8 results on '"Herpai D"'
Search Results
2. P08.13 A single pharmaceutic agent for molecular resection of Glioblastoma
- Author
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Sonawane, P., primary, Herpai, D., additional, Ferluga, S., additional, Tatter, S. B., additional, and Debinski, W., additional
- Published
- 2017
- Full Text
- View/download PDF
3. P08.14 In situ detection of hypoxia inducible factor 2 alpha in malignant gliomas
- Author
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Renfrow, J. J., primary, Strowd, R. E., additional, Huang, Y., additional, Herpai, D., additional, Mott, R. T., additional, Wong, T., additional, Lesser, G. J., additional, and Debinski, W., additional
- Published
- 2017
- Full Text
- View/download PDF
4. Phase I trial of convection-enhanced delivery of IL13RA2 and EPHA2 receptor targeted cytotoxins in dogs with spontaneous intracranial gliomas.
- Author
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Rossmeisl JH, Herpai D, Quigley M, Cecere TE, Robertson JL, D'Agostino RB, Hinckley J, Tatter SB, Dickinson PJ, and Debinski W
- Subjects
- Animals, Convection, Cytotoxins therapeutic use, Dogs, Drug Delivery Systems, Brain Neoplasms drug therapy, Glioma drug therapy, Receptor, EphA2
- Abstract
Background: The interleukin-13 receptor alpha 2 (IL13RA2) and ephrin type A receptor 2 (EPHA2) are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection-enhanced delivery (CED) method. In this study, IL-13 mutant and ephrin A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy., Methods: In this phase I, 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI monitoring. The primary endpoint was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas., Results: Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40-94%). Cytotoxins were well tolerated over a dose range of 0.012-1.278 μg/mL delivered to the target volume (median, 0.099 μg/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 μg/mL., Conclusions: This study provides preclinical data fundamental to the translation of this multireceptor targeted therapeutic approach to the human clinic., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
- Published
- 2021
- Full Text
- View/download PDF
5. Attenuating hypoxia driven malignant behavior in glioblastoma with a novel hypoxia-inducible factor 2 alpha inhibitor.
- Author
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Renfrow JJ, Soike MH, West JL, Ramkissoon SH, Metheny-Barlow L, Mott RT, Kittel CA, D'Agostino RB Jr, Tatter SB, Laxton AW, Frenkel MB, Hawkins GA, Herpai D, Sanders S, Sarkaria JN, Lesser GJ, Debinski W, and Strowd RE
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors antagonists & inhibitors, Carcinogenesis, Cell Line, Tumor, Cell Movement, Cell Proliferation, Humans, Indans pharmacology, Mice, Mice, Nude, Molecular Targeted Therapy, Sulfones pharmacology, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Basic Helix-Loop-Helix Transcription Factors metabolism, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Indans therapeutic use, Sulfones therapeutic use
- Abstract
Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.
- Published
- 2020
- Full Text
- View/download PDF
6. Multireceptor targeting of glioblastoma.
- Author
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Sharma P, Sonawane P, Herpai D, D'Agostino R, Rossmeisl J, Tatter S, and Debinski W
- Abstract
Background: Treatment for glioblastoma (GBM) remains an unmet need in medicine. Novel therapies that address GBM complexity and heterogeneity in particular are warranted. To this end, we target 4 tumor-associated receptors at a time that span virtually all of the GBM microenvironment including bulk tumor cells, infiltrating tumor cells, neovasculature, and tumor-infiltrating cells with one pharmaceutical agent delivering a cytotoxic load., Methods: We engineered multivalent ligand-based vector proteins termed QUAD with an ability to bind to 4 of the following GBM-associated receptors: IL-13RA2, EphA2, EphA3, and EphB2. We conjugated QUAD with a modified bacterial toxin PE38QQR and tested it in vitro and in vivo., Results: The QUAD variants preserved functional characteristics of the respective ligands for the 4 receptors. The QUAD 3.0 variant conjugate was highly cytotoxic to GBM cells, but it was nontoxic in mice, and the conjugate exhibited strong antitumor effect in a dog with spontaneous GBM., Conclusion: The QUAD addresses, to a large extent, the issues of intra- and intertumoral heterogeneity and, at the same time, it targets several pathophysiologically important tumor compartments in GBM through multiple receptors overexpressed in tumors allowing for what we call "molecular resection." QUAD-based targeted agents warrant further pre- and clinical development., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
- Published
- 2020
- Full Text
- View/download PDF
7. Drug Conjugates for Targeting Eph Receptors in Glioblastoma.
- Author
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Sharma P, Roberts C, Herpai D, Fokt ID, Priebe W, and Debinski W
- Abstract
Glioblastoma (GBM) is a complex and heterogeneous tumor that warrants a comprehensive therapeutic approach for treatment. Tumor-associated antigens offer an opportunity to selectively target various components of the GBM microenvironment while sparing the normal cells within the central nervous system. In this study, we conjugated a multivalent vector protein, QUAD 3.0, that can target four receptors: EphA3, EphA2, EphB2, and also IL-13RA2, spanning virtually 100% of the GBM microenvironment, to doxorubicin derivatives. The conjugates effectively bound to all four receptors, although to varying degrees, and delivered cytotoxic loads to both established and patient-derived GBM cell lines, with IC
50 values in the low nM range. The conjugates were also non-toxic to animals. We anticipate that the QUAD 3.0 Dox conjugates will be further used in preclinical models and possibly clinics in the foreseeable future.- Published
- 2020
- Full Text
- View/download PDF
8. miR-30 disrupts senescence and promotes cancer by targeting both p16 INK4A and DNA damage pathways.
- Author
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Su W, Hong L, Xu X, Huang S, Herpai D, Li L, Xu Y, Truong L, Hu WY, Wu X, Xiao C, Zhang W, Han J, Debinski W, Xiang R, and Sun P
- Subjects
- Animals, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p16 genetics, Gene Expression Regulation, Neoplastic physiology, Humans, Mice, Mice, Transgenic, Cell Transformation, Neoplastic genetics, Cellular Senescence genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA Damage genetics, MicroRNAs physiology
- Abstract
miR-30 is a microRNA frequently overexpressed in human cancers. However, the biological consequence of miR-30 overexpression in cancer has been unclear. In a genetic screen, miR-30 was found to abrogate oncogenic-induced senescence, a key tumor-suppressing mechanism that involves DNA damage responses, activation of p53 and induction of p16
INK4A . In cells and mouse models, miR-30 disrupts senescence and promotes cancer by suppressing 2 targets, CHD7 and TNRC6A. We show that while CHD7 is a transcriptional coactivator essential for induction of p16INK4A in senescent cells, TNRC6A, a miRNA machinery component, is required for expression and functionality of DNA damage response RNAs (DDRNAs) that mediate DNA damage responses and p53 activation by orchestrating histone modifications, chromatin remodeling and recruitment of DNA damage factors at damaged sites. Thus, miR-30 inhibits both p16INK4A and p53, 2 key senescence effectors, leading to efficient senescence disruption. These findings have identified novel signaling pathways mediating oncogene-induced senescence and tumor-suppression, and revealed the molecular and cellular mechanisms underlying the oncogenic activity of miR-30. Thus, the miR-30/CHD7/TNRC6A pathway is potentially a novel diagnostic biomarker and therapeutic target for cancer.- Published
- 2018
- Full Text
- View/download PDF
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