scholarly journals DDRE-33. MOLECULAR DIFFERENTIATION OF IMIPRIDONES ONC201 AND ONC206

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii68-ii68
Author(s):  
Varun Prabhu ◽  
Caroline Cuoco ◽  
Jinkyu Jung ◽  
Sara Morrow ◽  
Abed Rahman Kawakibi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Acquired Resistance ◽  
Cross Resistance ◽  
Glioblastoma Cells ◽  
Biodistribution Studies ◽  
Allosteric Sites ◽  
Receptor Pharmacology ◽  
The Impact

Abstract ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and agonist of ClpP in oncology. In clinical trials, the small molecule has induced durable tumor regressions and clinical benefit in H3 K27M-mutant glioma patients while being well tolerated. ONC206 is a chemical derivative of ONC201 with nanomolar anti-cancer potency. In this study, we describe receptor pharmacology, gene expression profiling, acquired resistance and biodistribution studies that suggest ONC206 exhibits distinct therapeutic properties relative to ONC201. ONC206 exhibited a nanomolar Ki for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. Six residues were critical for ONC201 and ONC206, however the impact varied between the two compounds and one allosteric residue was exclusive to ONC206. Structural mapping revealed that some ONC206-critical allosteric residue interactions are located at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. Gene expression profiling revealed ONC206 and ONC201 induce distinct signatures in U87 glioblastoma cells, further supporting distinct functional effects. Similarly, T98G glioblastoma cells with acquired resistance to ONC201 or ONC206 reveal partial cross resistance. Finally, rat biodistribution studies revealed nanomolar CSF concentrations that exceed therapeutic thresholds, unlike ONC201. In summary, ONC206 exhibits increased non-competitive DRD2 antagonism, nanomolar potency, distinct biodistribution, differentiated gene expression and disruption of DRD2 dimers relative to ONC201. Thus, ONC206 may be uniquely poised to address tumors that are not addressed by ONC201 or have developed acquired resistance.

The basal subtype to predict clinical benefit from neoadjuvant chemotherapy: Final results from a phase II clinical trial of DDMVAC plus bevacizumab.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 291-291 ◽  
Author(s):  
Arlene O. Siefker-Radtke ◽  
Woonyoung Choi ◽  
Sima P. Porten ◽  
Yu Shen ◽  
Ashish M. Kamat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Neoadjuvant Chemotherapy ◽  
Bone Metastases ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Urothelial Cancer ◽  
Basal Subtype ◽  
Clinical Trial Results ◽  
The Impact

291 Background: Gene expression profiling (GEP) suggests 3 main subtypes of urothelial cancer: basal, which historically has the worst prognosis with high proliferation and HIF-1 expression; p53-like, with decreased proliferation and increased markers of extracellular matrix (ECM); and luminal which has increased proliferation compared to p53-like tumors. We hypothesized that GEP of transurethral resections (TUR) and cystectomy specimens from patients on a neoadjuvant trial would predict benefit from chemotherapy. Methods: Sixty patients enrolled on a neoadjuvant trial of DDMVAC+B. TUR and cystectomy specimens were available for gene expression profiling in 39 and 33 patients, respectively, with matched specimens in 23 patients. The validation set consisted of 49 patients treated with perioperative MVAC on a previously published clinical trial. Results: Chemotherapy was quite active with pT0N0 and ≤ pT1N0 down-staging rates of 38% and 53%, respectively. Basal tumors had improved survival compared to luminal and p53-like (5-year OS 91%, 73% and 36%, p=0.015). A validation cohort of patients treated with perioperative MVAC confirmed this survival benefit (5-year OS basal, luminal, and p53-like 77%, 57%, and 57%, respectively, p =0.027). The use of bevacizumab in basal tumors did not confirm evidence of significant benefit in these small numbers of patients (5-year OS bevacizumab: 91% vs MVAC: 77%, p=0.68) Bone metastases within 2 years associated exclusively with the p53-like subtype (p53-like: 100%, luminal: 0%, basal 0%, p≤0.001). The p53-like subtype was enriched at cystectomy (basal to p53-like in 3/5 (60%), luminal to p53-like in 5/7 (71%), suggesting chemo-resistance in p53-like tumors. Conclusions: In contrast to historical expectations, the basal subtype was predictive of clinical outcomes from neoadjuvant chemotherapy, reflecting the impact of chemotherapy on highly proliferative tumors. Bone metastases were associated with the p53-like subtype which is enriched for ECM. We can no longer think of urothelial cancer as one disease; subtyping should be considered for all tumors, and may have implications on selecting therapy. Clinical trial information: NCT00506155.

Gene expression profiling and clinical relevance unravel the role hypoxia and immune signaling genes and pathways in breast cancer

2020 ◽  
Vol 1 ◽  
Author(s):  
Mohammad Azhar Kamal ◽  
Mohiuddin Khan Warsi ◽  
Afnan Alnajeebi ◽  
Haytham A Ali ◽  
Nawal Helmi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Gene Expression Profiling ◽  
Signaling Pathways ◽  
Expression Profiling ◽  
Gene List ◽  
Molecular Signatures ◽  
Biological Processes ◽  
Immune Signaling ◽  
The Impact

Hypoxia most often occurs in cancer and the occurrence of hypoxia helps the cells in adapting different responses than the normal such as the activation of of those signaling pathways which regulate proliferation, angiogenesis, and cell death. There are large number of genes which are known to be associated with diverse biological processes and their control and coordination and in different cancers, the hypoxia-response differs. In this study our goal is to understand the impact of alteration in expression of hypoxia and immune systems related genes and its survival in breast cancer and analyzed the hallmarks of molecular signatures. For this purpose we have collected the hypoxia-associated genes based on the literature related with diverse biological processes and functions. For all these genes, we have studied the survival analysis, breast cancer gene expression profiling, and relevant hypoxic genes alterations. Based on our study, we conclude that there are 17 critical pathways and 40 genes from hypoxic gene list appear to play the major roles in case of breast cancer and overall we observe that immune signaling pathways and its components are highly altered in case of breast cancer. Among the top raked hallmarks of molecular signatures are apoptosis, hypoxia, DNA repair, E2F targets, MYC targets, androgen and estrogen response, and TNFa signaling.

Patients With DLBCL Commonly Have B-Cell Lymphopenia and Circulating Clonal B-Cell Populations With a Phenotype Concordant With The Underlying Tumour

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3013-3013
Author(s):  
Ruth M de Tute ◽  
Sharon Barrans ◽  
Andy C. Rawstron ◽  
Peter W.M. Johnson ◽  
Andrew J Davies ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Peripheral Blood ◽  
Expression Profiling ◽  
Common Finding ◽  
Cell Populations ◽  
The Impact

Abstract Clonal B-cell populations with either a CLL or a non-CLL phenotype are a common finding in normal individuals but uncertainty remains about how this relates to the development of clinically significant disease. The aim of this study was to investigate the frequency of peripheral blood clonal B-cell populations and B-cell subset abnormalities in newly presenting DLBCL patients and to determine whether the incidence of these abnormalities differed between the GCB and ABC subtypes, which are regarded as having distinct pathogenesis. The study was carried out using peripheral blood samples collected from patients entered in the UK-REMoDL-B trial. This trial is testing the hypothesis that the ABC subtype of DLBCL responds preferentially to R-CHOP- Bortezomib. Gene expression profiling is performed on the diagnostic tissue biopsy (FFPE) using the Illumina WG-DASL assay prior to randomisation classified as GCB, ABC or unclassified (UN). The availability of GEP data allows meaningful comparison with the phenotype of clonal populations detected by flow cytometry. Peripheral blood taken prior to first treatment was analysed using multi-colour flow cytometry. Following red cell lysis with ammonium chloride, samples were incubated with a panel of antibodies comprising of a CD19 and CD20 backbone, with Kappa, Lambda, CD5, CD45, CD49d, LAIR-1, CXCR5, CD31, CD95, CD38 and CD10, supplemented in some cases by CD81, CD79b, and CD43. A minimum of 500,000 events were acquired on a FacsCanto II flow cytometer (Becton Dickinson). B-cells were enumerated and any monoclonal populations identified were classified as CLL, germinal centre (GC), non-GC or not otherwise specified (NOS) where the phenotype was indeterminate. 358 samples were eligible for inclusion from patients with an average age of 62.2years (range 22.9-86.1). Abnormalities were detected in 52% of cases (B-lymphopenia ((<0.06 x 109/l) 33%, B-lymphocytosis (>1 x 109/l) 2.8%, CLL clone 3.6%, GC clone 9.8%, non-GC clone 9.8%, clonal population NOS 2.2%). Gene expression profiling results were available for 278 individuals; 51% GCB, 32% ABC and 17% unclassified. The relationship between peripheral blood B-cell findings and the GEP determined phenotype of the tumour is shown in the table:TableB-lymphopeniaCLL CloneMonoclonal GC typeMonoclonalNon-GC typeMonoclonal NOSNormalB-cellGCB n=14241/142 (29%)5/142 (3.5%)21/142 (15%)8/142 (5.6%)2/142 (1%)72/142 (51%)ABC n=8927/89 (30%)2/89 (2%)2/89 (2%)12/89 (13.5%)2/89 (2%)49/89 (55%)Unclassified n=4726/47 (55%)0/50 (0%)2/47 (4%)6/47 (12%)6/47 (5%)14/47 (30%) In patients where clonal populations were detected in the peripheral blood there was striking concordance between the phenotype of the clone and the GEP of the underlying tumour. Presence of a GC-population by flow was highly predictive of GCB GEP (84% GC–type populations detected were in GCB cases). The number of discordant cases and the number of CLL clones detected approximate to the numbers that would be expected in a normal population of a similar age. It is, therefore, likely that in most cases circulating tumour cells or a closely related precursor clone are being detected. The similarity between the results of the ABC and unclassified GEP groups suggest that these are biologically related. An unexpected finding in this study was the high incidence of B-lymphopenia at a level that might be expected to be associated with increased risk of infection. This may reflect suppression of normal B-cells by the neoplastic clone or be a marker of underlying immune dysfunction that may predispose to the development of the tumour. Immuosuppression has a role in the pathogenesis of DLBCL in the elderly and this study suggests that this may also be a factor in the wider patient population. These results may have implications for prognostic assessment and may offer opportunities for early diagnosis and possibly response assessment in some patients. The impact on outcome will be assessed in the course of the trial. Disclosures: Jack: Roche /Genentech: Research Funding.

scholarly journals GENE EXPRESSION PROFILING AND EXPANDED IMMUNOHISTOCHEMISTRY TESTS TO GUIDE SELECTION OF CHEMOTHERAPY REGIMENS IN BREAST CANCER MANAGEMENT: A SYSTEMATIC REVIEW

2017 ◽  
Vol 33 (1) ◽  
pp. 32-45 ◽  
Author(s):  
Alison Scope ◽  
Munira Essat ◽  
Abdullah Pandor ◽  
Rachid Rafia ◽  
Sue E. Ward ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Systematic Review ◽  
Gene Expression Profiling ◽  
Early Breast Cancer ◽  
Expression Profiling ◽  
Clinical Effectiveness ◽  
Clinicopathological Parameters ◽  
Cancer Management ◽  
The Impact

Objectives:The aim of this report was to assess the clinical effectiveness of two Gene expression profiling (GEP) and two expanded immunohistochemistry (IHC) tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer.Methods:A systematic review of the evidence on clinical effectiveness of OncotypeDX, IHC4, MammaPrint, and Mammostrat, compared with current clinical practice using clinicopathological parameters, in women with early breast cancer was conducted. Ten databases were searched to include citations to May 2016.Results:Searches identified 7,064 citations, of which forty-one citations satisfied the criteria for the review. A narrative synthesis was performed. Evidence for OncotypeDX demonstrated the impact of the test on decision making and there was some support for OncotypeDX predicting chemotherapy benefit. There were relatively lower levels of evidence for the other three tests included in the analysis. MammaPrint, Mammostrat, and IHC4 tests were limited to a small number of studies. Limitations in relation to study design were identified for all tests.Conclusions:The evidence base for OncotypeDX is considered to be the most robust. Methodological weaknesses relating to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence were identified. Further evidence is required for all of the tests using prospective randomized controlled trial data.

Identification of Biologically Distinct and Clinically Relevant Subentities in Patients with Acute Myeloid Leukemia and Normal Karyotypes by Use of Gene Expression Profiling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 195-195 ◽  
Author(s):  
Wolfgang Kern ◽  
Claudia Schoch ◽  
Alexander Kohlmann ◽  
Martin Dugas ◽  
Sylvia Merk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Genetic Background ◽  
Prognostic Impact ◽  
Genetic Pathways ◽  
Group A ◽  
Group B ◽  
The Impact ◽  
Acute Myeloid

Abstract Genetic aberrations substantially contribute to the pathogenesis of acute myeloid leukemias (AML) and have significant prognostic impact. In most cases with AML and normal karyotypes (AML-NK), however, the respective genetic lesions have not yet been identified and patients are assigned an intermediate and thus largely unknown prognosis. To clarify the genetic background and to improve prognostication in AML-NK we analyzed gene expression profiles in 205 patients with untreated and newly diagnosed AML-NK. Samples were comprehensively characterized by cytomorphology, immunophenotyping, cytogenetics, and molecular genetics. For expression profiling, samples were hybridized to both U133A and U133B microarrays (Affymetrix). To identify genetically defined subgroups we performed an unsupervised principal component analysis (PCA) applying all 34023 probe sets from both arrays that were expressed in at least one of the analyzed samples. While the majority of cases (n=162, 79%; group A) clustered together, a subgroup comprizing 43 (21%) cases was identified (group B) which formed a distinct cluster. The analysis of known genetic markers (length mutations and point mutations of FLT3, partial tandem duplications of MLL, mutations of CEBPA, NRAS, or CKIT) did not reveal differences between groups A and B. Significant differences were found, however, in their phenotypes. There were more cases with monocytic leukemias in group B (84% vs. 20%, p<0.001) and the expression levels of CD4, CD56, CD65, CD15, CD14, CD64, CD11b, CD36, CD135, CD87, and CD116 were higher while those of MPO, CD34, and CD117 were lower (p<0.05 for all). To identify the genetic background of differences, samples from groups A and B were supervised compared. Using the top 100 differentially expressed genes and applying SVM with a 10-fold cross validation approach samples could be classified to groups A and B with an accuracy of 97.6% which was confirmed applying 100 runs of SVM with 2/3 of samples being randomly selected as training set and 1/3 as test set (median accuracy, 97.1%, range, 93.4% to 100%). Ingenuity software was used to identify genetic pathways differentially regulated between both groups. Most strikingly, CD14 was higher expressed (fold-change (fc), 10.6) and WT1 and MYCN were lower expressed (fc, 3.7 and 4.4) in group B. Also higher expressed was HCK (fc, 4.3) encoding a protein-tyrosine kinase which phosphorylates STAT3. Since phosphorylated STAT3 stimulates proliferation this may confer higher chemosensitivity and result in a better prognosis. The lower expression of HCK in group A cases may be due to the higher expression of SPTBN1 (fc, 3.4) which also has been shown to increase the transcription of C-FOS and to possibly reveal antiapoptotic effects. To prove the clinical importance of the newly identified subgroups of AML-NK event-free survival (EFS) and overall survival (OS) were compared. All patients were uniformly treated within the German AMLCG trials. Group B had a significantly better median EFS (13.3 vs. 7.0 months, p=0.0143) which was independent of the impact of age. In addition, there was a trend for a better OS in group B (13.3 vs. 9.5 months, n.s.). In conclusion, the identification of a biologically defined and clinically relevant subgroup of AML-NK has been accomplished by use of gene expression profiling based on differences in regulations of genetic pathways involving proliferation and apoptosis.

Custom microarray for glycobiologists: considerations for glycosyltransferase gene expression profiling

2002 ◽  
Vol 69 ◽  
pp. 135-142 ◽  
Author(s):  
Elena M. Comelli ◽  
Margarida Amado ◽  
Steven R. Head ◽  
James C. Paulson
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Affymetrix Genechip ◽  
Microarray Technology ◽  
Gene Arrays ◽  
Glycosyltransferase Gene

The development of microarray technology offers the unprecedented possibility of studying the expression of thousands of genes in one experiment. Its exploitation in the glycobiology field will eventually allow the parallel investigation of the expression of many glycosyltransferases, which will ultimately lead to an understanding of the regulation of glycoconjugate synthesis. While numerous gene arrays are available on the market, e.g. the Affymetrix GeneChip® arrays, glycosyltransferases are not adequately represented, which makes comprehensive surveys of their gene expression difficult. This chapter describes the main issues related to the establishment of a custom glycogenes array.

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