المؤلفون: Pandya, Bhavyata, Webb, Becky Slagle, Zacharia, Brad, Lathia, Justin, Rubin, Joshua, Berens, Michael, Barnholtz-Sloan, Jill

المصدر: Neuro-Oncology ; volume 23, issue Supplement_6, page vi209-vi209 ; ISSN 1522-8517 1523-5866

مصطلحات موضوعية: Cancer Research, Neurology (clinical), Oncology

الوصف: Sexual dimorphism in incidence and the clinical outcomes of Glioblastoma (GBM) has been reported, however, our knowledge of contributing biological mechanisms is limited. Iron acquisition is key to robust tumor growth. Upregulation of Transferrin (TF, iron transport protein)/Transferrin receptor (TFR) is critical for found in multiple different cancers, specifically, we have identified H-ferritin (FTH1) as a contributor to iron transport and protection in cancer stem cells. To interrogate brain tumor iron uptake mechanisms,we performed binding studies on homogenized samples of human male and female GBM tissue samples using 125I labeled TF and FTH1. Tumors from males had a ̴ 3.8-fold increased binding of both proteins compared to tumors from females. We interrogated iron uptake in a syngeneic orthotopic mouse model (GL261 cells) using male and female mice. After the tumors were established, radioactive 125I labeled TF and FTH1 proteins were injected retro-orbitally in the mice. After 24 hours, tumors wereremoved, and analyzed for TF and FTH1 uptake. Male tumors showed an increased uptake, of ̴ 3.2-fold, as compared to female tumors. There was no significant difference in TF uptake between male and female tumors nor between tumor and matched non-tumor brain tissue. We next queried role of FTH1 in the context of sexual dimorphism in GBM in a FTH1+/- mouse strain developed in our laboratory. Survival was monitored in the mice which were injected with GL261 cells at 3 months. Male mice that had reduced expression of FTH1 had poorer survival as compared to the male wild type controls whereas wild type and FTH+/- females had no major differences in survival outcomes. In summary, this study demonstrates sexual dimorphism in iron acquisition in GBM and animal models further suggesting a pathophysiological role of iron metabolism in GBM development and its possible role in prognosis.

الإتاحة: https://doi.org/10.1093/neuonc/noab196.837Test
https://academic.oup.com/neuro-oncology/article-pdf/23/Supplement_6/vi209/41141654/noab196.837.pdfTest

المؤلفون: Shenoy, Ganesh, Troike, Katie M, Kuhn, Madison, Webb, Becky Slagle, Snyder, Amanda, Khunsriraksakul, Chachrit, Lathia, Justin, Wang, Hong-Gang, Proctor, Elizabeth, Connor, James

المصدر: Neuro-Oncology ; volume 23, issue Supplement_6, page vi207-vi207 ; ISSN 1522-8517 1523-5866

مصطلحات موضوعية: Cancer Research, Neurology (clinical), Oncology

الوصف: Glioblastoma (GBM) remains one of the most difficult to treat malignancies facing modern medicine. The strong migratory and invasive capacity of GBM cells allows for diffuse invasion into neighboring healthy brain which presents a significant hurdle for complete surgical resection of these tumors. Unsurprisingly, even after receiving maximal surgical resection, radiation and chemotherapy, the majority of GBM patients end up with recurrent disease. Increased expression levels of the homeostatic iron regulator gene (HFE) in brain tumors such as GBM have been associated with poorer outcomes. In order to better understand how HFE expression impacts the adhesive and migratory capacity of GBM, we utilized syngeneic mouse glioma models (KR158, CT2A) that have been transfected to either over-express or under-express HFE. We observed that knocking down HFE in the KR158 model resulted in significantly decreased migratory capacity as well as decreased adhesion to fibronectin and artificial basement membrane. Likewise, overexpressing HFE in a CT2A model resulted in increased adhesion to fibronectin or artificial basement membrane. Since HFE is known to regulate iron uptake, we studied how modulating the iron status of GBM cells impacted their ability to migrate and adhere. We found that increasing the iron pool of these mouse glioma models by exposure to exogenous iron compounds decreased migratory capacity. To better understand mechanistically how HFE and iron status impacted migration and adhesion, we probed how expression of integrins and their downstream signaling molecules, the Rho GTPases were altered in response to iron. We found that exposure to iron decreased levels of the Rho GTPases Cdc42 and RhoA. Furthermore, cells that overexpressed HFE were found to have increased expression of integrin β1 and integrin α5 suggesting that HFE and iron may impact integrins and their downstream signaling pathways to alter migration of GBM cells.

الإتاحة: https://doi.org/10.1093/neuonc/noab196.825Test
https://academic.oup.com/neuro-oncology/article-pdf/23/Supplement_6/vi207/41141494/noab196.825.pdfTest

المؤلفون: Pavel, Helena, Ajeawung, Norbert, Faure, Robert, Poirier, Donald, Kamnasaran, Deepak, Joshi, Harish, Lun, Xueqing, Zemp, Franz, Sun, Beichen, Stechishin, Owen, Luchman, Artee, Kelly, John J., Weiss, Samuel, Hamilton, Mark G., Cairncross, Gregory, Senger, Donna L., Bell, John, McFadden, Grant, Forsyth, Peter A., Tzeng, Stephany Y., Guerrero-Cazares, Hugo, Martinez, Elliott E., Young, Noah P., Sunshine, Joel C., Quinones-Hinojosa, Alfredo, Green, Jordan J., Lei, Liang, D'Amico, Randy, Sisti, Julia, Leung, Richard, Sonabend, Adam M., Guarnieri, Paolo, Rosenfeld, Steven S., Bruce, Jeffrey N., Canoll, Peter, Baichwal, Vijay R., Reeves, Leslie, Chad, Bradford L., Zavitz, Kenton H., Beelen, Andrew P., Mather, Gary G., Carlson, Robert O., Manton, Christa, Chandra, Joya, Keir, Stephen T., Reardon, David A., Saling, Julia R., Gray, Lloyd S., Bigner, Darell D., Friedman, Henry S., Zhang, Jiqing, Brun, Jan, Ogbomo, Henry, Wang, Zhigang, Stojdl, David J., Kong, Ling-Yuan, Hatiboglu, Mustafa A., Wei, Jun, Wang, Yongtao, McEnery, Kayla A., Fuller, Gregory N., Qiao, Wei, Davies, Michael A., Priebe, Waldemar, Heimberger, Amy B., Amendolara, Benjamin, Gil, Orlando, Ivkovic, Sanja, Bruce, Jeffrey, Rosenfeld, Steven, Finniss, Susan, Perlstein, Benny, Miller, Cathie, Okhrimenko, Hana, Kazimirsky, Gila, Cazacu, Simona, Lemke, Nancy, Brodie, Shlomit, Rempel, Sandra A., Rosenblum, Mark, Mikkelsen, Tom, Margel, Shlomo, Brodie, Chaya, Guvenc, Hacer, Demir, Habibe, Gupta, Snehalata, Mazumder, Sarmistha, Ray-Chaundhury, Abhik, Li, Tom, Li, Chenglong, Nakano, Ichiro, Rahman, Ruman, Rahman, Cheryl, Smith, Stuart, Macarthur, Donald, Rose, Felicity, Shakesheff, Kevin, Grundy, Richard G., Brenner, Andrew J., Goins, Beth, Bao, Ande, Miller, Jessica, Trevino, Abram, Zuniga, Richard, Phillips, William T., Gilg, Anne G., Bowers, Karen G., Toole, Bryan P., Maria, Bernard L., Leung, Gilberto K., Sun, Stella, Wong, Stanley T., Zhang, Xiao Qin, Pu, Jenny K., Lui, Wai Man, Marino, Anna M., Hussaini, Isa M., Amos, Samson, Simpson, Kendra, Redpath, Gerard T., Lyons, Charles, Dipierro, Charles, Grant, Gerald A., Wilson, Christy, Salami, Sara, Macaroni, Paolo, Li, Shuqin, Park, Ji-Young, Needham, David, Bigner, Darell, Dewhirst, Mark, Ohlfest, John, Gallardo, Jose, Argawal, Sagar, Mittapalli, Rajendar, Donelson, Randy, Elmquist, William F., Nicolaides, Theodore, Hariono, Sujatmi, Barkovich, Krister, Hashizume, Rintaro, Rowitch, David, Weiss, William, Sheer, Denise, Baker, Suzanne, Paugh, Barbara, Waldman, Todd, Li, Huifang, Jones, Chris, Forshew, Tim, James, David, Caroline, Happold, Patrick, Roth, Katrin, Lamszus, Karl, Frei, Ghazaleh, Tabatabai, Michael, Weller, Albrecht, Valerie, Thorsteinsdottir, Jun, Wagner, Ernst, Tonn, Jörg-Christian, Ogris, Manfred, Schichor, Christian, Charest, Gabriel, Paquette, Benoit, Sanche, Léon, Mathieu, David, Fortin, David, Qi, Xiaoyang, Cuttitta, Franck, Chu, Zhengtao, Celerier, Jerome, Pakradouni, Jihane, Rixe, Olivier, Gragg, Ashley, Muller, Sabine, Banerjee, Anuradha, Phillips, Joanna, Prados, Michael, Haas-Kogan, Daphne, Gupta, Nalin, Florence, Lefranc, Gwendoline, Van Goietsenoven, Véronique, Mathieu, Robert, Kiss, Agarwal, Sagar, Mittapalli, Rajendar K., Cen, Ling, Carlson, Brett L., Sarkaria, Jann N., Sengupta, Soma, Weeraratne, Shyamal D., Rallapalli, Sundari, Amani, Vladimir, Pierre-Francois, Jessica, Teider, Natalia, Rotenberg, Alexander, Cook, James, Pomeroy, Scott L., Jenses, Frances, Cho, Yoon-Jae, Hjouj, Mohammad, Last, David, Guez, David, Daniels, Dianne, Lavee, Jacob, Rubinsky, Boris, Mardor, Yael, Serwer, Laura P., Noble, Charles O., Michaud, Karine, Drummond, Daryl C., Ozawa, Tomoko, Zhou, Yu, Marks, James D., Bankiewicz, Krystof, Park, John W., Wang, Weijun, Cho, Heeyeon, Weintraub, Michael, Jhaveri, Niyati, Torres, Shering, Petasis, Nicos, Schonthal, Axel H., Louie, Stan G., Hofman, Florence M., Chen, Thomas C., Grada, Zakaria, Hegde, Meenakshi, Schaffer, Donald R., Ghazi, Alexia, Byrd, Tiara, Dotti, Gianpietro, Wels, Winfried, Heslop, Helen E., Gottschalk, Stephen, Baker, Matthew, Ahmed, Nabil, Hamblett, Kevin J., Kozlosky, Carl J., Liu, Hua, Siu, Sophia, Arora, Taruna, Retter, Marc W., Matsuda, Katherine, Hill, John S., Fanslow, William C., Diaz, Roberto J., Etame, Arnold, Meaghan, O'Reilly, Mainprize, Todd, Smith, Christian, Hynynen, Kullervo, Rutka, James, Pradarelli, Jason, Yoo, Ji Young, Kaka, Azeem, Alvarez-Breckenridge, Christopher, Pan, Quintin, Chiocca, E. Antonio, Teknos, Theodoros, Kaur, Balveen, Lee, Sang Y., Slagle-Webb, Becky, Sheehan, Jonas M., Connor, James R., Cote, Jerome, Lepage, Martin, Gobeil, Fernand, Kleijn, Anne, Balvers, Rutger, Kloezeman, Jenneke, Dirven, Clemens, Lamfers, Martine, Leenstra, Sieger, See, Wendy, Tan, I-Li, Pieper, Russell, Jiang, Hong, White, Erin, Ríos-Vicil, Christian I., Yung, Wai-Kwan A., Gomez-Manzano, Candelaria, Fueyo, Juan, Zemp, Franz J., McKenzie, Brienne A., Mueller, Sabine, Yang, Xiaodong, Smirnov, Ivan, Prados, Micheal, James, David C., Phillips, Joanna J., Berger, Mitchel S., Rowitch, David H., Haas-Kogan, Daphne H., Kennedy, Benjamin, Gopalakrishnan, Vidya, Das, Chandramallika, Taylor, Pete, Kommagani, Ramakrishna, Su, Xiaohua, Aguilera, Dolly, Thomas, Alexandra, Wolff, Johannes, Flores, Elsa, Kadakia, Madhavi, Alkins, Ryan, Broderson, Peter, Sodhi, Rana, Chung, Sylvia A., McDonald, Kerrie L., Shen, Han, Day, Bryan W., Stringer, Brett W., Johns, Terrance, Decollogne, Stéphanie, Teo, Charlie, Hogg, Philip J., Dilda, Pierre J., Patel, Toral R., Zhou, Jiangbing, Piepmeier, Joseph M., Saltzman, W Mark, Vogelbaum, Michael A., Manchanda, Pooja, Ohlfest, John R., Kitange, Gaspar J., Mladek, Ann C., Schroeder, Mark A., Pokorny, Jenny L., Mody, Christopher, Forsyth, Peter, Dasgupta, Tina, James, C. David, Madhankumar, Achuthamangalam B., Webb, Becky Slagle, Park, Annie, Harbaugh, Kimberly, Sheehan, Jonas

مصطلحات موضوعية: Abstracts

الوصف: BACKGROUND: Medulloblastoma is one of the most common malignant tumors of the central nervous system in newborn infants and children and accounts for about 15% to 20% of pediatric brain tumors. Despite current diagnostic and therapeutic advances, the morbidity and mortality rates still remain high. Furthermore, children who survive medulloblastoma are at risk for long-term sequelae related to the neurological effects of the tumor and surgery, radiotherapy, and chemotherapy. Therefore, it is of great importance to identify new anticancer drugs that can significantly assist in improving the survival of children with minimal or no side effects. In this study, our primary objective was to identify and study the efficacy of new structural classes of drugs belonging to a family of steroid biogenesis inhibitors and in the peroxovanadium superfamily. METHODS: We chose to undertake our preclinical testing on malignant pediatric medulloblastoma cell lines. After determining the IC50 values of our experimental drugs, we subjected our preclinical cell line models to a wide variety of cancer assays, including viability/proliferation, cell death, cell cycle regulation and transformation assays. RESULTS AND CONCLUSIONS: Our data so far demonstrate that the panel of new structural classes of drugs examined can significantly affect the viability and transformation of malignant medulloblastoma preclinical cell line models. Most importantly, the toxicity of our drugs was almost devoid in our non-transformed control cell lines. Our current work continues to explore the efficacy of these drugs in additional malignant medulloblastoma preclinical models. This body of work is novel and highly significant in our effort to discover improved treatments for childhood brain tumors.

وصف الملف: text/html

العلاقة: http://neuro-oncology.oxfordjournals.org/cgi/content/short/13/suppl_3/iii107Test; http://dx.doi.org/10.1093/neuonc/nor158Test

الإتاحة: https://doi.org/10.1093/neuonc/nor158Test
http://neuro-oncology.oxfordjournals.org/cgi/content/short/13/suppl_3/iii107Test