BMI1 is a therapeutic target in recurrent medulloblastoma

David Bakhshinyan, Chitra Venugopal, Ashley A. Adile, Neha Garg, Branavan Manoranjan, Robin Hallett, Xin Wang, Sujeivan Mahendram, Parvez Vora, Thusyanth Vijayakumar, Minomi Subapanditha, Mohini Singh, Michelle Masayo Kameda-Smith, Maleeha Qazi, Nicole McFarlane, Aneet Mann, Olufemi A. Ajani, Blake Yarascavitch, Vijay Ramaswamy, Hamza Farooq & 18 others Sorana Morrissy, Liangxian Cao, Nadiya Sydorenko, Ramil Baiazitov, Wu Du, Josephine Sheedy, Marla Weetall, Young Choon Moon, Chang Sun Lee, Jacek M. Kwiecien, Kathleen H. Delaney, Brad Doble, Yoon-Jae Cho, Siddhartha Mitra, David Kaplan, Michael D. Taylor, Thomas W. Davis, Sheila K. Singh

Research output: Contribution to journalArticle

Abstract

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

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Medulloblastoma
Neoplasms
Factor IX
Brain Neoplasms
Therapeutics
Transplantation
Clinical Trials
Tumor Burden
Epigenomics
Survival Rate
Central Nervous System
Pediatrics
Recurrence
Survival
Mortality
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Bakhshinyan, D., Venugopal, C., Adile, A. A., Garg, N., Manoranjan, B., Hallett, R., ... Singh, S. K. (Accepted/In press). BMI1 is a therapeutic target in recurrent medulloblastoma. Oncogene. https://doi.org/10.1038/s41388-018-0549-9

BMI1 is a therapeutic target in recurrent medulloblastoma. / 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.; Singh, Sheila K.

In: Oncogene, 01.01.2018.

Research output: Contribution to journalArticle

Bakhshinyan, D, Venugopal, C, Adile, AA, Garg, N, Manoranjan, B, Hallett, R, Wang, X, Mahendram, S, Vora, P, Vijayakumar, T, Subapanditha, M, Singh, M, Kameda-Smith, MM, Qazi, M, McFarlane, N, Mann, A, Ajani, OA, Yarascavitch, B, Ramaswamy, V, Farooq, H, Morrissy, S, Cao, L, Sydorenko, N, Baiazitov, R, Du, W, Sheedy, J, Weetall, M, Moon, YC, Lee, CS, Kwiecien, JM, Delaney, KH, Doble, B, Cho, Y-J, Mitra, S, Kaplan, D, Taylor, MD, Davis, TW & Singh, SK 2018, 'BMI1 is a therapeutic target in recurrent medulloblastoma', Oncogene. https://doi.org/10.1038/s41388-018-0549-9
Bakhshinyan D, Venugopal C, Adile AA, Garg N, Manoranjan B, Hallett R et al. BMI1 is a therapeutic target in recurrent medulloblastoma. Oncogene. 2018 Jan 1. https://doi.org/10.1038/s41388-018-0549-9
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. ; Singh, Sheila K. / BMI1 is a therapeutic target in recurrent medulloblastoma. In: Oncogene. 2018.
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title = "BMI1 is a therapeutic target in recurrent medulloblastoma",
abstract = "Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20{\%} of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80{\%}, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.",
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T1 - BMI1 is a therapeutic target in recurrent medulloblastoma

AU - Bakhshinyan, David

AU - Venugopal, Chitra

AU - Adile, Ashley A.

AU - Garg, Neha

AU - Manoranjan, Branavan

AU - Hallett, Robin

AU - Wang, Xin

AU - Mahendram, Sujeivan

AU - Vora, Parvez

AU - Vijayakumar, Thusyanth

AU - Subapanditha, Minomi

AU - Singh, Mohini

AU - Kameda-Smith, Michelle Masayo

AU - Qazi, Maleeha

AU - McFarlane, Nicole

AU - Mann, Aneet

AU - Ajani, Olufemi A.

AU - Yarascavitch, Blake

AU - Ramaswamy, Vijay

AU - Farooq, Hamza

AU - Morrissy, Sorana

AU - Cao, Liangxian

AU - Sydorenko, Nadiya

AU - Baiazitov, Ramil

AU - Du, Wu

AU - Sheedy, Josephine

AU - Weetall, Marla

AU - Moon, Young Choon

AU - Lee, Chang Sun

AU - Kwiecien, Jacek M.

AU - Delaney, Kathleen H.

AU - Doble, Brad

AU - Cho, Yoon-Jae

AU - Mitra, Siddhartha

AU - Kaplan, David

AU - Taylor, Michael D.

AU - Davis, Thomas W.

AU - Singh, Sheila K.

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