scholarly journals RBTT-04. DGM1 MAY SERVE AS A NOVEL GENETIC BIOMARKER OF RESPONSE TO ENZASTAURIN IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi219-vi219
Author(s):  
Nicholas Butowski ◽  
Lei Zhang ◽  
Hong Sun ◽  
Isabel Han ◽  
Manoj jivani ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Predictive Biomarker ◽  
Chromosome 8 ◽  
Newly Diagnosed ◽  
Pivotal Study ◽  
Germline Polymorphism ◽  
A Genome ◽  
Genomic Marker ◽  
Daily Dose ◽  
Highly Correlated

Abstract BACKGROUND No significant progress has been made over the last decade in therapies available for glioblastoma (GBM) with survival remaining poor. Meaningful advances in treating this deadly malignancy may rely on precision medicine. A novel pharmacogenomic biomarker, Denovo Genomic Marker 1 (DGM1), for enzastaurin (enz) in treating lymphoma was discovered. It was evaluated to predict enz response in GBM. METHODS Biomarker discovery was performed by a genome-wide screen using DNA extracted from blood samples of a ph 3 enz lymphoma trial and confirmed in an independent ph 2 lymphoma trial. The biomarker was evaluated for its predictability in GBM using the archived DNA samples from a ph 1/2 enz GBM trial. RESULTS DGM1, a germline polymorphism on chromosome 8, was found to be highly correlated with response to enz in the two lymphoma trials. Using DNA extracted from pts blood of the single-arm ph 1/2 study with newly diagnosed GBM receiving enz added to radiation and temozolomide (tmz), we found median OS for DGM1+ pts treated with enz was 18 mon vs 12.8 mon for DGM1- pts, HR (95% CI) 0.68 (0.25, 1.81), p = 0.12. Pts receiving a mean daily dose of enz ≥ 245 mg had an OS of 19.8 mon vs 14.9 mon for pts receiving a mean daily dose of < 245 mg [HR (95% CI) 0.55 (0.34, 0.90)]. CONCLUSION These data are supportive of DGM1 as a potentially predictive biomarker for enz response in both lymphoma and GBM. There is an ongoing biomarker-driven pivotal study in lymphoma. DGM1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM with 500 mg/day of enz in combination with tmz.

DGM1 may serve as a novel genetic biomarker of response to enzastaurin in glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2023-2023
Author(s):  
Nicholas A. Butowski ◽  
Ronald L. Shazer ◽  
Hong Sun ◽  
Isabel Han ◽  
Manoj A. Jivani ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Predictive Biomarker ◽  
Chromosome 8 ◽  
Newly Diagnosed ◽  
Genome Wide ◽  
Germline Polymorphism ◽  
A Genome ◽  
Genomic Marker ◽  
Daily Dose ◽  
Highly Correlated

2023 Background: Despite countless clinical trials being conducted, little has changed over the last decade in the chemotherapies available for glioblastoma (GBM) with survival remaining poor. Meaningful advances in treating this deadly malignancy may rely on precision medicine. We discovered a novel pharmacogenomic biomarker for enzastaurin (enz) in treating lymphoma (lymph). We evaluated if this biomarker can be used to predict enz response in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from blood samples from a ph 3 enz lymph trial and confirmed in an independent ph 2 enz lymph trial. The biomarker was then evaluated for its predictability in GBM using the archived DNA samples from a prior ph 1/2 enz GBM trial. Results: A novel biomarker, Denovo Genomic Marker 1 (DGM1), a germline polymorphism on chromosome 8, was found to be highly correlated with response to enz in the two lymph trials. Using DNA extracted from blood of pts from the single-arm ph 1/2 study of newly diagnosed GBM receiving enz added to radiation and temozolomide (tmz), we found median OS for DGM1+ pts treated with enz was 18 mon vs 12.8 mon for DGM1- pts, HR (95% CI) 0.68 (0.25, 1.81), p = 0.12. In addition, we found pts in the GBM study receiving a mean daily dose of enz ≥ 245 mg had an OS of 19.8 mon vs 14.9 mon for pts receiving a mean daily dose of < 245 mg [HR (95% CI) 0.55 (0.34, 0.90)]; enz 500 mg/day was used in the lymph studies. Conclusions: These data are supportive of DGM1 as a potentially predictive biomarker for enz response in both lymph and GBM. There is an ongoing biomarker-driven pivotal ph 3 study in lymph at 500 mg/day, and DGM1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM with 500 mg/day of enz in combination with tmz.

CTNI-08. DB102-01 ENGAGE STUDY: A BIOMARKER-GUIDED, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER PHASE 3 CLINICAL TRIAL OF DB102 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi60-vi60
Author(s):  
Daniela Bota ◽  
Nicholas Butowski ◽  
David Piccioni ◽  
Macarena De la Fuente ◽  
Ying Mao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Methylation Status ◽  
Single Agent ◽  
Objective Response ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
A Genome ◽  
Genomic Marker

Abstract Precision medicine is vital for treating many cancers. Lack of valid biomarkers might contribute to the failure of drug therapy for GBM. The Denovo Genomic Marker 1 (DGM1), a novel pharmacogenomic biomarker, has been discovered by a genome-wide screen of patients treated with DB102 (enzastaurin) in a trial for lymphoma. Similarly, retrospective analyses showed that DB102 significantly improved outcomes in the biomarker positive GBM patients treated with DB102, regardless of MGMT promoter methylation status. The ENGAGE Study (DB102-01, NCT03776071) is a global Phase 3 clinical trial to confirm clinical benefits in patients with newly diagnosed GBM who are DGM1 biomarker positive. This is a prospective, randomized, double-blind, placebo-controlled, multi-center study. A total of 318 patients with newly diagnosed GBM will be enrolled. After screening, patients will be randomized to receive radiation therapy (RT) and temozolomide (TMZ) plus either DB102 or a matched placebo for 6 weeks in the Concurrent Phase, followed by DB102 or placebo for approximately 5 weeks in the Single-Agent Phase and then TMZ plus DB102 or placebo in the Adjuvant Phase (up to 12 cycles). Thereafter DB102 or placebo may be continued as a single agent for up to 2 years. The primary endpoint is overall survival (OS). The secondary endpoints include progression free survival (PFS), objective response rate (ORR) and drug safety. By April 2021, the safety-run-in part was completed. The study is now open for enrollment in the US and soon in Canada and China.

scholarly journals Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (14) ◽  
pp. 3224-3233
Author(s):  
Paul J. Martin ◽  
David M. Levine ◽  
Barry E. Storer ◽  
Sarah C. Nelson ◽  
Xinyuan Dong ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Genetic Variants ◽  
Hematopoietic Cell Transplantation ◽  
Genome Wide Association Study ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Grade 3 ◽  
Highly Correlated

Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

BIOM-32. ENDOPLASMIC RETICULUM PROTEIN SSR3 DETERMINES AND PREDICTS RESPONSE TO PACLITAXEL IN BREAST CANCER AND GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi17-vi18
Author(s):  
Crismita Dmello ◽  
Aarón Sonabend ◽  
Víctor Arrieta ◽  
Daniel Zhang ◽  
Deepak Kanojia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Glioma Cells ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Precision Oncology ◽  
Patient Response ◽  
Knock Out ◽  
Genome Wide ◽  
A Genome

Abstract Paclitaxel (PTX) is one the most potent and commonly used chemotherapies for breast and pancreatic cancer. Given the potency of this drug for glioblastomas (GBM) several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for this disease. In spite of the efficacy of PTX, individual tumors exhibit variable susceptibility to this drug, with response rate in the range of 30%-60%. To identify predictive biomarkers for response to PTX, we performed a genome-wide CRISPR knock-out screen using human glioma cells. The most enriched genes in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort. This led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with response to PTX in breast cancer cells, glioma cells, in multiple intracranial glioma xenografts and in GBM patient derived explant cultures. Knockout of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. In gliomas, SSR3-mediated susceptibility to PTX relates to modulation of phosphorylation of ER stress sensor IRE1α. Thus, by using genome-wide screen combined with patient response data, we discovered a biomarker that demonstrates causal and correlative relationship with response to PTX in breast cancer and GBM. Prospective validation of this biomarker is warranted for its broad implementation for precision oncology.

scholarly journals Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics

Metabolites ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 77 ◽  
Author(s):  
Xiao Pu ◽  
Yiqiao Gao ◽  
Ruiting Li ◽  
Wei Li ◽  
Yuan Tian ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cytochrome P450 ◽  
Biomarker Discovery ◽  
Absolute Quantification ◽  
Pharmacokinetic Analysis ◽  
Large Individual ◽  
Mrna Levels ◽  
Cytochrome P450 1A2 ◽  
Interindividual Variations ◽  
Highly Correlated

Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors. In order to discover non-invasive serum biomarkers associated with hepatic CYP1A2, mass spectrometry-based, untargeted metabolomics were first conducted, in order to dissect the metabolic differences in the serum and liver between control rats and β-naphthoflavone (an inducer of CYP1A2)-treated rats. Real-time reverse transcription polymerase chain reaction and pharmacokinetic analysis of phenacetin and paracetamol were performed, in order to determine the changes of mRNA levels and activity of CYP1A2 in these two groups, respectively. Branched-chain amino acids phenylalanine and tyrosine were ultimately focalized, as they were detected in both the serum and liver with the same trends. These findings were further confirmed by absolute quantification via a liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics approach. Furthermore, the ratio of phenylalanine to tyrosine concentration was also found to be highly correlated with CYP1A2 activity and gene expression. This study demonstrates that metabolomics can be a potentially useful tool for biomarker discovery associated with CYPs. Our findings contribute to explaining interindividual variations in CYP1A2-mediated drug metabolism.

scholarly journals Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (11) ◽  
pp. 2409-2417 ◽  
Author(s):  
Yoshihiro Inamoto ◽  
Paul J. Martin ◽  
Stephanie J. Lee ◽  
Amin A. Momin ◽  
Laura Tabellini ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Hematopoietic Cell Transplantation ◽  
Biomarker Discovery ◽  
Interleukin 1 ◽  
Chronic Gvhd ◽  
Linear Regression Analysis ◽  
Wnt Signaling Pathway ◽  
Mass Spectrometry Analysis ◽  
Newly Diagnosed ◽  
Related Protein

Abstract To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD.

scholarly journals Genetic dissection of climacteric fruit ripening in a melon population segregating for ripening behavior

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Lara Pereira ◽  
Miguel Santo Domingo ◽  
Valentino Ruggieri ◽  
Jason Argyris ◽  
Michael A. Phillips ◽  
...  
Keyword(s):  
Fruit Ripening ◽  
Ethylene Production ◽  
Genome Wide Association Study ◽  
Recombinant Inbred Lines ◽  
Introgression Line ◽  
Complex Trait ◽  
Chromosome 8 ◽  
Genetic Dissection ◽  
Climacteric Fruit ◽  
A Genome

Abstract Melon is as an alternative model to understand fruit ripening due to the coexistence of climacteric and non-climacteric varieties within the same species, allowing the study of the processes that regulate this complex trait with genetic approaches. We phenotyped a population of recombinant inbred lines (RILs), obtained by crossing a climacteric (Védrantais, cantalupensis type) and a non-climcteric variety (Piel de Sapo T111, inodorus type), for traits related to climacteric maturation and ethylene production. Individuals in the RIL population exhibited various combinations of phenotypes that differed in the amount of ethylene produced, the early onset of ethylene production, and other phenotypes associated with ripening. We characterized a major QTL on chromosome 8, ETHQV8.1, which is sufficient to activate climacteric ripening, and other minor QTLs that may modulate the climacteric response. The ETHQV8.1 allele was validated by using two reciprocal introgression line populations generated by crossing Védrantais and Piel de Sapo and analyzing the ETHQV8.1 region in each of the genetic backgrounds. A Genome-wide association study (GWAS) using 211 accessions of the ssp. melo further identified two regions on chromosome 8 associated with the production of aromas, one of these regions overlapping with the 154.1 kb interval containing ETHQV8.1. The ETHQV8.1 region contains several candidate genes that may be related to fruit ripening. This work sheds light into the regulation mechanisms of a complex trait such as fruit ripening.

scholarly journals DNA hydroxymethylation is associated with disease severity and persists at enhancers of oncogenic regions in multiple myeloma

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Jean-Baptiste Alberge ◽  
Florence Magrangeas ◽  
Mirko Wagner ◽  
Soline Denié ◽  
Catherine Guérin-Charbonnel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Tumor Biology ◽  
Prognostic Index ◽  
Clinical Aspects ◽  
Epigenetic Mark ◽  
Newly Diagnosed ◽  
Dna Hydroxymethylation ◽  
Large Patient ◽  
A Genome

Abstract Background Multiple myeloma (MM) is a heterogeneous plasma cell malignancy that remains challenging to cure. Global hypomethylation correlates with an aggressive phenotype of the disease, while hypermethylation is observed at particular regions of myeloma such as B cell-specific enhancers. The recently discovered active epigenetic mark 5-hydroxymethylCytosine (5hmC) may also play a role in tumor biology; however, little is known about its level and distribution in myeloma. In this study, we investigated the global level and the genomic localization of 5hmC in myeloma cells from 40 newly diagnosed patients, including paired relapses, and of control individuals. Results Compared to normal plasma cells, we found global 5hmC levels to be lower in myeloma (P < 0.001). Higher levels of 5hmC were found in lower grades of the International Staging System prognostic index (P < 0.05) and tend to associate with a longer overall survival (P < 0.1). From the hydroxymethylome data, we observed that the remaining 5hmC is organized in large domains overlapping with active chromatin marks and chromatin opening. We discovered that 5hmC strongly persists at key oncogenic genes such as CCND1, CCND2 and MMSET and characterized domains that are specifically hydroxymethylated in myeloma subgroups. Novel 5hmC-enriched domains were found at putative enhancers of CCND2 and MYC in newly diagnosed patients. Conclusions 5hmC level is associated with clinical aspects of MM. Mapping 5hmC at a genome-wide level provides insights into the disease biology directly from genomic DNA, which makes it a potent mark to study epigenetics on large patient cohorts.

Comparing three validated methods of patient self-reported fatigue in a prospective randomized clinical trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9108-9108
Author(s):  
Katherine Sams ◽  
L. Doug Case ◽  
Glenn Jay Lesser ◽  
Michelle Joy Naughton ◽  
Susan Kidwell Williford ◽  
...  
Keyword(s):  
Assessment Instruments ◽  
Profile Of Mood States ◽  
Newly Diagnosed ◽  
Analog Scale ◽  
Scale Scores ◽  
Vas Scores ◽  
Baseline Levels ◽  
Highly Correlated ◽  
Chemotherapy Initiation ◽  
Coenzyme Q10 Supplementation

9108 Background: Fatigue can be measured with different validated assessment instruments in symptom management trials. Methods: Between 2004-2009, the Wake Forest CCOP Research Base protocol 97202 randomized 236 women receiving adjuvant chemotherapy for newly diagnosed breast cancer to Coenzyme Q10 supplementation vs placebo. The primary endpoint was change in self-reported fatigue. Patients (pt) were assessed at baseline, 8, 16, and 24 weeks (wk) with 3 instruments: 1) Profile of Mood States – Fatigue (POMS; 7 questions; scored 0-4); 2) Functional Assessment of Cancer Treatment – Fatigue (FACIT; 13 questions; scored 0-4); and 3) Visual Analog Scale (VAS; one scale; scored 0-10). For comparison, each instrument was rescaled from 0 to 100; higher numbers indicate worse fatigue. Results: CoQ10 did not significantly affect fatigue (Lesser G et al, ASCO Proc., 2010). All 3 measures demonstrated an increase in fatigue after chemotherapy initiation at 8 & 16 wks with trend towards baseline levels at 24 wks. The fatigue measures were highly correlated: r ≥ 0.8 for all pairwise associations at all times. However, their scores varied. The Table shows mean rescaled scores for pt below/above the median fatigue level, calculated by taking mean of the three scores averaged across the four time periods. In general, POMS tended to give the lowest and VAS the highest scores, but differences between POMS and FACIT and FACIT and VAS depended on mean fatigue level. For pt experiencing lower (<median) fatigue, FACIT and VAS scores were similar, while POMS scores were significantly lower. For higher (>median) fatigue, POMS and FACIT scores were similar, while VAS was significantly higher. Conclusions: While POMS, FACIT, and VAS scores were highly correlated, their scale scores varied depending on the level of fatigue experienced by the pt. Fatigue assessment methods in clinical trials should be selected carefully as they do not always give equivalent results. Supported by NCI/DCP grant U10 CA81851. [Table: see text]

scholarly journals Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
S. Y. Liao ◽  
N. G. Casanova ◽  
C. Bime ◽  
S. M. Camp ◽  
H. Lynn ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Association Studies ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Genome Wide Association Studies ◽  
Potential Candidate ◽  
Gene Set ◽  
Protein Levels ◽  
N 93

AbstractThe lack of successful clinical trials in acute respiratory distress syndrome (ARDS) has highlighted the unmet need for biomarkers predicting ARDS mortality and for novel therapeutics to reduce ARDS mortality. We utilized a systems biology multi-“omics” approach to identify predictive biomarkers for ARDS mortality. Integrating analyses were designed to differentiate ARDS non-survivors and survivors (568 subjects, 27% overall 28-day mortality) using datasets derived from multiple ‘omics’ studies in a multi-institution ARDS cohort (54% European descent, 40% African descent). ‘Omics’ data was available for each subject and included genome-wide association studies (GWAS, n = 297), RNA sequencing (n = 93), DNA methylation data (n = 61), and selective proteomic network analysis (n = 240). Integration of available “omic” data identified a 9-gene set (TNPO1, NUP214, HDAC1, HNRNPA1, GATAD2A, FOSB, DDX17, PHF20, CREBBP) that differentiated ARDS survivors/non-survivors, results that were validated utilizing a longitudinal transcription dataset. Pathway analysis identified TP53-, HDAC1-, TGF-β-, and IL-6-signaling pathways to be associated with ARDS mortality. Predictive biomarker discovery identified transcription levels of the 9-gene set (AUC-0.83) and Day 7 angiopoietin 2 protein levels as potential candidate predictors of ARDS mortality (AUC-0.70). These results underscore the value of utilizing integrated “multi-omics” approaches in underpowered datasets from racially diverse ARDS subjects.

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