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RNA sequencing profiles and diagnostic signatures linked with response to ramucirumab in gastric cancer

Published on Feb 14, 2020
· DOI :10.1101/MCS.A004945
Maxim Sorokin9
Estimated H-index: 9
,
Elena Poddubskaya9
Estimated H-index: 9
(MSMU: I.M. Sechenov First Moscow State Medical University)
+ 9 AuthorsAndrew Garazha10
Estimated H-index: 10
Abstract
Gastric cancer (GC) is the fifth cancer type by associated mortality. Proportion of early diagnosis is low, and most patients are diagnosed at the advanced stages. First line therapy standardly includes fluoropyrimidines and platinum compounds with trastuzumab for HER2-positive cases. For the recurrent disease there are several alternative options including ramucirumab, a monoclonal therapeutic antibody that inhibits VEGF-mediated tumor angiogenesis by binding with VEGFR2, alone or in combination with other cancer drugs. However, control over disease rate following ramucirumab or its combinations is 30-80% of the patients, suggesting that personalization of drug prescription is needed to increase efficacy of treatment. We report here original tumor RNA sequencing profiles for 15 advanced GC patients linked with data on clinical response to ramucirumab or its combinations. Three genes showed differential expression in the tumors-responders vs non-responders: CHRM3, LRFN1 and TEX15. Of them, CHRM3 was upregulated in the responders. Using bioinformatic platform Oncobox we simulated ramucirumab efficiency and compared output model results with actual tumor response data. An agreement was observed between predicted and real clinical outcomes (AUC >/= 0.7). These results suggest that RNA sequencing may be used to personalize prescription of ramucirumab for GC and indicate on potential molecular mechanisms underlying ramucirumab resistance. The RNA sequencing profiles obtained here are fully compatible with the previously published Oncobox Atlas of Normal Tissue Expression (ANTE) data.
  • References (61)
  • Citations (2)
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References61
Newest
#1Anton Buzdin (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 9
#2Maxim Sorokin (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 9
Last. Alexey Moiseev (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 1
view all 14 authors...
Abstract Molecular diagnostics is becoming one of the major drivers of personalized oncology. With hundreds of different approved anticancer drugs and regimens of their administration, selecting the proper treatment for a patient is at least nontrivial task. This is especially sound for the cases of recurrent and metastatic cancers where the standard lines of therapy failed. Recent trials demonstrated that mutation assays have a strong limitation in personalized selection of therapeutics, conseq...
1 CitationsSource
#1Victor TkachevH-Index: 5
#2Maxim Sorokin (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 9
Last. Anton Buzdin (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 9
view all 5 authors...
We describe here the Oncobox method for scoring efficiencies of anticancer target drugs (ATDs) using high throughput gene expression data. The method rationale, design, and validation are given along with the examples of its practical applications in biomedicine. The method is based on the analysis of intracellular molecular pathways activation and measuring expressions of molecular target genes for every ATD under consideration. Using Oncobox method requires collection of normal (control) expre...
4 CitationsSource
#1Nicolas BorisovH-Index: 8
#2Maxim SorokinH-Index: 9
Last. Anton BuzdinH-Index: 9
view all 4 authors...
Intracellular molecular pathways (IMPs) control all major events in the living cell. IMPs are considered hotspots in biomedical sciences and thousands of IMPs have been discovered for humans and model organisms. Knowledge of IMPs activation is essential for understanding biological functions and differences between the biological objects at the molecular level. Here we describe the Oncobox system for accurate quantitative scoring activities of up to several thousand molecular pathways based on h...
7 CitationsSource
#1Gagandeep BrarH-Index: 2
#2Manish A. Shah (NewYork–Presbyterian Hospital)H-Index: 49
Gastric cancer is a leading cause of cancer-related death worldwide. Recent evidence suggests that gastric cancer is a complex and heterogenous disease with emerging subtypes shown to affect respon...
Source
#1Anton BuzdinH-Index: 26
#2Andrew GarazhaH-Index: 10
Last. Nurshat Gaifullin (MSU: Moscow State University)H-Index: 8
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e13032Background: Intracellular molecular pathways (IMPs) control all major events in the living cell. They are considered hotspots in contemporary oncology because knowledge of IMPs activation is ...
Source
#1Elena PoddubskayaH-Index: 6
#2Anton BuzdinH-Index: 26
Last. Nikolay M. Borisov (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 14
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e13143Background: Anticancer Targeted Drugs (ATDs) specifically target one or a few types of tumor-related molecules in a cell. More than two hundred of ATDs were approved worldwide. They have diff...
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#1Maria SuntsovaH-Index: 9
#2Nurshat Gaifullin (MSU: Moscow State University)H-Index: 8
Last. Anton Buzdin (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 9
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Comprehensive analysis of molecular pathology requires a collection of reference samples representing normal tissues from healthy donors. For the available limited collections of normal tissues from postmortal donors, there is a problem of data incompatibility, as different datasets generated using different experimental platforms often cannot be merged in a single panel. Here, we constructed and deposited the gene expression database of normal human tissues based on uniformly screened original ...
2 CitationsSource
#1Jordi Rodon (University of Texas MD Anderson Cancer Center)H-Index: 23
#2Jean-Charles SoriaH-Index: 79
Last. Razelle Kurzrock (UCSD: University of California, San Diego)H-Index: 99
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Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-h...
14 CitationsSource
#1Elena PoddubskayaH-Index: 6
#2Madina P. BaranovaH-Index: 2
Last. Alexey AleshinH-Index: 4
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4 CitationsSource
#1Anton Buzdin (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 9
#2Maxim Sorokin (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 9
Last. Nicolas Borisov (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 8
view all 4 authors...
We recently reviewed the current progress in the use of high-throughput molecular “omics” data for the quantitative analysis of molecular pathway activation. These quantitative metrics may be used in many ways, and we focused on their application as tumor biomarkers. Here, we provide an update of the most recent conceptual findings related to pathway analysis in tumor biology, which were not included in the previous review. The major novelties include a method enabling calculation of pathway-sca...
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#1Alexey Moisseev (MSMU: I.M. Sechenov First Moscow State Medical University)H-Index: 1
view all 5 authors...
Gastric cancer is globally the fifth leading cause of cancer death. We present a case report describing the unique genomic characteristics of an Epstein–Barr virus-negative gastric cancer with esophageal invasion and regional lymph node metastasis. Genomic tests were performed first with the stomach biopsy using platforms FoundationOne, OncoDNA, and Oncopanel at Dana Farber Institute. Following neoadjuvant chemotherapy, residual tumor was resected and the stomach and esophageal residual tumor sa...
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#1Marianna A. Zolotovskaia (MIPT: Moscow Institute of Physics and Technology)H-Index: 1
Last. A. D. KaprinH-Index: 12
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Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions. Here, we compared interpatient molecular heterogeneities of tumors and repertoires of drugs or their molecular targets currently in use in clinical oncology. We estimated molecular heterogeneity using genomic (whole exome sequencing) and transcriptomic (RNA sequencing) data for 4890 tumors taken from The Cancer Genome Atlas database. For thirteen m...
Source