plus Tarceva as Salvage Treatment in EGFR Overexpressed Metastatic Colorectal Cancer Patients Who Were Failed After Standard Chemotherapy

ABSTRACT: This study is single center single arm prospective phase II study. In this study, efficacy and side effects of pemetrexed as salvage regimen on patients who failed all standard chemotherapy and total of 29 patients will be enrolled. Pemetrexed will be continued until disease progression is happened.

DISEASE(S): Colorectal Neoplasms,Colo-rectal Cancer

PROVIDER: 2239263 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Pemetrexed Alone as Salvage Treatment in Metastatic Colorectal Cancer Patients Who Were Failed After Standard Chemotherapy: A Phase II Single Arm Prospective Study

Project description:Pemetrexed is an anticancer agent that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides.Pemetrexed is used as a standard therapeutic agent for lung cancer, pleural mesothelioma, peritoneal mesothelioma.In addition to these effective anti-cancer effect, Pemetrexed is not severe side effects of the medicine. Pemetrexed has been research in colon cancer. Zhang, etc., demonstrated the anti-cancer effect of Pemetrexed in human colon cancer Cells. Although sometimes made also two or more clinical studies, Pemetrexed was reported 15-17% of the treatment response rate in these two studies.

| 2201098 | ecrin-mdr-crc

Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed

Project description:To test the effects of uracil DNA glycosylase (UNG) loss on the formation of double strand breaks (DSBs) by the anti-cancer agent pemetrexed, we performed ChIP-seq for serine 139-phosphorylated H2AX (gammaH2AX), a marker of DSBs, in human cells wild-type or deficient for UNG in combination with pemetrexed treatment. UNG deficiency results in an increase in DSBs upon pemetrexed treatment, and we found that pemetrexed treatment induces DSBs at different genomic locations in UNG wild-type and knockout cells. Similar results were observed upon cisplatin treatment of UNG wild-type and knockout cells, and the genomic locations of DSBs were distinct between pemetrexed-treated and cisplatin-treated samples. Taken together, our results suggest differential mechanisms for DSB formation in UNG-competent and UNG-deficient cells.

2013-10-28 | GSE50692 | GEO

Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed

Project description:To test the effects of uracil DNA glycosylase (UNG) loss on the formation of double strand breaks (DSBs) by the anti-cancer agent pemetrexed, we performed ChIP-seq for serine 139-phosphorylated H2AX (gammaH2AX), a marker of DSBs, in human cells wild-type or deficient for UNG in combination with pemetrexed treatment. UNG deficiency results in an increase in DSBs upon pemetrexed treatment, and we found that pemetrexed treatment induces DSBs at different genomic locations in UNG wild-type and knockout cells. Similar results were observed upon cisplatin treatment of UNG wild-type and knockout cells, and the genomic locations of DSBs were distinct between pemetrexed-treated and cisplatin-treated samples. Taken together, our results suggst differential mechanisms for DSB formation in UNG-competent and UNG-deficient cells. The genomic distribution of gammaH2AX in UNG WT and KO cells treated with pemetrexed or cisplatin was determined by ChIP-seq

2013-10-28 | E-GEOD-50692 | biostudies-arrayexpress

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

Project description:We devised a high-throughput, cell-based assay to identify novel therapeutic compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs, grown as neurospheres, were screened against a library of approximately 7,000 compounds including FDA-approved drugs. We identified two FDA-approved drugs, pemetrexed and gemcitabine that preferentially inhibited tumor proliferation in vitro compared to control neurospheres, and substantially inhibited tumor proliferation in vivo. When combined, the two drugs significantly increased survival P7 Trp53-/-, Cdkn2c-/- neurospheres and MYC mouse cells were compared treated and untreated with drugs pemetrexed+gemcitabine

2014-04-15 | E-GEOD-46406 | biostudies-arrayexpress

Pemetrexed alters inflammatory profile in EA.hy 926 cells grown under low-folate conditions.

Project description:Pemetrexed is an antifolate drug used in the treatment of lung cancer. EA.hy 926 cells grown under low (Lo) and normal (Hi) folate conditions were treated with PMX. Microarray analysis was used to examine changes in gene expression due to PMX treatment.

2012-10-03 | GSE31986 | GEO

Transcription profiling by array of mesothelioma pre- and post-resistance biopsies in order to determine a resistance signature to pemetrexed/carboplatin treatment

Project description:Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Innate and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment.

2012-10-01 | E-MTAB-1109 | biostudies-arrayexpress

NAD Salvage Supports Serine Biosynthesis

Project description:Maintenance of NAD+ levels by mitochondrial complex I, the NAD+ salvage pathway, and other routes is an important factor in of neurodegenerative disease and cancer. Both the production of NAD+ and the metabolic enzymes that require it as a redox cofactor or substrate differ widely in abundance across cell types and conditions. Disruption in the NAD+ supply thus exerts different effects depending on the cellular NAD+ requirements existing in the cell. Pharmacological depletion of NAD+ is actively being pursued in cancer and other diseases but these effects are not fully understood. Here, we combine quantitative proteomics and metabolomics to understand the consequences of disrupting cellular NAD+ levels and find that inhibiting the NAD+ salvage pathway depletes serine biosynthesis from glucose by impeding the NAD+-dependent protein 3-phosphoglycerate dehydrogenase (PHGDH). Importantly, breast cancers that depend on PHGDH are exquisitely sensitive to blocking the NAD+ salvage pathway. PHGDH, and the rate-limiting enzyme of NAD+ salvage are also correlated in public tumor proteome and transcript datasets. These findings are immediately translatable to the pharmacological inhibition of NAMPT in PHGDH-dependent cancers.

2018-08-14 | PXD007790 | Pride

A Novel Molecular Target in Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer treated with a Combination of Osimertinib and Pemetrexed

Project description:In this study, we evaluate the therapeutic potential of combining osimertinib with pemetrexed and clarify the underlying molecular mechanisms in order to establish novel therapeutic strategies for EGFR-mutant NSCLC. We found that the combination of osimertinib and pemetrexed could induce strong apoptotic activity and enhance anti-tumor effects compared to monotherapy in two NSCLC cell lines harboring an EGFR mutation. In addition, we have identified PLK1 as a therapeutic target for combination therapy and as a promising treatment target for overcoming resistance to osimertinib in EGFR-mutated NSCLC patients.

2021-10-14 | GSE165029 | GEO

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

2014-04-15 | GSE46406 | GEO

The antifolate pemetrexed induces innate tolerance in human macrophages

Project description:Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. GM-CSF drives the generation of human monocyte-derived macrophages with a potent pro-inflammatory activity upon stimulation. One-carbon metabolism (OCM) is a complex network of biosynthetic pathways that includes de novo biosynthesis of purines and thymidylate, amino acid metabolism, and methylation reactions. We explored the molecular impact of blocking OCM with the anti-folate pemetrexed (PMX) on the gene expression profile in LPS-activated GM-CSF-primed human monocyte derived macrophages. The specificity of blocking OCM with the anti-folate PMX was demonstrated with folinic acid.

2021-10-28 | GSE159380 | GEO

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