scholarly journals High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas

2021 ◽  
Vol 10 (14) ◽  
pp. 3150
Author(s):  
Philip D. Tatman ◽  
Tadeusz H. Wroblewski ◽  
Anthony R. Fringuello ◽  
Samuel R. Scherer ◽  
William B. Foreman ◽  
...  
Keyword(s):  
Hdac Inhibitors ◽  
Tumor Grade ◽  
Potential Treatment ◽  
Target Class ◽  
Recurrence Rates ◽  
Average Cell ◽  
Patient Gender ◽  
Resected Patient ◽  
Meningioma Cell ◽  
Hc Toxin

Background: Meningiomas are the most common primary central nervous system tumors. 20–30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. Methods: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. Results: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. Conclusions: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use.

DDRE-10. SCREENING OF EPIGENETIC COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS FOR THEIR POTENTIAL TREATMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi76-vi76
Author(s):  
Philip Tatman ◽  
Tadeusz Wroblewski ◽  
Anthony Fringuello ◽  
Sam Scherer ◽  
William Foreman ◽  
...  
Keyword(s):  
De Novo ◽  
Hdac Inhibitors ◽  
Tumor Grade ◽  
Hdac Inhibition ◽  
Patient Gender ◽  
Average Survival ◽  
Tumor Viability ◽  
Hc Toxin ◽  
Inhibitor Compounds

Abstract BACKGROUND 28% of primary central nervous system tumors are glioma and glioblastoma. These tumors are responsible for 80% of malignant brain neoplasms and most brain tumor related deaths. Despite modern therapies, patients with grade II gliomas have an average survival of 8-15 years, while patients with grade III tumors have an average survival of 3-5 years, and patients with glioblastoma have an average survival of 12-15 months. The lack of a curative treatment for this group of tumors supports additional research and novel approaches to identify more effective therapies. METHODS In this study, we developed a high-throughput drug screen and culture system to identify epigenetic inhibitor compounds with the potential to reduce glioma and glioblastoma viability. RESULTS We screened 33 tumors: 18 glioblastoma, 8 oligodendroglioma, and 7 astrocytoma. The top three most effective compounds across the full glioma cohort were all HDAC inhibitors; in order from most effective: panobinostat (average tumor viability = 52.5% +/-14.1SD; p=2.16x10-61), LAQ824 (average tumor viability = 58.1% +/-18SD; p=1.48x10-45), and HC Toxin (average tumor viability = 64% +/-21.1SD; p= 1.16x10-33). Additionally, HDAC inhibition was also the most effective across each histopathological glioma type: astrocytoma, oligodendroglioma, and glioblastoma. UNC0631(G9a inhibitor) and JIB-04(KDM inhibitor) were the most effective compounds in the six recurrent tumors, though HDAC inhibition was still significantly effective in this group. We also evaluated drug sensitivity with respect to tumor grade, prior treatment, de novo vs progressive etiology, EGFR amplification, IDH mutation, MGMT methylation, and patient gender. CONCLUSIONS After screening a large glioma cohort against a panel of epigenetic inhibitors, we found HDAC inhibition most effectively reduced tumor viability across all histopathological types and grades. These findings require further in vivo validation.

scholarly journals EXTH-64. SMALL GTPASES IN MENINGIOMAS: PROLIFERATION, MIGRATION, SURVIVAL, POTENTIAL TREATMENT AND INTERACTIONS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii101-ii101
Author(s):  
Christoph Kesseler ◽  
Julian Kahr ◽  
Natalie Waldt ◽  
Nele Stroscher ◽  
Josephine Liebig ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Lines ◽  
Small Gtpases ◽  
Potential Treatment ◽  
Rock Inhibitor ◽  
Meningioma Cell ◽  
And Migration ◽  
Proliferation And Migration

Abstract PURPOSE To evaluate the role of the small GTPases RhoA, Rac1 and Cdc42 in meningiomas as therapeutic targets and their interactions in meningiomas. EXPERIMENTAL DESIGN We analyzed expression of GTPases in human meningioma samples and meningioma cell lines of various WHO grades. Malignant IOMM-Lee meningioma cells were used to generate shRNA mediated knockdowns of GTPases RhoA, Rac1 or Cdc42 and to study knockdown effects on proliferation and migration, as well as analysis of cell morphology by confocal microscopy. The same tests were used to investigate effects of the two inhibitors Fasudil and EHT-1864 of malignant IOMM-Lee, KT21 and benign Ben-Men cells and the effects of these drugs on IOMM-Lee knockdown cells. The effects of GTPase knockdowns and Fasudil treatment were studied in terms of overall survival by intracranial xenografts of mice. Potential interactions of GTPases regarding NF2, mTOR and FAK-Paxillin were examined. RESULTS Small GTPases were upregulated in meningiomas of higher tumor grades. Reduced proliferation and migration could be achieved by GTPase knockdown in IOMM-Lee cells. Additionally, the ROCK-inhibitor Fasudil and Rac1-inhibitor EHT-1864 reduced proliferation in different meningioma cell lines and reduced proliferation and migration independent of GTPase knockdowns/status. Moreover, overall survival in vivo could also be increased by knockdowns of RhoA and Rac1 as well as Fasudil treatment. GTPase expression was affected dependent on the NF2 status but effects were not very distinct, indicating that NF2 is not strongly involved in GTPase regulation in meningiomas. In terms of mTOR and FAK-Paxillin signaling, each GTPase changes those pathways in a different manner. CONCLUSION Small GTPases are important effectors in meningioma proliferation and migration in vitro as well as survival in vivo and their inhibition should be considered as potential treatment option.

scholarly journals Predictors of Outcome of Non–Muscle-Invasive and Muscle-Invasive Bladder Cancer

2011 ◽  
Vol 11 ◽  
pp. 369-381 ◽  
Author(s):  
Ramy F. Youssef ◽  
Yair Lotan
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Predictive Accuracy ◽  
Staging System ◽  
Tumor Grade ◽  
Invasive Disease ◽  
Tnm Staging ◽  
High Rate ◽  
Recurrence Rates ◽  
Muscle Invasive

Bladder cancer is a major cause of morbidity and mortality. At initial diagnosis, 75% of patients present with non–muscle-invasive disease and 25% of patients have muscle-invasive or metastatic disease.Patients with noninvasive disease suffer from a high rate of recurrence and 10–30% will have disease progression. Patients with muscle-invasive disease are primarily treated with radical cystectomy, but frequently succumb to their disease despite improvements in surgical technique. In non–muscle-invasive disease, multiplicity, tumor size, and prior recurrence rates are the most important predictors for recurrence, while tumor grade, stage, and carcinomain situare the most important predictors for progression. The most common tool that clinicians use to predict outcomes after radical cystectomy is still the tumor-node-metastasis (TNM) staging system, with lymph node involvement representing the most important prognostic factor. However, the predictive accuracy of staging and grading systems are limited, and nomograms incorporating clinical and pathologic factors can improve prediction of bladder cancer outcomes. One limitation of current staging is the fact that tumors of a similar stage and grade can have significantly different biology. The integration of molecular markers, especially in a panel approach, has the potential to further improve the accuracy of predictive models and may also identify targets for therapeutic intervention or patients who will respond to systemic therapies.

scholarly journals Histomorphological and Immunophenotypic Characterization of Feline Injection Site-Associated Sarcoma

2021 ◽  
Vol 49 ◽  
Author(s):  
Sílvia Teixeira Pereira ◽  
Conrado Oliveira Gamba ◽  
Rodrigo Santos Horta ◽  
Rúbia Monteiro de Castro Cunha ◽  
Gleidice Eunice Lavalle ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Grade ◽  
Histologic Grade ◽  
Biological Behavior ◽  
Histological Subtypes ◽  
Recurrence Rates ◽  
Ki 67 ◽  
Nerve Sheath ◽  
Cox 2 ◽  
Grade Iii

Background: Feline Injection Site-Associated Sarcoma (FISS) is a mesenchymal neoplasia of aggressive behavior that develops in sites where vaccine or drugs were administered. FISS is clinically characterized by the appearance of a solitary firm nodule or a diffuse mass, adhered to tissues, in regions associated to vaccine or drug applications. Despite low prevalence, tumor recurrence rates can reach 80%. FISS present more aggressive histological characteristics when compared to sarcomas not associated to injection sites. The aim of this paper is to contribute towards the understanding of the biological behavior of FISS.Materials, Methods & Results: Sixteen samples of FISS were analyzed. Fibrosarcomas were the most frequent histological subtype (62.5%). Malignant peripheral nerve sheath tumor was diagnosed in 18.75% cases. Ten (62.5%) FISS were classified as grade II; 4/16 (25%) grade I, and 2/16 (12.5%) grade III. Cox-2 overexpression occurred in 3/16 (18.75%) samples, with positive correlation between Cox-2 expression and cellularity (r = 0.696, P = 0.003). Mitotic index lower than 9 events was found in 11/16 (68.7%) samples and between 10 and 19 mitotic events in 5/16 (31.3%) cases. Mean Ki-67 expression was 2.39 ± 2.48%. FISS characterized as fibrosarcomas presented longer overall survival (median 545 days) than other histological subtypes (median 130.5 days) [P = 0.01].Discussion: Patients with FISS generally present with larger nodules than those with sarcomas not associated to injections, suggesting a challenge for pet owners to note subcutaneous tumors in the interscapular region, in addition to the aggressive biological behavior of FISS. The influence of size on prognosis remains controversial. An association between histologic grade and the development of metastasis has been observed, with patients with grade III FISS associated with an increase in the metastatic rate. The present study did not find a correlation between overall survival and histologic grade. A positive correlation between the presence of giant multinucleated cells and tumor grade has been observed.Despite the absence of such correlation in the present study, possibly due to a small sample, a trend for higher frequency of giant cells in advanced histologic grade was observed. Cox-2 expression in 81.75% and overexpression in 18.75% of our samples contrasts with the 64% Cox-2 expression and the absence of Cox-2 expression found by other authors. A positive moderate correlation between cellularity and Cox-2 expression was also observed, while another study did not find a correlation of Cox-2 expression with tumor grade, recurrence rates or overall survival. Cox metabolites such as prostaglandins can enhance cellular proliferation, inhibit apoptosis, induce angiogenesis, alter cellular adherence to facilitate metastatic development and inhibit immune surveillance. In the present study, no correlation was found between Cox-2 and angiogenesis in FISS. Our findings demonstrated low immunolabeling for Ki-67. A previous study analyzed 52 samples of FISS, 51% of them considered grade III, with a mean Ki-67 labeling of 14%. The lower Ki-67 staining in the samples of the present study may be related to the lower number of samples of grade III FISS or to a difference in the studied population. Fibrosarcomas are associated with better prognosis than other histological subtypes. Furthermore, malignant peripheral nerve sheath tumors were diagnosed as a possible histological subtype of FISS.

scholarly journals Characterization of Inhibitor-Resistant Histone Deacetylase Activity in Plant-Pathogenic Fungi

2002 ◽  
Vol 1 (4) ◽  
pp. 538-547 ◽  
Author(s):  
Dipnath Baidyaroy ◽  
Gerald Brosch ◽  
Stefan Graessle ◽  
Patrick Trojer ◽  
Jonathan D. Walton
Keyword(s):  
Histone Deacetylase ◽  
Cyclic Peptide ◽  
Hdac Inhibitors ◽  
Pathogenic Fungi ◽  
Alternaria Brassicicola ◽  
Resistant Isolate ◽  
Protection Factor ◽  
Hdac Activity ◽  
Crude Extracts ◽  
Hc Toxin

ABSTRACT HC-toxin, a cyclic peptide made by the filamentous fungus Cochliobolus carbonum, is an inhibitor of histone deacetylase (HDAC) from many organisms. It was shown earlier that the HDAC activity in crude extracts of C. carbonum is relatively insensitive to HC-toxin as well as to the chemically unrelated HDAC inhibitors trichostatin and D85, whereas the HDAC activity of Aspergillus nidulans is sensitive (G. Brosch et al., Biochemistry 40:12855-12863, 2001). Here we report that HC-toxin-resistant HDAC activity was present in other, but not all, plant-pathogenic Cochliobolus species but not in any of the saprophytic species tested. The HDAC activities of the fungi Alternaria brassicicola and Diheterospora chlamydosporia, which also make HDAC inhibitors, were resistant. The HDAC activities of all C. carbonum isolates tested, except one non-toxin-producing isolate, were resistant. In a cross between a sensitive isolate and a resistant isolate, resistance genetically cosegregated with HC-toxin production. When fractionated by anion-exchange chromatography, extracts of resistant and sensitive isolates and species had two peaks of HDAC activity, one that was fully HC-toxin resistant and a second that was larger and sensitive. The first peak was consistently smaller in extracts of sensitive fungi than in resistant fungi, but the difference appeared to be insufficiently large to explain the differential sensitivities of the crude extracts. Differences in mRNA expression levels of the four known HDAC genes of C. carbonum did not account for the observed differences in HDAC activity profiles. When mixed together, resistant extracts protected extracts of sensitive C. carbonum but did not protect other sensitive Cochlibolus species or Neurospora crassa. Production of this extrinsic protection factor was dependent on TOXE, the transcription factor that regulates the HC-toxin biosynthetic genes. The results suggest that C. carbonum has multiple mechanisms of self-protection against HC-toxin.

scholarly journals P.168 Prediction of Pituitary Adenoma Recurrence using the SIPAP Classification

2021 ◽  
Vol 48 (s3) ◽  
pp. S68-S68
Author(s):  
M Alahmari ◽  
A Lasso ◽  
F Banaz ◽  
S Mohajeri ◽  
P Masoudian ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Tumor ◽  
Tumor Grade ◽  
Tumor Type ◽  
Imaging Data ◽  
Recurrence Rates ◽  
Endoscopic Endonasal ◽  
Adenoma Recurrence ◽  
Logarithmic Curve

Background: Pituitary tumor recurrence following endoscopic endonasal transsphenoidal surgery (EETS) has been reported widely. We evaluated a modified score using the SIPAP classification system, combining the suprasellar and paraseller extension scores of the pituitary tumor, to determine its impact on adenoma recurrence. Methods: A retrospective cohort study design with patient characteristics, tumor type, endocrine, operation, imaging data collected. Preoperative MRI images were reviewed and SIPAP classification applied. Postoperative data were extracted for the follow-up period available for each patient.The suprasellar score and the highest parasellar scoring from both sides were numerically summed in a bilateral suprasellar and parasellar (SaP) score and combined to make 4 grades. Results: 276 patients were identified, 56.5% of the cohort was male. The mean cohort age was 54 years old.The mean follow up period was 32 months. Patient perioperative tumor grade according to SaP classification and recurrence rate was: Grade 1: 11%: Grade 2: 10%; Grade 3: 15%; Grade 4: 22%. The results followed a pattern of logarithmic curve. Conclusions: The SaP classification was useful in determining the pituitary tumor expected recurrence following EETS. The advanced tumors had the highest recurrence rates. Use of the SaP score may allow for more accurate preoperative counselling of patients with pituitary adenoma.

scholarly journals SAT-122 Expression of Cell Synthesis and Dna Repair Markers in Meningioma Recurrence or Regrowth

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Carolina Garcia Soares Leães Rech ◽  
Camila Batista de Oliveira Silva ◽  
Barbara Ongaratti ◽  
Geraldine Trott ◽  
Ricardo Kunde Minuzzi ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cyclin D1 ◽  
Significant Relationship ◽  
Tumor Grade ◽  
Biological Behavior ◽  
Recurrence Rates ◽  
Free Survival ◽  
Kaplan Meier ◽  
The Central Nervous System ◽  
Cell Synthesis

Abstract Meningiomas correspond to 37% of intracranial tumors and are considered the second most common neoplasm of the central nervous system in adults. Most of them are benign with slow growth pattern, common from the fifth decade, more frequent in women and with high recurrence rates. In tumors, there is a reduction in the efficiency of DNA error repair, allowing the proliferation of tumor cells. In this work, we evaluated the protein expression of markers involved in cell synthesis (cyclin D1) and repair of DNA errors (MUTYH, XPF, and XPG) in meningiomas. To date, this is the first study to use the immunohistochemical technique in the evaluation of these repair proteins, relating them to clinical data, tumor variables and recurrence-regrowth free survival. 85 samples were included in the study, patients with a mean age of 52 + 13.3 years, 68% female, in proportion 2:1. Most cases were classified as grade I (79%), meningothelial subtype (38%) and transitional (25%). Regarding surgery, 59% of the patients underwent total resection. Regarding location, the most common was the peripheral (62.2%). Most tumors (64%) were larger than 3cm, with a mean of 3.6±2cm. The median recurrence-regrowth free survival was 67 months (95% CI:57.8-76.6). According to the Kaplan-Meier curve, the recurrence-regrowth free survival rate was 94.4% at 1 year, 76.6% at 2 years and 64.7% at 3 years and 49.4% at 5 years. Grades II and III were prognostic factors for tumor recurrence-regrowth (p<0.05). Cyclin D1 was positive in 92%, 77% in grade I and 23% in grades II and III. A statistically significant relationship was found between cyclin D1 and tumor grade (p = 0.001), with higher expression in grade II and III. Repair proteins were expressed in most meningiomas. MUTYH (63.5%), 43.5% in grades I and 20% in grades II and III, with a significant relationship between grades II and III and, expression 10-50% (p=0.02). Significant association was observed with MUTYH (p=0.001) and XPF (p=0.019). XPF and XPG were associated with grades II and III (p=0.002 and p<0.001) and XPF with size >3cm (p=0.03). There was a positive correlation between XPF and XPG (p= 0.02) and between MUTYH and XPF (p=0.003). XP proteins were related to recurrence-regrowth (p=0.04), but not with recurrence-regrowth free survival. Our results demonstrate the activation of repair pathways and increased cell synthesis in grades II and III in meningiomas. Cellular synthesis and DNA repair markers are important tools to broaden knowledge about the biological behavior of meningiomas.

Intravesical irrigation to prevent early bladder recurrence in patients undergoing laparoscopic radical nephroureterectomy for upper urinary tract cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 454-454
Author(s):  
Takaaki Tamura ◽  
Shinichi Sakamoto ◽  
Satoshi Yamamoto ◽  
Maihulan Maimaiti ◽  
Yusuke Imamura ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Tumor Grade ◽  
Upper Urinary Tract ◽  
Distilled Water ◽  
Radical Nephroureterectomy ◽  
Recurrence Rates ◽  
Tract Cancer ◽  
Urinary Tract Cancer ◽  
Upper Urinary Tract Cancer ◽  
Bladder Recurrence

454 Background: The bladder carcinoma recurrence rate after nephroureterectomy is known to be high. Here we studied the clinical benefit of Intravesical irrigation during laparoscopic radical nephroureterectomy in upper urinary tract cancer (UUTUC) patients. Methods: This study enrolled 197 UUTUC patients who receive laparoscopic radical nephroureterectomy at Chiba University Hospital and Yokohama Rosai Hospital between 2001 and 2019. Association between the various clinical factors and postoperative recurrence rates within two years were statistically analyzed. Intravesical irrigation was carried out only during surgery and by using distilled water or saline. Results: Bladder recurrence was confirmed for 79 of the 197 patients. Irrigation was carried out in 75 cases (distilled water, 49 cases; saline, 26 cases). Tumor grade (G1-2 vs G3; p=0.0029) and irrigation (with vs. without; p<0.0001) were related to bladder recurrence on univariate analysis. Even on multivariate analysis, both tumor grade (p=0.0094) and irrigation ( p<0.0001) remained as independent factors. Comparison between the irrigation and non-irrigation groups showed that bladder recurrence rates were significantly lower in the irrigation groups (irrigation group vs non-irrigation group: 29.3% vs 46.7%, p=0.015). There was no prognostic difference between the type of irrigation (distilled water vs saline, p=0.177). Conclusions: Intravesical irrigation prevented early bladder recurrence in patients undergoing radical nephroureterectomy for UUTUC. [Table: see text]

scholarly journals DDIS-26. HIGH-THROUGHPUT DRUG SCREENING OF MENINGIOMAS IDENTIFIES HDAC INHIBITORS AS PROMISING TARGETS ACROSS GRADES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi68-vi69
Author(s):  
Philip Tatman ◽  
Anthony Fringuello ◽  
Teddy Wroblewski ◽  
Sam Scherer ◽  
William Foreman ◽  
...  
Keyword(s):  
Cell Viability ◽  
Therapeutic Potential ◽  
Statistical Significance ◽  
Hdac Inhibitors ◽  
World Health ◽  
Who Grade ◽  
Hc Toxin ◽  
Cns Neoplasms ◽  
Health Organization

Abstract Meningiomas are a common central nervous system (CNS) tumor, accounting for one third of CNS neoplasms. To date, no FDA approved pharmacotherapy exists for meningiomas. In an effort to identify potential treatments for meningiomas we created a culture system that allows us to grow and screen tumors across hundreds of compounds within two weeks of resection. We screened 32 meningiomas, six of which were World Health Organization (WHO) grade II, against the National Cancer Institute’s (NCI) FDA-approved cancer compound library and Caymen Chemical’s epigenetic inhibitor library, totaling to more than 300 compounds. The NCI library was screened at 1um, and the Caymen library was screened at 5um. Each library was screened in triplicate, allowing us to calculate statistical significance. We used an MTS assay to determine cell viability after three days. The data was background subtracted and normalized to controls. Significant changes in cell viability were determined for individual drugs using a Mann-Whitney-U test compared to untreated controls. On average, regardless of grade, 5.9 compounds per hundred screened significantly reduced tumor viability. We identified four compounds in the NCI FDA-approved library that reduced cell viability, on average across all tumors screened, by at least 50%: romidepsin, panobinostat, daunorubicin, and carfilzomib. Using the same criteria, we identified the following drugs from the Caymen epigenetic library: LAQ824, panobinostat, and HC toxin. Of the six compounds implicated as possible treatments for meningiomas, four are histone deacetylase (HDAC) inhibitors. HDAC inhibitors may represent a promising target for the treatment of meningiomas. Based on this data, we have begun in vivo work using PDX mouse models to investigate the therapeutic potential of HDAC inhibitors for the treatment of meningiomas.

Sign in / Sign up

Export Citation Format

Share Document