Dataset Information

Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers.

ABSTRACT: Preoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre- and post-metformin-treated tumor tissues from a recently completed preoperative window trial of metformin in EEC patients (ClinicalTrials.gov: NCT01911247) were analyzed by mass spectrometry (MS)-based proteomic and immunohistochemical analyses. Jupiter microtubule-associated homolog 1 (JPT1) was significantly elevated in metformin responders (n = 13) vs nonresponders (n = 7), and found to decrease in abundance in metformin responders following treatment; observations that were verified by immunohistochemical staining for JPT1. Metformin response and loss of JPT1 were assessed in RL95-2 and ACI-181 endometrial cancer (EC) cell lines. We further identified that silencing of JPT1 abundance does not alter cellular response to metformin or basal cell proliferation, but that JPT1 abundance does decrease in response to metformin treatment in RL95-2 and ACI-181 EC cell lines. These data suggest that JPT1 represents a predictive and pharmacodynamic biomarker of metformin response that, if validated in larger patient populations, may enable preoperative EEC patient stratification to metformin treatment and the ability to monitor patient response.

SUBMITTER: Bateman NW

PROVIDER: S-EPMC6997075 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers.

Bateman Nicholas W NW Teng Pang-Ning PN Hope Erica E Hood Brian L BL Oliver Julie J Ao Wei W Zhou Ming M Wang Guisong G Tommarello Domenic D Wilson Katlin K Litzy Tracy T Conrads Kelly A KA Hamilton Chad A CA Darcy Kathleen M KM Casablanca Yovanni Y Maxwell George Larry GL Bae-Jump Victoria V Conrads Thomas P TP

Cancer medicine 20191206 3

Preoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre- and post-metformin-treated tumor tissues from a recently completed preoperative window trial of metformin in EEC patients (ClinicalT ...[more]

PMID: 31808620

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Project description:Background: There has been evidence that Polybromo-1 (PBRM1) mutation was closely associated with immunotherapy response in clear cell renal cell carcinoma (ccRCC). However, it remains incompletely unclear whether PBRM1 mutations correlate with ICI response in pan-cancer. Methods: The clinical data and whole exome sequencing (WES) data were collected from seven published immunotherapy studies to evaluate the association between PBRM1 mutation and ICIs efficacy in the discovery cohort. In order to provide further insight into the relationship between PBRM1 and immunity, we analyzed a relatively large sample as a validation cohort. Moreover, we also collected the clinical data and mutation information of 134 non-small cell lung cancer (NSCLC) patients from the First Affiliated Hospital of Nanjing Medical University to verify the findings. Gene set enrichment analysis (GSEA) was used to evaluate the relationship between PBRM1 and immune-related pathway. Results: Our results found that PBRM1 mutation were associated with immune response in the discovery cohort (Progression free survival [PFS]: hazard ratio (HR) = .51, 95% CI: .28-.95, p = .030; objective response rate [ORR]: 47.92% vs. 28.21%, p = .0044; disease control rate [DCR]: 72.92% vs. 47.53%, p = .0008). In the validation cohort, the patients with PBRM1 mutation had a longer overall survival (OS) (hazard ratio = .69, 95% CI: .53-.91, p = .006). In our non-small cell lung cancer cohort, PFS, objective response rate and disease control rate had obvious superiority in the patients with PBRM1 mutation than those without PBRM1 mutation (PFS: HR = .268, 95% CI: 084-.854, p = .04, ORR: 55.56% vs. 20.00%, p = .027, DCR: 100% vs. 75.20%). Using the Gene set enrichment analysis (GSEA) in TCGA cohorts, PBRM1 mutation was closely related to immune efficacy and immune microenvironment, including killer cell mediated immunity regulation, cell cytokine production, CD8+ T-cell activation and MHC protein binding process. Conclusion: There is a strong correlation between PBRM1 mutation and prognosis and immune response. Based on the findings, PBRM1 mutation may be a promising immunotherapeutic signature that could guide clinical management and personalized immunotherapy.

Project description:BackgroundA critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking.MethodsClinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis.ResultsAmong fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor.ConclusionsEPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.

Dataset Information

Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers.

Publications

Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers.

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