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152. Transcriptional Response to Hypoxia in Human Tumors

Author

Lal, Anita, Peters, Hans, St. Croix, Brad, Haroon, Zishan A., Dewhirst, Mark W., Strausberg, Robert L., Kaanders, Johannes H. A. M., van der Kogel, Albert J., and Riggins, Gregory J.

Published
2001

154. Genes Expressed in Human Tumor Endothelium

Author

Croix, Brad St., Rago, Carlo, Velculescu, Victor, Traverso, Giovanni, Romans, Katharine E., Montgomery, Elizabeth, Lal, Anita, Riggins, Gregory J., Lengauer, Christoph, Vogelstein, Bert, and Kinzler, Kenneth W.

Published
2000

155. Post‐9/11 excess risk of thyroid cancer: Surveillance or exposure?

Author

van Gerwen, Maaike, Cerutti, Janete M., Rapp, Joseph, Genden, Eric, Riggins, Gregory J., and Taioli, Emanuela

Subjects
THYROID cancer, DISEASE risk factors, EXPOSURE therapy, POLLUTANTS, PHYSICIANS, CANCER diagnosis
Abstract

An excess risk of thyroid cancer has been reported in different World Trade Center (WTC)‐dust exposed cohorts. Increased surveillance of these cohorts has been suggested as a potential explanation of this reported excess thyroid cancer risk leading to an increased diagnosis of earlier‐stage thyroid cancers. However, the uncertainty to what extent surveillance or physician bias may be contributing to the reported incidence of thyroid cancer in WTC‐dust exposed populations remains, highlighting the need to investigate a potential causal link between WTC dust exposure and thyroid cancer. Future studies are therefore indicated to investigate potential consequences of WTC dust exposure on the thyroid gland. Studies of the heavily exposed populations offer the possibility to better understand the mechanisms behind the exposure to a variety of environmental contaminants, and may provide useful insights into exposures harmful to the thyroid. These can be used in risk stratification when implementing screening in high‐risk populations and may inform shared decision‐making regarding the extent of thyroid cancer treatment. [ABSTRACT FROM AUTHOR]

Published
2021
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156. The Small Bowel Cancer Incidence Enigma

Author

Assumpção, Paulo, primary, Khayat, André, additional, Araújo, Taíssa, additional, Barra, Williams, additional, Ishak, Geraldo, additional, Cruz, Aline, additional, Santos, Sidney, additional, Santos, Ândrea, additional, Demachki, Samia, additional, Assumpção, Paula, additional, Calcagno, Danielle, additional, Santos, Ney, additional, Assumpção, Mônica, additional, Moreira, Fabiano, additional, Santos, André, additional, Assumpção, Carolina, additional, Riggins, Gregory, additional, and Burbano, Rommel, additional

Published
2019
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160. Supplemental_Material_for_Mutation_Profiles_in_Glioblastoma_3D_Oncospheres_Modulate_Drug_Efficacy_by_Wilson,_et_al. – Supplemental material for Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy

Author

Wilson, Kelli M., Mathews-Griner, Lesley A., Williamson, Tara, Rajarshi Guha, Chen, Lu, Shinn, Paul, McKnight, Crystal, Michael, Sam, Klumpp-Thomas, Carleen, Binder, Zev A., Ferrer, Marc, Gallia, Gary L., Thomas, Craig J., and Riggins, Gregory J.

Subjects
FOS: Clinical medicine, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
Abstract

Supplemental material, Supplemental_Material_for_Mutation_Profiles_in_Glioblastoma_3D_Oncospheres_Modulate_Drug_Efficacy_by_Wilson,_et_al. for Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy by Kelli M. Wilson, Lesley A. Mathews-Griner, Tara Williamson, Rajarshi Guha, Lu Chen, Paul Shinn, Crystal McKnight, Sam Michael, Carleen Klumpp-Thomas, Zev A. Binder, Marc Ferrer, Gary L. Gallia, Craig J. Thomas and Gregory J. Riggins in SLAS Technology

Published
2018
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166. N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

Author

Zimmermann, Sarah C., primary, Tichý, Tomáš, additional, Vávra, Jan, additional, Dash, Ranjeet P., additional, Slusher, C. Ethan, additional, Gadiano, Alexandra J., additional, Wu, Ying, additional, Jančařík, Andrej, additional, Tenora, Lukáš, additional, Monincová, Lenka, additional, Prchalová, Eva, additional, Riggins, Gregory J., additional, Majer, Pavel, additional, Slusher, Barbara S., additional, and Rais, Rana, additional

Published
2018
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168. GEJ cancers: gastric or esophageal tumors? searching for the answer according to molecular identity

Author

Barra, Williams Fernandes, primary, Moreira, Fabiano Cordeiro, additional, Pereira Cruz, Aline Maria, additional, Khayat, André Salim, additional, Calcagno, Danielle Queiroz, additional, Carneiro dos Santos, Ney Pereira, additional, Mascarenhas Junior, Rui Wanderley, additional, Thomaz Araújo, Taíssa Maíra, additional, Ishak, Geraldo, additional, Demachki, Samia, additional, Rodríguez Burbano, Rommel Mario, additional, Campos Ribeiro dos Santos, Ândrea Kely, additional, Batista dos Santos, Sidney Emanuel, additional, Riggins, Gregory Joseph, additional, and Pimentel de Assumpção, Paulo, additional

Published
2017
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169. Synergistic and targeted therapy with a procaspase-3 activator and temozolomide extends survival in glioma rodent models and is feasible for the treatment of canine malignant glioma patients

Author

Joshi, Avadhut D., primary, Botham, Rachel C., additional, Schlein, Lisa J., additional, Roth, Howard S., additional, Mangraviti, Antonella, additional, Borodovsky, Alexandra, additional, Tyler, Betty, additional, Joslyn, Steve, additional, Looper, Jayme S., additional, Podell, Michael, additional, Fan, Timothy M., additional, Hergenrother, Paul J., additional, and Riggins, Gregory J., additional

Published
2017
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170. HAM56-Immunoreactive Macrophages in Untreated Infiltrating Gliomas

Author

Cummings, Thomas J., Hulette, Christine M., Bigner, Sandra H., Riggins, Gregory J., and McLendon, Roger E.

Subjects
Monoclonal antibodies, Gliomas -- Diagnosis
Abstract

* Context.--Classic diagnostic neuropathologic teachings have cautioned against making the diagnosis of neoplasia in the presence of a macrophage population. The knowledge of macrophage distribution should prove useful when confronted with an infiltrating glioma containing macrophages. Objective.--To identify macrophages in untreated, infiltrating gliomas using the monoclonal antibody HAM56, and to confirm their presence in an untreated glioblastoma multiforme (GBM) with the serial analysis of gene expression (SAGE) method. Methods.--We evaluated the presence of macrophages in 16 cases of untreated, supratentorial infiltrating gliomas with the macrophage monoclonal antibody HAM56. We performed SAGE for one case of GBM and for normal brain tissue. Results.--In World Health Organization (WHO) grade II well-differentiated astrocytoma and oligodendroglioma, HAM56 reactivity was noted only in endothelial cells, and unequivocal macrophages were not identified. In WHO grade III anaplastic astrocytoma and anaplastic oligodendroglioma, rare HAM56-positive macrophages were noted in solid areas of tumor. In WHO grade IV GBM, HAM56-positive macrophages were identified in areas of solid tumor (mean labeling index, 8.6%). In all cases of GBM, nonquantitated HAM56-positive macrophages were identified in foci of pseudopalisading cells abutting necrosis and in foci of microvascular proliferations. In none of the cases were granulomas or microglial nodules found, and there was no prior history of surgical intervention, radiation therapy, chemotherapy, or head trauma in these cases. By SAGE, the macrophage-related proteins osteopontin and macrophage-capping protein were overexpressed 12-fold and eightfold, respectively, in one untreated GBM compared with normal brain tissue. In this case, numerous HAM56-positive macrophages (labeling index, 24.5%) were present in the solid portion of tumor, and abundant nonquantified macrophages were identified in foci of pseudopalisading cells abutting necrosis and in foci of microvascular proliferations. Conclusions.--This study confirms the utility of the monoclonal antibody HAM56 in identifying macrophages within untreated infiltrating gliomas. The overexpression of macrophage-related proteins in one case of GBM as detected by SAGE signifies that macrophages may be present in untreated GBMs. (Arch Pathol Lab Med. 2001;125:637-641), In surgical neuropathology, a potential diagnostic pitfall is the failure to recognize macrophages. Freezing artifact, inadequate processing of tissue, and reactive astrocytosis may distort the characteristic morphologic features of macrophages [...]

Published
2001

171. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study

Author

Cromm, Philipp M., Crews, Craig M., Mainolfi, Nello, Rasmusson, Tim, Poulikakos, Poulikos I., Zhang, Chao, Bollag, Gideon, Shokat, Kevan M., Rosen, Neal, Agianian, Bogos, Gavathiotis, Evripidis, Raina, Kanak, Durrant, David E., Morrison, Deborah K., Neklesa, Taavi K., Winkler, James D., Chang, F., Steelman, L. S., Lee, J. T., Shelton, J. G., Navolanic, P. M., Blalock, W. L., Franklin, R. A., McCubrey, J. A., Burslem, George M., Smith, Blake E., Lai, Ashton C., Jaime-Figueroa, Saul, McQuaid, Daniel C., Bondeson, Daniel P., Toure, Momar, Dong, Hanqing, Qian, Yimin, Wang, Jing, Crew, Andrew P., Hines, John, Sanchez, Jaquelyn N., Wang, Ton, Cohen, Mark S., Shelledy, PharmD, Lindsay, Roman, PharmD, BCOP, Danielle, Davies, Helen, Bignell, Graham R., Cox, Charles, Stephens, Philip, Edkins, Sarah, Clegg, Sheila, Teague, Jon, Woffendin, Hayley, Garnett, Mathew J., Bottomley, William, Davis, Neil, Dicks, Ed, Ewing, Rebecca, Floyd, Yvonne, Gray, Kristian, Hall, Sarah, Hawes, Rachel, Hughes, Jaime, Kosmidou, Vivian, Menzies, Andrew, Mould, Catherine, Parker, Adrian, Stevens, Claire, Watt, Stephen, Hooper, Steven, Jayatilake, Hiran, Gusterson, Barry A., Cooper, Colin, Shipley, Janet, Hargrave, Darren, Pritchard-Jones, Katherine, Maitland, Norman, Chenevix-Trench, Georgia, Riggins, Gregory J., Bigner, Darell D., Palmieri, Giuseppe, Cossu, Antonio, Flanagan, Adrienne, Nicholson, Andrew, Ho, Judy W.C., Leung, Suet Y., Yuen, Siu T., Weber, Barbara L., Seigler, Hilliard F., Darrow, Timothy L., Paterson, Hugh, Wooster, Richard, Stratton, Michael R., Futreal, P. Andrew, Spevak, Wayne, Zhang, Ying, Burton, Elizabeth A., Ma, Yan, Habets, Gaston, Zhang, Jiazhong, Lin, Jack, Ewing, Todd, Matusow, Bernice, Tsang, Garson, Marimuthu, Adhirai, Cho, Hanna, Wu, Guoxian, Wang, Weiru, Fong, Daniel, Nguyen, Hoa, Shi, Songyuan, Womack, Patrick, Nespi, Marika, Shellooe, Rafe, Carias, Heidi, Powell, Ben, Light, Emily, Sanftner, Laura, Walters, Jason, Tsai, James, West, Brian L., Visor, Gary, Rezaei, Hamid, Lin, Paul S., Nolop, Keith, Ibrahim, Prabha N., Hirth, Peter, Arozarena, Imanol, Wellbrock, Claudia, Samatar, Ahmed A., Karoulia, Zoi, Chapman, Paul B., Hauschild, Axel, Robert, Caroline, Haanen, John B., Ascierto, Paolo, Larkin, James, Dummer, Reinhard, Garbe, Claus, Testori, Alessandro, Maio, Michele, Hogg, David, Lorigan, Paul, Lebbe, Celeste, Jouary, Thomas, Schadendorf, Dirk, Ribas, Antoni, O'Day, Steven J., Sosman, Jeffrey A., Kirkwood, John M., Eggermont, Alexander M.M., Dreno, Brigitte, Li, Jiang, Nelson, Betty, Hou, Jeannie, Lee, Richard J., Flaherty, Keith T., McArthur, Grant A., Vogelstein, Bert, Papadopoulos, Nickolas, Velculescu, Victor E., Zhou, Shibin, Diaz, Luis A., Kinzler, Kenneth W., Millington, G. W.M., Buhimschi, Alexandru D., Hamman, Brian D., and Ishchenko, Alexey

Subjects
0301 basic medicine, Small molecular weight membrane-permeable inhibito, MAPK/p38, selective degradation, Raf kinases, Clinical Biochemistry, Receptor Protein-Tyrosine Kinases, protein-protein interactions, Signal transduction, Ligands, ERK cascade, protein dimerisation, Biochemistry, ternary complex, Receptor tyrosine kinase, Therapeutic intervention, 0302 clinical medicine, PROTACs, Drug Discovery, Kinome, Enzyme Inhibitors, Cereblon, E3 ligase, SNIPER, receptor tyrosine kinases, Manchester Cancer Research Centre, biology, Ras pathway, targeted degradation, Ubiquitin ligase, Raf inhibitors, 030220 oncology & carcinogenesis, Cytokines, cancer therapy, Molecular Medicine, Protein family, Ubiquitin-Protein Ligases, EGFR, hydrophobic tagging, Undruggable proteome, chemical biology, Protein degradation, Article, PROTAC, 03 medical and health sciences, proteomics, HER2, VHL, Humans, Molecular Biology, c-Met, Pharmacology, Heterobifunctional degrader, ResearchInstitutes_Networks_Beacons/mcrc, Proteolysis targeting chimera, Ubiquitination, Oncogenes, 030104 developmental biology, MAPK kinase cascade, CRBN, Proteolysis, biology.protein, Targeted protein degradation
Abstract

Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach. Burslem, Smith et al. describe the development of PROTACs capable of degrading transmembrane receptor tyrosine kinases and further highlight the advantages of degradation over inhibition in terms of potency, duration of effect, and combating compensatory signaling.

Published
2018
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173. Symptoms based cancer diagnosis–An inconceivable strategy

Author

Fernandes Barra, Williams, primary, Thomaz Araújo, Taíssa Maíra, additional, Queiroz Calcagno, Danielle, additional, Salim Khayat, André, additional, Batista dos Santos, Sidney Emanuel, additional, Carneiro dos Santos, Ney Pereira, additional, Baraúna Assumpção, Carolina, additional, Maria Pereira Cruz, Aline, additional, Ishak, Geraldo, additional, Ribeiro-dos-Santos, Ândrea Kely Campos, additional, Rodriguez Burbano, Rommel Mario, additional, Joseph Riggins, Gregory, additional, and de Assumpção, Paulo Pimentel, additional

Published
2017
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174. A High-Throughput Screen Identifies 2,9-Diazaspiro[5.5]Undecanes as Inducers of the Endoplasmic Reticulum Stress Response with Cytotoxic Activity in 3D Glioma Cell Models

Author

70378529, 70182194, Martinez, Natalia J., Rai, Ganesha, Yasgar, Adam, Lea, Wendy A., Sun, Hongmao, Wang, Yuhong, Luci, Diane K., Yang, Shyh-Ming, Nishihara, Kana, Takeda, Shunichi, Sagor, Mohiuddin, Earnshaw, Irina, Okada, Tetsuya, Mori, Kazutoshi, Wilson, Kelli, Riggins, Gregory J., Xia, Menghang, Grimaldi, Maurizio, Jadhav, Ajit, Maloney, David J., Simeonov, Anton, 70378529, 70182194, Martinez, Natalia J., Rai, Ganesha, Yasgar, Adam, Lea, Wendy A., Sun, Hongmao, Wang, Yuhong, Luci, Diane K., Yang, Shyh-Ming, Nishihara, Kana, Takeda, Shunichi, Sagor, Mohiuddin, Earnshaw, Irina, Okada, Tetsuya, Mori, Kazutoshi, Wilson, Kelli, Riggins, Gregory J., Xia, Menghang, Grimaldi, Maurizio, Jadhav, Ajit, Maloney, David J., and Simeonov, Anton

Abstract

The endoplasmic reticulum (ER) is involved in Ca2+ signaling and protein folding. ER Ca2+ depletion and accumulation of unfolded proteins activate the molecular chaperone GRP78 (glucose-regulated protein 78) which in turn triggers the ER stress response (ERSR) pathway aimed to restore ER homeostasis. Failure to adapt to stress, however, results in apoptosis. We and others have shown that malignant cells are more susceptible to ERSR-induced apoptosis than their normal counterparts, implicating the ERSR as a potential target for cancer therapeutics. Predicated on these findings, we developed an assay that uses a GRP78 biosensor to identify small molecule activators of ERSR in glioma cells. We performed a quantitative high-throughput screen (qHTS) against a collection of ~425, 000 compounds and a comprehensive panel of orthogonal secondary assays was formulated for stringent compound validation. We identified novel activators of ERSR, including a compound with a 2, 9-diazaspiro[5.5]undecane core, which depletes intracellular Ca2+ stores and induces apoptosis-mediated cell death in several cancer cell lines, including patient-derived and 3D cultures of glioma cells. This study demonstrates that our screening platform enables the identification and profiling of ERSR inducers with cytotoxic activity and advocates for characterization of these compound in in vivo models.

Published
2016

176. Somatic retrotransposition is infrequent in glioblastomas

Author

Achanta, Pragathi, primary, Steranka, Jared P., additional, Tang, Zuojian, additional, Rodić, Nemanja, additional, Sharma, Reema, additional, Yang, Wan Rou, additional, Ma, Sisi, additional, Grivainis, Mark, additional, Huang, Cheng Ran Lisa, additional, Schneider, Anna M., additional, Gallia, Gary L., additional, Riggins, Gregory J., additional, Quinones-Hinojosa, Alfredo, additional, Fenyö, David, additional, Boeke, Jef D., additional, and Burns, Kathleen H., additional

Published
2016
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178. A High-Throughput Screen Identifies 2,9-Diazaspiro[5.5]Undecanes as Inducers of the Endoplasmic Reticulum Stress Response with Cytotoxic Activity in 3D Glioma Cell Models

Author

Martinez, Natalia J., primary, Rai, Ganesha, additional, Yasgar, Adam, additional, Lea, Wendy A., additional, Sun, Hongmao, additional, Wang, Yuhong, additional, Luci, Diane K., additional, Yang, Shyh-Ming, additional, Nishihara, Kana, additional, Takeda, Shunichi, additional, Sagor, Mohiuddin, additional, Earnshaw, Irina, additional, Okada, Tetsuya, additional, Mori, Kazutoshi, additional, Wilson, Kelli, additional, Riggins, Gregory J., additional, Xia, Menghang, additional, Grimaldi, Maurizio, additional, Jadhav, Ajit, additional, Maloney, David J., additional, and Simeonov, Anton, additional

Published
2016
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179. Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines

Author

Binder, Zev A., primary, Wilson, Kelli M., additional, Salmasi, Vafi, additional, Orr, Brent A., additional, Eberhart, Charles G., additional, Siu, I-Mei, additional, Lim, Michael, additional, Weingart, Jon D., additional, Quinones-Hinojosa, Alfredo, additional, Bettegowda, Chetan, additional, Kassam, Amin B., additional, Olivi, Alessandro, additional, Brem, Henry, additional, Riggins, Gregory J., additional, and Gallia, Gary L., additional

Published
2016
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181. Non-invasive imaging of infection after treatment with tumor-homing bacteria using chemical exchange saturation transfer (CEST) MRI

Author

Liu, Guanshu, Bettegowda, Chetan, Qiao, Yuan, Staedtke, Verena, Chan, Kannie W.Y., Bai, Renyuan, Li, Yuguo, Riggins, Gregory J., Kinzler, Kenneth W., Bulte, Jeff W.M., McMahon, Michael T., Gilad, Assaf A., Vogelstein, Bert, Zhou, Shibin, and van Zijl, Peter C.M.

Subjects
Clostridium, Mice, Inbred BALB C, Reproducibility of Results, Magnetic Resonance Imaging, Sensitivity and Specificity, Article, Biological Therapy, Mice, Cell Line, Tumor, Image Interpretation, Computer-Assisted, Clostridium Infections, Animals, Humans, Female, Colorectal Neoplasms
Abstract

To develop a noninvasive MRI method for determining the germination and infection of tumor-homing bacteria in bacteriolytic cancer therapy using endogenous CEST contrast.The CEST parameters of the anaerobic gram-positive bacterium Clostridium novyi-NT (C. novyi-NT) were first characterized in vitro, then used to detect C. novyi-NT germination and infection in subcutaneous CT26 colorectal tumor-bearing mice (n = 6) after injection of 300 million bacterial spores. Lipopolysacharide (LPS) injected mice were used to exclude that the changes of CEST MRI were due to inflammation.CEST contrast was observed over a broad frequency range for bacterial suspensions in vitro, with the maximum contrast around 2.6 ppm from the water resonance. No signal could be detected for bacterial spores, demonstrating the specificity for germination. In vivo, a significant elevation of CEST contrast was identified in C. novyi-NT infected tumors as compared to those before bacterial germination and infection (P 0.05; n = 6). No significant change was observed in tumors with LPS-induced sterile inflammation (P 0.05; n = 4).Endogenous bacterial CEST contrast (bacCEST) can be used to monitor the germination and proliferation of the therapeutic bacterium C. novyi-NT without a need for exogenous cell labeling probes.

Published
2013

182. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome.

Author

Staedtke, Verena, Bai, Ren-Yuan, Kim, Kibem, Darvas, Martin, Davila, Marco L., Riggins, Gregory J., Rothman, Paul B., Papadopoulos, Nickolas, Kinzler, Kenneth W., Vogelstein, Bert, and Zhou, Shibin

Abstract

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response. Atrial natriuretic peptide, an anti-inflammatory protein, can protect against cytokine release syndrome induced by therapeutic agents such as tumour-targeting bacteria and CAR-T cells by blocking catecholamine synthesis by macrophages. [ABSTRACT FROM AUTHOR]

Published
2018
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183. Mebendazole and radiation in combination increase survival through anticancer mechanisms in an intracranial rodent model of malignant meningioma.

Author

Skibinski, Christine G., Williamson, Tara, and Riggins, Gregory J.

Abstract

Purpose: Meningiomas are a frequent tumor of the central nervous system. Although mostly benign, approximately 5% present as atypical or malignant tumors. Treatments for atypical meningiomas include gross total resection and radiotherapy, but about 33% of patients have recurrent tumors, sometimes as a higher grade. Recently, the brain penetrant anthelmintic drug, mebendazole, has shown promise as an anticancer agent in rodent models of glioblastoma and medulloblastoma.Methods: The half maximal inhibitory concentration (IC50) effect on colony formation, cell proliferation, and caspase-3/7 markers of apoptosis of mebendazole with and without radiation was measured in vitro. Mice intracranially implanted with KT21MG1 human meningioma were administered mebendazole alone or in combination with radiation. Survival benefit was evaluated, while tumors were investigated by immunohistochemical staining for apoptosis, cell proliferation, and vascular density.Results: In vitro experiments on meningioma cell lines showed the IC50 for mebendazole in the range of 0.26-0.42 µM. Mebendazole alone induced cytotoxicity, however the combination had a greater reduction in colony formation and resulted in higher levels of cleaved caspase-3. The in vivo study showed both, mebendazole alone and the combination, to have a survival benefit with an increase in apoptosis, and decreases in tumor cell and vascular proliferation.Conclusion: These preclinical findings indicate that mebendazole alone or in combination with radiation can be considered for the treatment of malignant meningioma. The mechanism of action for this combination may include an increase in apoptosis, a reduction in proliferation and angiogenesis, or a combination of these effects. [ABSTRACT FROM AUTHOR]

Published
2018
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184. Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors

Author

Bai, Ren-Yuan, Esposito, Dominic, Tam, Ada, McCormick, Frank, Riggins, Gregory, Wade Clapp, D., and Staedtke, Verena

Abstract

Neurofibromatosis type 1, including the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), is featured by the loss of functional neurofibromin 1 (NF1) protein resulting from genetic alterations. A major function of NF1 is suppressing Ras activities, which is conveyed by an intrinsic GTPase-activating protein-related domain (GRD). In this study, we explored the feasibility of restoring Ras GTPase via exogenous expression of various GRD constructs, via gene delivery using a panel of adeno-associated virus (AAV) vectors in MPNST and human Schwann cells (HSCs). We demonstrated that several AAV serotypes achieved favorable transduction efficacies in those cells and a membrane-targeting GRD fused with an H-Ras C-terminal motif (C10) dramatically inhibited the Ras pathway and MPNST cells in a NF1-specific manner. Our results opened up a venue of gene replacement therapy in NF1-related tumors.

Published
2019
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188. The role of piRNA and its potential clinical implications in cancer

Author

Assumpção, Carolina Baraúna, primary, Calcagno, Danielle Queiroz, additional, Araújo, Taíssa Maíra Thomaz, additional, Batista dos Santos, Sidney Emmanuel, additional, Ribeiro dos Santos, Ândrea Kely Campos, additional, Riggins, Gregory Joseph, additional, Burbano, Rommel Rodriguez, additional, and Assumpção, Paulo Pimentel, additional

Published
2015
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194. Re-expression of ABI3BP Suppresses Thyroid Tumor Growth by Promoting Senescence and Inhibiting Invasion

Author

Latini, Flavia R. M., Hemerly, Jefferson P., Oler, Gisele, Riggins, Gregory J., and Cerutti, Janete M.

Subjects
Male, Cell Survival, Mice, Nude, Transfection, Xenograft Model Antitumor Assays, Article, Up-Regulation, Gene Expression Regulation, Neoplastic, Mice, Cell Movement, Cell Line, Tumor, Adenocarcinoma, Follicular, Animals, Humans, Neoplasm Invasiveness, Thyroid Neoplasms, Carrier Proteins, Cellular Senescence, Tumor Stem Cell Assay, Cell Proliferation
Abstract

Loss of ABI gene family member 3-binding protein (ABI3BP) expression may be functionally involved in the pathogenesis of cancer. Previous reports have indicated a loss of expression in lung cancer and a presumed role in inducing cellular senescence. We show here that ABI3BP expression is significantly decreased in most malignant thyroid tumors of all types. To better understand ABI3BP's role, we created a model by re-expressing ABI3BP in two thyroid cancer cell lines. Re-expression of ABI3BP in thyroid cells resulted in a decrease in transforming activity, cell growth, cell viability, migration, invasion, and tumor growth in nude mice. ABI3BP re-expression appears to trigger cellular senescence through the p21 pathway. Additionally, ABI3BP induced formation of heterochromatin 1-binding protein gamma-positive senescence-associated (SA) heterochromatin foci and accumulation of SA beta-galactosidase. The combination of a decrease in cell growth, invasion, and other effects upon ABI3BP re-expression in vitro helps to explain the large reduction in tumor growth that we observed in nude mice. Together, our data provide evidence that the loss of ABI3BP expression could play a functional role in thyroid tumorigenesis. Activation of ABI3BP or its pathway may represent a possible basis for targeted therapy of certain cancers.

Published
2008

195. Antihelminthic Benzimidazoles Are Novel HIF Activators That Prevent Oxidative Neuronal DeathviaBinding to Tubulin

Author

Aleyasin, Hossein, primary, Karuppagounder, Saravanan S., additional, Kumar, Amit, additional, Sleiman, Sama, additional, Basso, Manuela, additional, Ma, Thong, additional, Siddiq, Ambreena, additional, Chinta, Shankar J., additional, Brochier, Camille, additional, Langley, Brett, additional, Haskew-Layton, Renee, additional, Bane, Susan L., additional, Riggins, Gregory J., additional, Gazaryan, Irina, additional, Starkov, Anatoly A., additional, Andersen, Julie K., additional, and Ratan, Rajiv R., additional

Published
2015
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197. Detection of circulating tumor DNA in early- and late-stage human malignancies

Author

Bettegowda, Chetan, Sausen, Mark, Leary, Rebecca J, Kinde, Isaac, Wang, Yuxuan, Agrawal, Nishant, Bartlett, Bjarne R, Wang, Hao, Luber, Brandon, Alani, Rhoda M, Antonarakis, Emmanuel S, Azad, Nilofer S, Bardelli, Alberto, Brem, Henry, Cameron, John L, Lee, Clarence C, Fecher, Leslie A, Gallia, Gary L, Gibbs, Peter, Le, Dung, Giuntoli, Robert L, Goggins, Michael, Hogarty, Michael D, Holdhoff, Matthias, Hong, Seung-Mo, Jiao, Yuchen, Juhl, Hartmut H, Kim, Jenny J, Siravegna, Giulia, Laheru, Daniel A, Lauricella, Calogero, Lim, Michael, Lipson, Evan J, Marie, Suely Kazue Nagahashi, Netto, George J, Oliner, Kelly S, Olivi, Alessandro, Olsson, Louise, Riggins, Gregory J, Sartore-Bianchi, Andrea, Schmidt, Kerstin, Shih, le-Ming, Oba-Shinjo, Sueli Mieko, Siena, Salvatore, Theodorescu, Dan, Tie, Jeanne, Harkins, Timothy T, Veronese, Silvio, Wang, Tian-Li, Weingart, Jon D, Wolfgang, Christopher L, Wood, Laura D, Xing, Dongmei, Hruban, Ralph H, Wu, Jian, Allen, Peter J, Schmidt, C Max, Choti, Michael A, Velculescu, Victor E, Kinzler, Kenneth W, Vogelstein, Bert, Papadopoulos, Nickolas, Diaz, Luis A, Bettegowda, Chetan, Sausen, Mark, Leary, Rebecca J, Kinde, Isaac, Wang, Yuxuan, Agrawal, Nishant, Bartlett, Bjarne R, Wang, Hao, Luber, Brandon, Alani, Rhoda M, Antonarakis, Emmanuel S, Azad, Nilofer S, Bardelli, Alberto, Brem, Henry, Cameron, John L, Lee, Clarence C, Fecher, Leslie A, Gallia, Gary L, Gibbs, Peter, Le, Dung, Giuntoli, Robert L, Goggins, Michael, Hogarty, Michael D, Holdhoff, Matthias, Hong, Seung-Mo, Jiao, Yuchen, Juhl, Hartmut H, Kim, Jenny J, Siravegna, Giulia, Laheru, Daniel A, Lauricella, Calogero, Lim, Michael, Lipson, Evan J, Marie, Suely Kazue Nagahashi, Netto, George J, Oliner, Kelly S, Olivi, Alessandro, Olsson, Louise, Riggins, Gregory J, Sartore-Bianchi, Andrea, Schmidt, Kerstin, Shih, le-Ming, Oba-Shinjo, Sueli Mieko, Siena, Salvatore, Theodorescu, Dan, Tie, Jeanne, Harkins, Timothy T, Veronese, Silvio, Wang, Tian-Li, Weingart, Jon D, Wolfgang, Christopher L, Wood, Laura D, Xing, Dongmei, Hruban, Ralph H, Wu, Jian, Allen, Peter J, Schmidt, C Max, Choti, Michael A, Velculescu, Victor E, Kinzler, Kenneth W, Vogelstein, Bert, Papadopoulos, Nickolas, and Diaz, Luis A

Abstract

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Published
2014
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