Search

Your search keyword '"Webster K. Cavenee"' showing total 274 results
Start Over Author "Webster K. Cavenee" Search Limiters Full Text
274 results on '"Webster K. Cavenee"'

1. DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma

Author

Mio Harachi, Kenta Masui, Erika Shimizu, Kumiko Murakami, Hiromi Onizuka, Yoshihiro Muragaki, Takakazu Kawamata, Hisako Nakayama, Mariko Miyata, Takashi Komori, Webster K. Cavenee, Paul S. Mischel, Atsushi Kurata, and Noriyuki Shibata

Subjects
DNA hypomethylation, mTORC2, DNMT3A, EZH2, Glutamate metabolism, Glioblastoma, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global “hypomethylator phenotype”, are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.

Published
2024
Full Text
View/download PDF

2. Insights into the Mechanisms of Action of MDA-7/IL-24: A Ubiquitous Cancer-Suppressing Protein

Author

Jinkal Modi, Abhishek Roy, Anjan K. Pradhan, Amit Kumar, Sarmistha Talukdar, Praveen Bhoopathi, Santanu Maji, Padmanabhan Mannangatti, Daniel Sanchez De La Rosa, Jiong Li, Chunqing Guo, Mark A. Subler, Jolene J. Windle, Webster K. Cavenee, Devanand Sarkar, Xiang-Yang Wang, Swadesh K. Das, Luni Emdad, and Paul B. Fisher

Subjects
MDA-7/IL-24, cytokine, apoptosis, bystander antitumor activity, combinatorial therapy, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24), a secreted protein of the IL-10 family, was first identified more than two decades ago as a novel gene differentially expressed in terminally differentiating human metastatic melanoma cells. MDA-7/IL-24 functions as a potent tumor suppressor exerting a diverse array of functions including the inhibition of tumor growth, invasion, angiogenesis, and metastasis, and induction of potent “bystander” antitumor activity and synergy with conventional cancer therapeutics. MDA-7/IL-24 induces cancer-specific cell death through apoptosis or toxic autophagy, which was initially established in vitro and in preclinical animal models in vivo and later in a Phase I clinical trial in patients with advanced cancers. This review summarizes the history and our current understanding of the molecular/biological mechanisms of MDA-7/IL-24 action rendering it a potent cancer suppressor.

Published
2021
Full Text
View/download PDF

3. Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme

Author

Jennifer P. Newman, Grace Y. Wang, Kazuhiko Arima, Shou P. Guan, Michael R. Waters, Webster K. Cavenee, Edward Pan, Edita Aliwarga, Siao T. Chong, Catherine Y. L. Kok, Berwini B. Endaya, Amyn A. Habib, Tomohisa Horibe, Wai H. Ng, Ivy A. W. Ho, Kam M. Hui, Tomasz Kordula, and Paula Y. P. Lam

Subjects
Science
Abstract

Interleukin-13 receptor alpha 2 is highly expressed in glioblastoma multiforme but its role in this malignancy is unclear. Here the authors show that this receptor interacts with mutant EGFR, stimulating its kinase activity, thus inducing proliferation.

Published
2017
Full Text
View/download PDF

4. PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3

Author

Jorge A. Benitez, Jianhui Ma, Matteo D’Antonio, Antonia Boyer, Maria Fernanda Camargo, Ciro Zanca, Stephen Kelly, Alireza Khodadadi-Jamayran, Nathan M. Jameson, Michael Andersen, Hrvoje Miletic, Shahram Saberi, Kelly A. Frazer, Webster K. Cavenee, and Frank B. Furnari

Subjects
Science
Abstract

PTEN mutations are frequent in glioblastoma and often are associated with therapeutic resistance. Here, the authors demonstrate that PTEN regulates gene expression at the chromatin level by interacting with the histone chaperone DAXX and H3.3, and that DAXX inhibition inhibits PTEN-deficient GBM growth in vivo.

Published
2017
Full Text
View/download PDF

5. Precision cancer therapy is impacted by oncogene-dependent epigenome remodeling

Author

Feng Liu, Paul S. Mischel, and Webster K. Cavenee

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The cancer genome provides the blueprint for identifying oncogenic mutations driving tumor growth and these mutant proteins and pathways are the targets for precision cancer therapies. However, many oncogenes are capable of reprogramming the landscape of active portion of the genome, commonly known as the epigenome. This creates fluidity, and thereby heterogeneity, that demands consideration of this additional layer of complexity for effective therapeutic design and application. Molecular dissection of the epigenome may identify oncogene-induced, actionable vulnerabilities, broadening the spectrum of precision oncology treatments.

Published
2017
Full Text
View/download PDF

6. Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer

Author

Mio Harachi, Kenta Masui, Webster K. Cavenee, Paul S. Mischel, and Noriyuki Shibata

Subjects
metabolic reprogramming, microenvironment, protein acetylation, epigenetics, mechanistic target of rapamycin (mTOR) complexes, Microbiology, QR1-502
Abstract

Metabolic reprogramming is an emerging hallmark of cancer and is driven by abnormalities of oncogenes and tumor suppressors. Accelerated metabolism causes cancer cell aggression through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. However, the mechanisms by which a shift in the metabolic landscape reshapes the intracellular signaling to promote the survival of cancer cells remain to be clarified. Recent high-resolution mass spectrometry-based proteomic analyses have spotlighted that, unexpectedly, lysine residues of numerous cytosolic as well as nuclear proteins are acetylated and that this modification modulates protein activity, sublocalization and stability, with profound impact on cellular function. More importantly, cancer cells exploit acetylation as a post-translational protein for microenvironmental adaptation, nominating it as a means for dynamic modulation of the phenotypes of cancer cells at the interface between genetics and environments. The objectives of this review were to describe the functional implications of protein lysine acetylation in cancer biology by examining recent evidence that implicates oncogenic signaling as a strong driver of protein acetylation, which might be exploitable for novel therapeutic strategies against cancer.

Published
2021
Full Text
View/download PDF

7. Emerging function of mTORC2 as a core regulator in glioblastoma: metabolic reprogramming and drug resistance

Author

Si-Han Wu, Jun-Feng Bi, Timothy Cloughesy, Webster K. Cavenee, and Paul S. Mischel

Subjects
Glioblastoma, mTOR, metabolic reprogramming, mTORC2, Warburg effect, PI3K, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses define the molecular architecture of GBM and highlight a central function for mechanistic target of rapamycin (mTOR) signaling. mTOR kinase exists in two multi-protein complexes, namely, mTORC1 and mTORC2. These complexes differ in terms of function, regulation and rapamycin sensitivity. mTORC1 is well established as a cancer drug target, whereas the functions of mTORC2 in cancer, including GBM, remains poorly understood. This study reviews the recent findings that demonstrate a central function of mTORC2 in regulating tumor growth, metabolic reprogramming, and targeted therapy resistance in GBM, which makes mTORC2 as a critical GBM drug target.

Published
2014
Full Text
View/download PDF

8. Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks

Author

German G. Gomez, Jill Wykosky, Ciro Zanca, Frank B. Furnari, and Webster K. Cavenee

Subjects
Epidermal growth factor receptor, microRNA, tyrosine kinase inhibitors, therapeutic resistance, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) regulate cellular homeostatic processes. EGFR activates downstream signaling cascades that promote tumor cell survival, proliferation and migration. Dysregulation of EGFR signaling as a consequence of overexpression, amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes. Consequently, concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR. However, limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies. A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses. Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors. We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.

Published
2013
Full Text
View/download PDF

9. Correction: Publisher Correction: PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3

Author

Jorge A. Benitez, Jianhui Ma, Matteo D’Antonio, Antonia Boyer, Maria Fernanda Camargo, Ciro Zanca, Stephen Kelly, Alireza Khodadadi-Jamayran, Nathan M. Jameson, Michael Andersen, Hrvoje Miletic, Shahram Saberi, Kelly A. Frazer, Webster K. Cavenee, and Frank B. Furnari

Subjects
Science
Abstract

Nature Communications 8:15223 doi: (2017); Published 12 May 2017; Updated 25 May 2018 The originally published version of this Article contained an error in Fig. 1. In panel d, the uppermost western blot was inadvertently inverted during typesetting of the figure. This has now been corrected in boththe PDF and HTML versions of the Article.

Published
2018
Full Text
View/download PDF

11. Data from MicroRNA-138 Modulates DNA Damage Response by Repressing Histone H2AX Expression

Author

Toshiyasu Taniguchi, Frank B. Furnari, Muneesh Tewari, Xiaofeng Zhou, Patrick S. Mitchell, Webster K. Cavenee, Ming Li, Jen-Wei Huang, and Yemin Wang

Abstract

Precise regulation of DNA damage response is crucial for cellular survival after DNA damage, and its abrogation often results in genomic instability in cancer. Phosphorylated histone H2AX (γH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. MicroRNAs (miRNA) are short, nonprotein-encoding RNA molecules, which posttranscriptionally regulate gene expression by repressing translation of and/or degrading mRNA. How miRNAs modulate DNA damage response is largely unknown. In this study, we developed a cell-based screening assay using ionizing radiation (IR)-induced γH2AX foci formation in a human osteosarcoma cell line, U2OS, as the readout. By screening a library of human miRNA mimics, we identified several miRNAs that inhibited γH2AX foci formation. Among them, miR-138 directly targeted the histone H2AX 3′-untranslated region, reduced histone H2AX expression, and induced chromosomal instability after DNA damage. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA-damaging agents (cisplatin, camptothecin, and IR). Reintroduction of histone H2AX in miR-138 overexpressing cells attenuated miR-138–mediated sensitization to cisplatin and camptothecin. Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA-damaging agents. Mol Cancer Res; 9(8); 1100–11. ©2011 AACR.

Published
2023

13. Supplementary Figure 2 from De-Repression of PDGFRβ Transcription Promotes Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Glioblastoma Patients

Author

Paul S. Mischel, Steven J. Bensinger, Webster K. Cavenee, Tim F. Cloughesy, Harley I. Kornblum, C. David James, Takashi Sasayama, Fuyuhiko Tamanoi, Mitchell Flagg, William H. Yong, Harry V. Vinters, Julie Dang, Huijun Yang, Ali Nael, Kazuhiro Tanaka, Genaro R. Villa, Ivan Babic, David Nathanson, Kevin J. Williams, Alex A. Nourian, Alexandra L. Pourzia, and David Akhavan

Abstract

PDF file - 212K, Fig. S2. Ligand-dependent PDGFRβ stimulation promotes the proliferation of erlotinib-treated glioblastoma cells.

Published
2023

14. Supplementary Data, Supplemental Figures 1-7 from Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM

Author

Noriyuki Shibata, Paul S. Mischel, Webster K. Cavenee, Takakazu Kawamata, Yoshihiro Muragaki, Hiroaki Honda, Kenta Masui, and Mio Harachi

Abstract

Figure S1. mTORC1 and mTORC2 are activated downstream of aberrant EGFR signaling in human GBM. Figure S2. mTOR complexes regulate expression of EZH2 and H3K27me3 in GBM cell lines and other types of cancer cell lines. Figure S3. EGFR activation translationally increases the level of EZH2. Figure S4. Aberrant EGFR signaling renders GBM cells sensitive to EZH2 inhibitors. Figure S5. mTORC1 regulates the expression of EZH2 translationally. Figure S6. mTORC2 regulates the production of S-adenosylmethionine (SAM). Figure S7. mTOR-dependent histone methylation epigenetically regulates tumor suppressor gene CDKN1A (p21) in GBM cells.

Published
2023

15. Interview with Dr. Mischel from Oncogenic EGFR Signaling Activates an mTORC2–NF-κB Pathway That Promotes Chemotherapy Resistance

Author

Paul S. Mischel, Albert S. Baldwin, Brendan D. Manning, Timothy F. Cloughesy, Webster K. Cavenee, Joseph F. Gera, Harry V. Vinters, William H. Yong, Amanda Rinkenbaugh, Hancai Dan, Christian C. Dibble, Yinan Zhang, Ali Nael Amzajerdi, Jason De Jesus, Huijun Yang, Shaojun Zhu, Julie Dang, Beatrice Gini, Deliang Guo, David Akhavan, David Nathanson, Ivan Babic, and Kazuhiro Tanaka

Abstract

mp3 file (9.8 MB). In the November edition of the Cancer Discovery podcast, Executive Editor Mark Landis talks with Paul S. Mischel about his paper, which identifies mTORC2 as a novel mediator of drug resistance and regulator of NF-κB signaling in glioblastoma.

Published
2023

16. Data from Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM

Author

Noriyuki Shibata, Paul S. Mischel, Webster K. Cavenee, Takakazu Kawamata, Yoshihiro Muragaki, Hiroaki Honda, Kenta Masui, and Mio Harachi

Abstract

Epigenetic regulation known for DNA methylation and histone modification is critical for securing proper gene expression and chromosomal function, and its aberration induces various pathologic conditions including cancer. Trimethylation of histone H3 on lysine 27 (H3K27me3) is known to suppress various genes related to cancer cell survival and the level of H3K27me3 may have an influence on tumor progression and malignancy. However, it remains unclear how histone methylation is regulated in response to genetic mutation and microenvironmental cues to facilitate the cancer cell survival. Here, we report a novel mechanism of the specific regulation of H3K27me3 by cooperatively two mTOR complexes, mTORC1 and mTORC2 in human glioblastoma (GBM). Integrated analyses revealed that mTORC1 upregulates the protein expression of enhancer of zeste homolog 2, a main component of polycomb repressive complex 2 which is known as H3K27-specific methyltransferase. The other mTOR complex, mTORC2, regulates production of S-adenosylmethionine, an essential substrate for histone methylation. This cooperative regulation causes H3K27 hypermethylation which subsequently promotes tumor cell survival both in vitro and in vivo xenografted mouse tumor model. These results indicate that activated mTORC1 and mTORC2 complexes cooperatively contribute to tumor progression through specific epigenetic regulation, nominating them as an exploitable therapeutic target against cancer.Implications:A dynamic regulation of histone methylation by mTOR complexes promotes tumor growth in human GBM, but at the same time could be exploitable as a novel therapeutic target against this deadly tumor.

Published
2023

17. Supplementary Figures 1-13, Tables 1-2 from Oncogenic EGFR Signaling Activates an mTORC2–NF-κB Pathway That Promotes Chemotherapy Resistance

Author

Paul S. Mischel, Albert S. Baldwin, Brendan D. Manning, Timothy F. Cloughesy, Webster K. Cavenee, Joseph F. Gera, Harry V. Vinters, William H. Yong, Amanda Rinkenbaugh, Hancai Dan, Christian C. Dibble, Yinan Zhang, Ali Nael Amzajerdi, Jason De Jesus, Huijun Yang, Shaojun Zhu, Julie Dang, Beatrice Gini, Deliang Guo, David Akhavan, David Nathanson, Ivan Babic, and Kazuhiro Tanaka

Abstract

PDF file - 1MB

Published
2023

18. Supplementary Material from Oncogenic EGFR Signaling Activates an mTORC2–NF-κB Pathway That Promotes Chemotherapy Resistance

Author

Paul S. Mischel, Albert S. Baldwin, Brendan D. Manning, Timothy F. Cloughesy, Webster K. Cavenee, Joseph F. Gera, Harry V. Vinters, William H. Yong, Amanda Rinkenbaugh, Hancai Dan, Christian C. Dibble, Yinan Zhang, Ali Nael Amzajerdi, Jason De Jesus, Huijun Yang, Shaojun Zhu, Julie Dang, Beatrice Gini, Deliang Guo, David Akhavan, David Nathanson, Ivan Babic, and Kazuhiro Tanaka

Abstract

PDF file - 161K

Published
2023

20. Supplementary Figure 1 from De-Repression of PDGFRβ Transcription Promotes Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Glioblastoma Patients

Author

Paul S. Mischel, Steven J. Bensinger, Webster K. Cavenee, Tim F. Cloughesy, Harley I. Kornblum, C. David James, Takashi Sasayama, Fuyuhiko Tamanoi, Mitchell Flagg, William H. Yong, Harry V. Vinters, Julie Dang, Huijun Yang, Ali Nael, Kazuhiro Tanaka, Genaro R. Villa, Ivan Babic, David Nathanson, Kevin J. Williams, Alex A. Nourian, Alexandra L. Pourzia, and David Akhavan

Abstract

PDF file - 199K, Fig. S1. EGFRvIII and wild type EGFR signaling regulate PDGFRβ in vitro.

Published
2023

22. Supplementary Data 4 from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Figures S2, S3 and S4. Morphometric analysis of laminin-411 β1 chain (S2) and cancer stem cell markers (Notch-1, Notch-3, CD133, Nestin, and c-Myc; S3 and S4) on frozen sections of patient brain tumors. The expression of all markers significantly correlated with glioma grade

Published
2023

23. Supplementary Video from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Video schematically shows the mechanism of glioblastoma treatment by laminin-411 inhibiting nanobioconjugate

Published
2023

24. Supplementary Figure 5 from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 2080K, Tunable expression of EGFRvIII in genetically modified models correlates with autophagy induction upon CC214-1 treatment.

Published
2023

25. Data from Development of a Real-time RT-PCR Assay for Detecting EGFRvIII in Glioblastoma Samples

Author

Paul S. Mischel, Timothy F. Cloughesy, Webster K. Cavenee, Steve Horvath, Ingo K. Mellinghoff, Darell D. Bigner, Arnab Chakravarti, Henrik Winther, Nagesh Rao, Zhenggang Xiong, William H. Yong, David B. Seligson, Rebecca Dumont, Tiffany Huang, David Nathanson, Shaojun Zhu, Julie Dang, and Koji Yoshimoto

Abstract

Purpose: Epidermal growth factor receptor variant III (EGFRvIII) is an oncogenic, constitutively active mutant form of the EGFR that is commonly expressed in glioblastoma and is also detected in a number of epithelial cancers. EGFRvIII presents a unique antigenic target for anti-EGFRvIII vaccines and it has been shown to modulate response to EGFR kinase inhibitor therapy. Thus, detection in clinical samples may be warranted. Existing patents preclude the use of anti-EGFRvIII antibodies for clinical detection. Further, frozen tissue is not routinely available, particularly for patients treated in the community. Thus, detection of EGFRvIII in formalin-fixed paraffin-embedded (FFPE) clinical samples is a major challenge.Experimental Design: We developed a real-time reverse transcription-PCR (RT-PCR) assay for detecting EGFRvIII in FFPE samples and analyzed 59 FFPE glioblastoma clinical samples with paired frozen tissue from the same surgical resection. We assessed EGFRvIII protein expression by immunohistochemistry using two distinct specific anti-EGFRvIII antibodies and examined EGFR gene amplification by fluorescence in situ hybridization.Results: The FFPE RT-PCR assay detected EGFRvIII in 16 of 59 (27%) samples, exclusively in cases with EGFR amplification, consistent with the expected frequency of this alteration. The FFPE RT-PCR assay was more sensitive and specific for detecting EGFRvIII than either of the two antibodies alone, or in combination, with a sensitivity of 93% (95% confidence interval, 0.78-1.00) and a specificity of 98% (95% confidence interval, 0.93-1.00).Conclusion: This assay will facilitate accurate assessment of EGFRvIII in clinical samples and may aid in the development of strategies for stratifying patients for EGFRvIII-directed therapies.

Published
2023

26. Supplementary Figure Legend from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 91K

Published
2023

27. Supplementary Data 5 from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Figure S5. Binding of the nanobioconjugates to U87MG studied by flow cytometry is inhibited by human soluble TfR. This shows that the chimeric anti-human TfR antibody as part of nanobioconjugate fully retained its activity

Published
2023

28. Supplementary Figure 2 from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 5300K, CC214-1 synergizes at low doses with rapamycin. Quantification of the blots shown in Fig. 2B. PTEN detection on DEAL captured GBM39 cells upon CC214-1 treatment.

Published
2023

29. Supplementary Data 8 from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Figure S10. Expression of Notch-1 and its ligand Jagged1 is significantly decreased in patient-derived glioblastoma cell lines with laminin-411 disruption by CRISPR/Cas9

Published
2023

30. Supplementary Figure 1 from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 3457K, Time course dependent CC214-1 treatment in a panel of isogenic GBM cell lines, U87EGFRvIII, U251 and LN229.

Published
2023

31. Supplementary Data 7 from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Figures S8 and S9. Quantification of expression of laminin-411 β1 chain, its binding β1 integrin, Notch family members and other stem cell markers after nanobioconjugate treatment. All markers were significantly suppressed in treated tumors.

Published
2023

32. Supplementary Figure 3 from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 1554K, Cap-dependent translation is enhanced by EGFRvIII expression and CC214-1 strongly inhibits P-4E-BP1 phosphorylation.

Published
2023

33. Supplementary Data from Development of a Real-time RT-PCR Assay for Detecting EGFRvIII in Glioblastoma Samples

Author

Paul S. Mischel, Timothy F. Cloughesy, Webster K. Cavenee, Steve Horvath, Ingo K. Mellinghoff, Darell D. Bigner, Arnab Chakravarti, Henrik Winther, Nagesh Rao, Zhenggang Xiong, William H. Yong, David B. Seligson, Rebecca Dumont, Tiffany Huang, David Nathanson, Shaojun Zhu, Julie Dang, and Koji Yoshimoto

Abstract

Supplementary Data from Development of a Real-time RT-PCR Assay for Detecting EGFRvIII in Glioblastoma Samples

Published
2023

34. Supplementary Figure 6 from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 2561K, Treatment with CC214-1, leads to induction of autophagy in GBM39 cells and genetic inhibition of autophagy sensitizes U87EGFRvIII cells to apoptosis.

Published
2023

35. Supplementary Figure 7 from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 5321K, In vitro and in vivo pharmacological inhibition of autophagy sensitizes U87EGFRvIII cells and orthotopic xenografts to CC214-1/CC214-2 mediated apoptosis.

Published
2023

36. Supplementary Data 6 from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Figures S6 and S7. Localization of labeled nanobioconjugates in tumors and biodistribution in brain. The nano drug is seen in the tumor parenchyma outside of blood vessels (S6) and preferentially accumulates in the tumor (peaks at 6 hr post-injection) as compared to contralateral brain tissue (S7)

Published
2023

37. Supplementary Data 1 from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Tables S1, S2 and S3, and Figure S1. List of used antibodies (Table S1), and immunohistochemical expression of laminin-411 and laminin-421 in human gliomas of various grades (Tables S2 and S3). Expression of laminin-411 vs. laminin-421 increases with glioma grade and in GBMs it correlates with shorter patient survival and faster tumor recurrence (Figure S1)

Published
2023

38. Data from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it.Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance.Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death.Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.

Published
2023

39. Supplementary Figure 4 from The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Author

Paul S. Mischel, Timothy F. Cloughesy, Rajesh Chopra, Kristen Hege, James R. Heath, Guido Kroemer, C. David James, Frank B. Furnari, Webster K. Cavenee, Heather K. Raymon, Shuichan Xu, Deborah S. Mortensen, Bruno Bonetti, Yuchao Gu, Alvaro Assuncao, Kelly Lin, David Akhavan, Ivan Babic, Kazuhiro Tanaka, Shaojun Zhu, David Shackelford, Genaro R. Villa, David Nathanson, Huijun Yang, Shiro Ikegami, Kenta Masui, Tomoo Matsutani, Deliang Guo, Ciro Zanca, and Beatrice Gini

Abstract

PDF file - 1694K, EGFRvIII expression sensitizes cells to CC214-1 mediated inhibition of proliferation and to autophagy.

Published
2023

40. Supplementary Data 2 from Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

Author

Julia Y. Ljubimova, Keith L. Black, Alexander V. Ljubimov, Eggehard Holler, Manuel L. Penichet, Tracy R. Daniels-Wells, Lai S. Leoh, Yongmei L. Chen, Alexander V. Lyubimov, Vida Falahatian, Arthur Rekechenetskiy, Zachary B. Grodzinski, Jethro Hu, Jeremy D. Rudnick, Chirag G. Patil, Serguei I. Bannykh, Adam N. Mamelak, Debiao Li, Shawn Wagner, Ekaterina S. Shatalova, Vladimir A. Ljubimov, Frank B. Furnari, Webster K. Cavenee, Alexandra Chesnokova, Hui Ding, Dmytro Klymyshyn, Anna Galstyan, Rameshwar Patil, and Tao Sun

Abstract

Table S4. Physico-chemical characterization of used control and treatment nanobioconjugates

Published
2023

43. Data from Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells

Author

Paul S. Mischel, Charles L. Sawyers, Timothy F. Cloughesy, Ingo K. Mellinghoff, Webster K. Cavenee, Gregory M. Shackleford, Igor Vivanco, Ederlyn Q. Dia, Shaojun Zhu, Kan V. Lu, and Maria Y. Wang

Abstract

The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma, making it a compelling molecular target for therapy. We have recently shown that coexpression of EGFRvIII and PTEN protein by glioblastoma cells is strongly associated with clinical response to EGFR kinase inhibitor therapy. PTEN loss, by dissociating inhibition of the EGFR from downstream phosphatidylinositol 3-kinase (PI3K) pathway inhibition, seems to act as a resistance factor. Because 40% to 50% of glioblastomas are PTEN deficient, a critical challenge is to identify strategies that promote responsiveness to EGFR kinase inhibitors in patients whose tumors lack PTEN. Here, we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin enhances the sensitivity of PTEN-deficient tumor cells to the EGFR kinase inhibitor erlotinib. In two isogenic model systems (U87MG glioblastoma cells expressing EGFR, EGFRvIII, and PTEN in relevant combinations, and SF295 glioblastoma cells in which PTEN protein expression has been stably restored), we show that combined EGFR/mTOR kinase inhibition inhibits tumor cell growth and has an additive effect on inhibiting downstream PI3K pathway signaling. We also show that combination therapy provides added benefit in promoting cell death in PTEN-deficient tumor cells. These studies provide strong rationale for combined mTOR/EGFR kinase inhibitor therapy in glioblastoma patients, particularly those with PTEN-deficient tumors. (Cancer Res 2006; 66(16): 7864-9)

Published
2023

44. Supplementary Methods and Materials from Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients

Author

Paul S. Mischel, Terrance G. Johns, Webster K. Cavenee, C. David James, Frank B. Furnari, Thomas Graeber, Gabriele Bergers, Stanley F. Nelson, Timothy F. Cloughesy, Roberto Weinmann, Francis Y. Lee, Arnab Chakravari, David Seligson, Joseph A. Loo, Yongmin Xie, Jeremy S. Caldwell, Zugen Chen, Yohan Lee, Isaac Oderberg, Seema B. Plaisier, Eduard B. Dinca, Julie Dang, David Ahkavan, Shawn Sarkaria, Tiffany T. Huang, Anna Cvrljevic, Shaojun Zhu, and Kan V. Lu

Abstract

Supplementary Methods and Materials from Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients

Published
2023

48. Supplementary Table 1 from Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells

Author

Paul S. Mischel, Charles L. Sawyers, Timothy F. Cloughesy, Ingo K. Mellinghoff, Webster K. Cavenee, Gregory M. Shackleford, Igor Vivanco, Ederlyn Q. Dia, Shaojun Zhu, Kan V. Lu, and Maria Y. Wang

Abstract

Supplementary Table 1 from Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells

Published
2023

49. Supplementary Figures 1-6 from Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients

Author

Paul S. Mischel, Terrance G. Johns, Webster K. Cavenee, C. David James, Frank B. Furnari, Thomas Graeber, Gabriele Bergers, Stanley F. Nelson, Timothy F. Cloughesy, Roberto Weinmann, Francis Y. Lee, Arnab Chakravari, David Seligson, Joseph A. Loo, Yongmin Xie, Jeremy S. Caldwell, Zugen Chen, Yohan Lee, Isaac Oderberg, Seema B. Plaisier, Eduard B. Dinca, Julie Dang, David Ahkavan, Shawn Sarkaria, Tiffany T. Huang, Anna Cvrljevic, Shaojun Zhu, and Kan V. Lu

Abstract

Supplementary Figures 1-6 from Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients

Published
2023

Catalog

Books, media, physical & digital resources
See catalog results