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1. ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip

Author

Lee, John J. Y., Tao, Ran, You, Zhen, Haldipur, Parthiv, Erickson, Anders W., Farooq, Hamza, Hendriske, Liam D., Abeysundara, Namal, Richman, Cory M., Wang, Evan Y., Das Gupta, Neha, Hadley, Jennifer, Batts, Melissa, Mount, Christopher W., Wu, Xiaochong, Rasnitsyn, Alex, Bailey, Swneke, Cavalli, Florence M. G., Morrissy, Sorana, Garzia, Livia, Michealraj, Kulandaimanuvel Antony, Visvanathan, Abhi, Fong, Vernon, Palotta, Jonelle, Suarez, Raul, Livingston, Bryn G., Liu, Miao, Luu, Betty, Daniels, Craig, Loukides, James, Bendel, Anne, French, Pim J., Kros, Johan M., Korshunov, Andrey, Kool, Marcel, Chico Ponce de León, Fernando, Perezpeña-Diazconti, Mario, Lach, Boleslaw, Singh, Sheila K., Leary, Sarah E. S., Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Lee, Ji-Yeoun, Tominaga, Teiji, Weiss, William A., Phillips, Joanna J., Dai, Shizhong, Zadeh, Gelareh, Saad, Ali G., Bognár, László, Klekner, Almos, Pollack, Ian F., Hamilton, Ronald L., Ra, Young-shin, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Thompson, Reid C., Kenney, Anna M., Cooper, Michael K., Mack, Stephen C., Jabado, Nada, Lupien, Mathieu, Gallo, Marco, Ramaswamy, Vijay, Suva, Mario L., Suzuki, Hiromichi, Millen, Kathleen J., Huang, L. Frank, Northcott, Paul A., and Taylor, Michael D.

Published
2025
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2. Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

Author

Chokshi, Chirayu R., Shaikh, Muhammad Vaseem, Brakel, Benjamin, Rossotti, Martin A., Tieu, David, Maich, William, Anand, Alisha, Chafe, Shawn C., Zhai, Kui, Suk, Yujin, Kieliszek, Agata M., Miletic, Petar, Mikolajewicz, Nicholas, Chen, David, McNicol, Jamie D., Chan, Katherine, Tong, Amy H. Y., Kuhlmann, Laura, Liu, Lina, Alizada, Zahra, Mobilio, Daniel, Tatari, Nazanin, Savage, Neil, Aghaei, Nikoo, Grewal, Shan, Puri, Anish, Subapanditha, Minomi, McKenna, Dillon, Ignatchenko, Vladimir, Salamoun, Joseph M., Kwiecien, Jacek M., Wipf, Peter, Sharlow, Elizabeth R., Provias, John P., Lu, Jian-Qiang, Lazo, John S., Kislinger, Thomas, Lu, Yu, Brown, Kevin R., Venugopal, Chitra, Henry, Kevin A., Moffat, Jason, and Singh, Sheila K.

Published
2024
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4. National multicentered retrospective review of clinical and intraoperative factors associated with the development of cerebellar mutism after pediatric posterior fossa tumor resection

Author

Kameda-Smith, Michelle M., Ragulojan, Malavan, Elliott, Cameron, Bliss, Lori, Moore, Hanna, Sader, Nicholas, Alsuwaihel, Mosaab, Tso, Michael K., Dakson, Ayoub, Ajani, Olufemi, Yarascavitch, Blake, Fleming, Adam, Mehta, Vivek, Aminnejad, Minoo, Farrokhyar, Forough, and Singh, Sheila K.

Published
2024
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5. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers

Author

Tatari, Nazanin, Khan, Shahbaz, Livingstone, Julie, Zhai, Kui, Mckenna, Dillon, Ignatchenko, Vladimir, Chokshi, Chirayu, Gwynne, William D, Singh, Manoj, Revill, Spencer, Mikolajewicz, Nicholas, Zhu, Chenghao, Chan, Jennifer, Hawkins, Cynthia, Lu, Jian-Qiang, Provias, John P, Ask, Kjetil, Morrissy, Sorana, Brown, Samuel, Weiss, Tobias, Weller, Michael, Han, Hong, Greenspoon, Jeffrey N, Moffat, Jason, Venugopal, Chitra, Boutros, Paul C, Singh, Sheila K, and Kislinger, Thomas

Subjects
Biomedical and Clinical Sciences, Neurosciences, Cancer, Brain Disorders, Brain Cancer, Human Genome, Genetics, Rare Diseases, Biotechnology, Orphan Drug, Clinical Research, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Glioblastoma, Brain Neoplasms, Proteomics, Neoplasm Recurrence, Local, Transcriptome, Immunosuppression, OAS2, Clinical Sciences, Neurology & Neurosurgery
Abstract

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

Published
2022

6. De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases

Author

Kieliszek, Agata M., Mobilio, Daniel, Bassey-Archibong, Blessing I., Johnson, Jarrod W., Piotrowski, Mathew L., de Araujo, Elvin D., Sedighi, Abootaleb, Aghaei, Nikoo, Escudero, Laura, Ang, Patrick, Gwynne, William D., Zhang, Cunjie, Quaile, Andrew, McKenna, Dillon, Subapanditha, Minomi, Tokar, Tomas, Vaseem Shaikh, Muhammad, Zhai, Kui, Chafe, Shawn C., Gunning, Patrick T., Montenegro-Burke, J. Rafael, Venugopal, Chitra, Magolan, Jakob, and Singh, Sheila K.

Published
2024
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8. Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma

Author

Kameda-Smith, Michelle M, Zhu, Helen, Luo, En-Ching, Suk, Yujin, Xella, Agata, Yee, Brian, Chokshi, Chirayu, Xing, Sansi, Tan, Frederick, Fox, Raymond G, Adile, Ashley A, Bakhshinyan, David, Brown, Kevin, Gwynne, William D, Subapanditha, Minomi, Miletic, Petar, Picard, Daniel, Burns, Ian, Moffat, Jason, Paruch, Kamil, Fleming, Adam, Hope, Kristin, Provias, John P, Remke, Marc, Lu, Yu, Reya, Tannishtha, Venugopal, Chitra, Reimand, Jüri, Wechsler-Reya, Robert J, Yeo, Gene W, and Singh, Sheila K

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Neurosciences, Stem Cell Research, Human Genome, Orphan Drug, Brain Disorders, Brain Cancer, Biotechnology, Cancer, Rare Diseases, Genetics, Pediatric, Pediatric Cancer, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Animals, Mice, Humans, Proteomics, Medulloblastoma, RNA-Binding Proteins, Brain Neoplasms, Cerebellar Neoplasms, Nerve Tissue Proteins
Abstract

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

Published
2022

12. Author Correction: Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma

Author

Kameda-Smith, Michelle M., Zhu, Helen, Luo, En-Ching, Suk, Yujin, Xella, Agata, Yee, Brian, Chokshi, Chirayu, Xing, Sansi, Tan, Frederick, Fox, Raymond G., Adile, Ashley A., Bakhshinyan, David, Brown, Kevin, Gwynne, William D., Subapanditha, Minomi, Miletic, Petar, Picard, Daniel, Burns, Ian, Moffat, Jason, Paruch, Kamil, Fleming, Adam, Hope, Kristin, Provias, John P., Remke, Marc, Lu, Yu, Reya, Tannishtha, Venugopal, Chitra, Reimand, Jüri, Wechsler-Reya, Robert J., Yeo, Gene W., and Singh, Sheila K.

Published
2023
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15. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Author

Sin-Chan, Patrick, Mumal, Iqra, Suwal, Tannu, Ho, Ben, Fan, Xiaolian, Singh, Irtisha, Du, Yuchen, Lu, Mei, Patel, Neilket, Torchia, Jonathon, Popovski, Dean, Fouladi, Maryam, Guilhamon, Paul, Hansford, Jordan R, Leary, Sarah, Hoffman, Lindsey M, Levy, Jean M Mulcahy, Lassaletta, Alvaro, Solano-Paez, Palma, Rivas, Eloy, Reddy, Alyssa, Gillespie, G Yancey, Gupta, Nalin, Van Meter, Timothy E, Nakamura, Hideo, Wong, Tai-Tong, Ra, Young-Shin, Kim, Seung-Ki, Massimi, Luca, Grundy, Richard G, Fangusaro, Jason, Johnston, Donna, Chan, Jennifer, Lafay-Cousin, Lucie, Hwang, Eugene I, Wang, Yin, Catchpoole, Daniel, Michaud, Jean, Ellezam, Benjamin, Ramanujachar, Ramya, Lindsay, Holly, Taylor, Michael D, Hawkins, Cynthia E, Bouffet, Eric, Jabado, Nada, Singh, Sheila K, Kleinman, Claudia L, Barsyte-Lovejoy, Dalia, Li, Xiao-Nan, Dirks, Peter B, Lin, Charles Y, Mack, Stephen C, Rich, Jeremy N, and Huang, Annie

Subjects
Rare Diseases, Neurosciences, Cancer, Genetics, Biotechnology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biomarkers, Tumor, Brain Neoplasms, Cell Cycle, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 2, DNA Copy Number Variations, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, MicroRNAs, Models, Biological, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Germ Cell and Embryonal, Oncogenes, RNA-Binding Proteins, C19MC, ETMR, LIN28A, MYCN, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Published
2019

16. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma

Author

Gwynne, William D., Suk, Yujin, Custers, Stefan, Mikolajewicz, Nicholas, Chan, Jeremy K., Zador, Zsolt, Chafe, Shawn C., Zhai, Kui, Escudero, Laura, Zhang, Cunjie, Zaslaver, Olga, Chokshi, Chirayu, Shaikh, Muhammad Vaseem, Bakhshinyan, David, Burns, Ian, Chaudhry, Iqra, Nachmani, Omri, Mobilio, Daniel, Maich, William T., Mero, Patricia, Brown, Kevin R., Quaile, Andrew T., Venugopal, Chitra, Moffat, Jason, Montenegro-Burke, J. Rafael, and Singh, Sheila K.

Published
2022
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17. Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma

Author

Qazi, Maleeha A., Salim, Sabra K., Brown, Kevin R., Mikolajewicz, Nicholas, Savage, Neil, Han, Hong, Subapanditha, Minomi K., Bakhshinyan, David, Nixon, Allison, Vora, Parvez, Desmond, Kimberly, Chokshi, Chirayu, Singh, Mohini, Khoo, Amanda, Macklin, Andrew, Khan, Shahbaz, Tatari, Nazanin, Winegarden, Neil, Richards, Laura, Pugh, Trevor, Bock, Nicholas, Mansouri, Alireza, Venugopal, Chitra, Kislinger, Thomas, Goyal, Sidhartha, Moffat, Jason, and Singh, Sheila K.

Published
2022
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19. ZIC1is a context-dependent medulloblastoma driver in the rhombic lip

Author

Lee, John J. Y., Tao, Ran, You, Zhen, Haldipur, Parthiv, Erickson, Anders W., Farooq, Hamza, Hendriske, Liam D., Abeysundara, Namal, Richman, Cory M., Wang, Evan Y., Das Gupta, Neha, Hadley, Jennifer, Batts, Melissa, Mount, Christopher W., Wu, Xiaochong, Rasnitsyn, Alex, Bailey, Swneke, Cavalli, Florence M. G., Morrissy, Sorana, Garzia, Livia, Michealraj, Kulandaimanuvel Antony, Visvanathan, Abhi, Fong, Vernon, Palotta, Jonelle, Suarez, Raul, Livingston, Bryn G., Liu, Miao, Luu, Betty, Daniels, Craig, Loukides, James, Bendel, Anne, French, Pim J., Kros, Johan M., Korshunov, Andrey, Kool, Marcel, Chico Ponce de León, Fernando, Perezpeña-Diazconti, Mario, Lach, Boleslaw, Singh, Sheila K., Leary, Sarah E. S., Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Lee, Ji-Yeoun, Tominaga, Teiji, Weiss, William A., Phillips, Joanna J., Dai, Shizhong, Zadeh, Gelareh, Saad, Ali G., Bognár, László, Klekner, Almos, Pollack, Ian F., Hamilton, Ronald L., Ra, Young-shin, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Thompson, Reid C., Kenney, Anna M., Cooper, Michael K., Mack, Stephen C., Jabado, Nada, Lupien, Mathieu, Gallo, Marco, Ramaswamy, Vijay, Suva, Mario L., Suzuki, Hiromichi, Millen, Kathleen J., Huang, L. Frank, Northcott, Paul A., and Taylor, Michael D.

Abstract

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1as an exquisitely context-dependent driver gene in medulloblastoma.

Published
2025
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24. Supplementary Data 1 from Intratumoral Delivery of Chimeric Antigen Receptor T Cells Targeting CD133 Effectively Treats Brain Metastases

Author

Kieliszek, Agata M., primary, Mobilio, Daniel, primary, Upreti, Deepak, primary, Bloemberg, Darin, primary, Escudero, Laura, primary, Kwiecien, Jacek M., primary, Alizada, Zahra, primary, Zhai, Kui, primary, Ang, Patrick, primary, Chafe, Shawn C., primary, Vora, Parvez, primary, Venugopal, Chitra, primary, and Singh, Sheila K., primary

Published
2024
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26. Contributors

Author

Ahluwalia, Manmeet S., primary, Ahmed, Mohammed, additional, Akbari, Mohsen, additional, Alvarado, Alvaro G., additional, Amereh, Meitham, additional, Angara, Kartik, additional, Arbab, Ali S., additional, Ashley, David M., additional, Atkins, Ryan J., additional, Babikir, Husam A., additional, Bagley, Stephen J., additional, Batich, Kristen A., additional, Battista, Sabrina, additional, Casati, Giacomo, additional, Censullo, Maria Luigia, additional, Cerchia, Laura, additional, Corcoran, Niall M., additional, Cordero, Alex, additional, Das, Sunit, additional, Dastghaib, Sanaz, additional, Declèves, Xavier, additional, Diceglie, Cecilia, additional, Dunne, Nicholas J., additional, Eljarrah, Adam, additional, Fares, Jawad, additional, Fedele, Monica, additional, Friedman, Henry S., additional, Gergues, Marina, additional, Ghavami, Saeid, additional, Giunti, Laura, additional, Guidi, Milena, additional, Gupta, Kshama, additional, Hajiahmadi, Sima, additional, Hara, Akira, additional, Hovens, Christopher M., additional, Idbaih, Ahmed, additional, Iorio, Anna Lisa, additional, Iwama, Toru, additional, Jaloudi, Mohammed, additional, Janaki Ramaiah, M., additional, Jena, Lynn, additional, Kamson, David Olayinka, additional, Kanojia, Deepak, additional, Khasraw, Mustafa, additional, Khela, Harmon Singh, additional, Kinoshita, Takamasa, additional, Kitange, Gaspar J., additional, Kornblum, Harley I., additional, Kutala, Vijay Kumar, additional, Laterra, John, additional, Lee, Hakho, additional, Lee, Sang Y., additional, Lesniak, Maciej S., additional, Liu, James K., additional, Lo Dico, Alessia, additional, Ludwig, Kirsten, additional, Maich, William T., additional, Mantamadiotis, Theo, additional, Martelli, Cristina, additional, Massoud, Tarik F., additional, McCarthy, Helen O., additional, Miyai, Masafumi, additional, Mohammad Naushad, Shaik, additional, Mokarram, Pooneh, additional, Musah-Eroje, Ahmed, additional, Muthukrishnan, Sree Deepthi, additional, Natarajan, Arutselvan, additional, Nikolopoulos, Marina, additional, Ottobrini, Luisa, additional, Paulmurugan, Ramasamy, additional, Prado, David, additional, Rameshwar, Pranela, additional, Rauf, Yasmeen, additional, Reddy Manyam, Rajasekhar, additional, Rombi, Barbara, additional, Salim, Sabra K., additional, Salvatore, Daniela, additional, Sampson, John H., additional, Sardi, Iacopo, additional, Savage, Neil, additional, Savanur, Vibha Harindra, additional, Seyfoori, Amir, additional, Shahsavari, Zahra, additional, Shao, Huilin, additional, Shojaei, Shahla, additional, Singh, Sheila K., additional, Solomou, Georgios, additional, Sordillo, Laura A., additional, Sordillo, Peter P., additional, Stylli, Stanley S., additional, Sukumar, Uday Kumar, additional, Tomita, Hiroyuki, additional, Tomiyama, Arata, additional, Ulasov, Ilya, additional, Venugopal, Chitra, additional, Verreault, Maite, additional, Watts, Colin, additional, Wong, Chi Yan, additional, and Zamani, Mozhdeh, additional

Published
2021
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29. Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells

Author

Vora, Parvez, Seyfrid, Mathieu, Venugopal, Chitra, Qazi, Maleeha A., Salim, Sabra, Isserlin, Ruth, Subapanditha, Minomi, O’Farrell, Erin, Mahendram, Sujeivan, Singh, Mohini, Bakhshinyan, David, Chokshi, Chirayu, McFarlane, Nicole, Dvorkin-Gheva, Anna, Brown, Kevin R., Murty, Naresh, Moffat, Jason, Bader, Gary D., and Singh, Sheila K.

Published
2019
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30. BMI1 is a therapeutic target in recurrent medulloblastoma

Author

Bakhshinyan, David, Venugopal, Chitra, Adile, Ashley A., Garg, Neha, Manoranjan, Branavan, Hallett, Robin, Wang, Xin, Mahendram, Sujeivan, Vora, Parvez, Vijayakumar, Thusyanth, Subapanditha, Minomi, Singh, Mohini, Kameda-Smith, Michelle Masayo, Qazi, Maleeha, McFarlane, Nicole, Mann, Aneet, Ajani, Olufemi A., Yarascavitch, Blake, Ramaswamy, Vijay, Farooq, Hamza, Morrissy, Sorana, Cao, Liangxian, Sydorenko, Nadiya, Baiazitov, Ramil, Du, Wu, Sheedy, Josephine, Weetall, Marla, Moon, Young-Choon, Lee, Chang-Sun, Kwiecien, Jacek M., Delaney, Kathleen H., Doble, Brad, Cho, Yoon-Jae, Mitra, Siddhartha, Kaplan, David, Taylor, Michael D., Davis, Thomas W., and Singh, Sheila K.

Published
2019
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32. EXTH-08. IMMUNOTHERAPEUTIC TARGETING OF FIBROBLAST ACTIVATION PROTEIN (FAP) IN TREATMENT REFRACTORY GLIOBLASTOMA USING NOVEL CAR-T CELL THERAPY

Author

Tatari, Nazanin, primary, Hedad, Hayget Mohamed Seid, additional, Zingg, Andreas, additional, Bartoszek, Ewelina M, additional, Tschan, Viviane J, additional, Schenker, Timo, additional, Ritz, Marie-Françoise, additional, Miletic, Petar, additional, Venugopal, Chitra, additional, Etter, Manina M, additional, Singh, Sheila K, additional, Läubli, Heinz, additional, and Hutter, Gregor, additional

Published
2023
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34. Intratumoral Delivery of Chimeric Antigen Receptor T Cells Targeting CD133 Effectively Treats Brain Metastases

Author

Kieliszek, Agata M., primary, Mobilio, Daniel, additional, Upreti, Deepak, additional, Bloemberg, Darin, additional, Escudero, Laura, additional, Kwiecien, Jacek M., additional, Alizada, Zahra, additional, Zhai, Kui, additional, Ang, Patrick, additional, Chafe, Shawn C., additional, Vora, Parvez, additional, Venugopal, Chitra, additional, and Singh, Sheila K., additional

Published
2023
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35. Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma

Author

Badodi, Sara, Dubuc, Adrian, Zhang, Xinyu, Rosser, Gabriel, Da Cunha Jaeger, Mariane, Kameda-Smith, Michelle M., Morrissy, Anca Sorana, Guilhamon, Paul, Suetterlin, Philipp, Li, Xiao-Nan, Guglielmi, Loredana, Merve, Ashirwad, Farooq, Hamza, Lupien, Mathieu, Singh, Sheila K., Basson, M. Albert, Taylor, Michael D., and Marino, Silvia

Published
2017
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37. Wnt activation as a therapeutic strategy in medulloblastoma

Author

Manoranjan, Branavan, Venugopal, Chitra, Bakhshinyan, David, Adile, Ashley A., Richards, Laura, Kameda-Smith, Michelle M., Whitley, Owen, Dvorkin-Gheva, Anna, Subapanditha, Minomi, Savage, Neil, Tatari, Nazanin, McKenna, Dillon, Bassey-Archibong, Blessing, Winegarden, Neil, Hallett, Robin, Provias, John P., Yarascavitch, Blake, Ajani, Olufemi, Fleming, Adam, Bader, Gary D., Pugh, Trevor J., Doble, Bradley W., and Singh, Sheila K.

Published
2020
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38. 89Zr-labeled ImmunoPET targeting the cancer stem cell antigen CD133 using fully-human antibody constructs.

Author

Wyszatko, Kevin, Janzen, Nancy, Silva, Luis Rafael, Kwon, Luke, Komal, Teesha, Ventura, Manuela, Venugopal, Chitra, Singh, Sheila K., Valliant, John F., and Sadeghi, Saman

Subjects
CANCER stem cells, POSITRON emission tomography, RADIOCHEMICAL purification, FC receptors, BINDING site assay, TUMOR growth, ANTIGENS, MOLECULAR probes
Abstract

Background: Cancer stem cells play an important role in driving tumor growth and treatment resistance, which makes them a promising therapeutic target to prevent cancer recurrence. Emerging cancer stem cell-targeted therapies would benefit from companion diagnostic imaging probes to aid in patient selection and monitoring response to therapy. To this end, zirconium-89-radiolabeled immunoPET probes that target the cancer stem cell-antigen CD133 were developed using fully human antibody and antibody scFv-Fc scaffolds. Results: ImmunoPET probes [89Zr]-DFO-RW03IgG (CA = 0.7 ± 0.1), [89Zr]-DFO-RW03IgG (CA = 3.0 ± 0.3), and [89Zr]-DFO-RW03scFv − Fc (CA = 2.9 ± 0.3) were radiolabeled with zirconium-89 (radiochemical yield 42 ± 5%, 97 ± 2%, 86 ± 12%, respectively) and each was isolated in > 97% radiochemical purity with specific activities of 120 ± 30, 270 ± 90, and 200 ± 60 MBq/mg, respectively. In vitro binding assays showed a low-nanomolar binding affinity of 0.6 to 1.1 nM (95% CI) for DFO-RW03IgG (CA = 0.7 ± 0.1), 0.3 to 1.9 nM (95% CI) for DFO-RW03IgG (CA = 3.0 ± 0.3), and 1.5 to 3.3 nM (95% CI) for DFO-RW03scFv − Fc (C/A = 0.3). Biodistribution studies found that [89Zr]-DFO-RW03scFv − Fc (CA = 2.9 ± 0.3) exhibited the highest tumor uptake (23 ± 4, 21 ± 2, and 23 ± 4%ID/g at 24, 48, and 72 h, respectively) and showed low uptake (< 6%ID/g) in all off-target organs at each timepoint (24, 48, and 72 h). Comparatively, [89Zr]-DFO-RW03IgG (CA = 0.7 ± 0.1) and [89Zr]-DFO-RW03IgG (CA = 3.0 ± 0.3) both reached maximum tumor uptake (16 ± 3%ID/g and 16 ± 2%ID/g, respectively) at 96 h p.i. and showed higher liver uptake (10.2 ± 3%ID/g and 15 ± 3%ID/g, respectively) at that timepoint. Region of interest analysis to assess PET images of mice administered [89Zr]-DFO-RW03scFv − Fc (CA = 2.9 ± 0.3) showed that this probe reached a maximum tumor uptake of 22 ± 1%ID/cc at 96 h, providing a tumor-to-liver ratio that exceeded 1:1 at 48 h p.i. Antibody-antigen mediated tumor uptake was demonstrated through biodistribution and PET imaging studies, where for each probe, co-injection of excess unlabeled RW03IgG resulted in > 60% reduced tumor uptake. Conclusions: Fully human CD133-targeted immunoPET probes [89Zr]-DFO-RW03IgG and [89Zr]-DFO-RW03scFv − Fc accumulate in CD133-expressing tumors to enable their delineation through PET imaging. Having identified [89Zr]-DFO-RW03scFv − Fc (CA = 2.9 ± 0.3) as the most attractive construct for CD133-expressing tumor delineation, the next step is to evaluate this probe using patient-derived tumor models to test its detection limit prior to clinical translation. [ABSTRACT FROM AUTHOR]

Published
2024
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40. SYST-33 GENERATION OF ALLOGENEIC CAR-T CIRCUMVENTS FUNCTIONAL DEFICITS IN PATIENT-DERIVED AUTOLOGOUS PRODUCT FOR GLIOBLASTOMA

Author

Shaikh, Muhammad Vaseem, primary, Salim, Sabra K, additional, Maich, William T, additional, Anand, Alisha, additional, Wei, Jeffrey, additional, Subapanditha, Minomi K, additional, Suk, Yujin, additional, Singh, Manoj, additional, Tabunshchyk, Zoya, additional, Chen, Katie, additional, Vora, Parvez, additional, Venugopal, Chitra, additional, Moffat, Jason, additional, and Singh, Sheila K, additional

Published
2023
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