Network based analysis identifies TP53m-BRCA1/2wt-homologous recombination proficient (HRP) population with enhanced susceptibility to Vigil immunotherapy
| Autor: | John Nemunaitis, Phylicia Aaron, David Willoughby, Elyssa Sliheet, Khalil Choucair, Susan Morand, Molly Robinson, Ernest Bognar, Laura Stanbery |
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| Rok vydání: | 2021 |
| Předmět: |
Oncology
Vigil Cancer Research medicine.medical_specialty medicine.medical_treatment Population Modafinil medicine.disease_cause Placebo Internal medicine medicine Humans education Homologous Recombination Molecular Biology Ovarian Neoplasms Mutation education.field_of_study business.industry BRCA1 Protein Cancer Immunotherapy medicine.disease Molecular Medicine Biomarker (medicine) Female Neoplasm Recurrence Local Ovarian cancer business |
| Zdroj: | Cancer gene therapy. 29(7) |
| ISSN: | 1476-5500 |
| Popis: | Thus far immunotherapy has had limited impact on ovarian cancer. Vigil (a novel DNA-based multifunctional immune-therapeutic) has shown clinical benefit to prolong relapse-free survival (RFS) and overall survival (OS) in the BRCA wild type and HRP populations. We further analyzed molecular signals related to sensitivity of Vigil treatment. Tissue from patients enrolled in the randomized double-blind trial of Vigil vs. placebo as maintenance in frontline management of advanced resectable ovarian cancer underwent DNA polymorphism analysis. Data was generated from a 981 gene panel to determine the tumor mutation burden and classify variants using Ingenuity Variant Analysis software (Qiagen) or NIH ClinVar. Only variants classified as pathogenic or likely pathogenic were included. STRING application (version 1.5.1) was used to create a protein-protein interaction network. Topological distance and probability of co-mutation were used to calculated the C-score and cumulative C-score (cumC-score). Kaplan–Meier analysis was used to determine the relationship between gene pairs with a high cumC-score and clinical parameters. Improved relapse free survival in Vigil treated patients was found for the TP53m-BRCAwt-HRP group compared to placebo (21.1 months versus 5.6 months p = 0.0013). Analysis of tumor mutation burden did not reveal statistical benefit in patients receiving Vigil versus placebo. Results suggest a subset of ovarian cancer patients with enhanced susceptibility to Vigil immunotherapy. The hypothesis-generating data presented invites a validation study of Vigil in target identified populations, and supports clinical consideration of STRING-generated network application to biomarker characterization with other cancer patients targeted with Vigil. |
| Databáze: | OpenAIRE |
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