Journal Article

BMI1 is a therapeutic target in recurrent medulloblastoma

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

2019

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 13/106 / 13/109 / 13/31 / 13/51 / 38/77 / 38/90 / 631/45 / 631/67/1922 / 64/60 / 82/80 / 96/34 / Animals / Apoptosis / Brain cancer / Brain tumors / Cancer / Cancer metastasis / Cancer recurrence / Care and treatment / Cell Biology / Cell Line, Tumor / Cell Proliferation - drug effects / Cell self-renewal / Cell Survival - drug effects / Central nervous system / Cerebellar Neoplasms - drug therapy / Cerebellar Neoplasms - genetics / Cerebellar Neoplasms - metabolism / Child / Childhood cancer / Children / Clinical trials / Epigenesis, Genetic / Epigenetic inheritance / Gene Expression Regulation, Neoplastic - drug effects / Genetic aspects / Genomics / Gliomas / Human Genetics / Humans / Internal Medicine / Medical schools / Medicine / Medicine & Public Health / Medulloblastoma / Medulloblastoma - drug therapy / Medulloblastoma - genetics / Medulloblastoma - metabolism / Metastases / Metastasis / Mice / Mortality / Neoplastic Stem Cells - cytology / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - metabolism / Neurotoxicity / Oncology / Palliation / Patients / Pediatrics / Polycomb Repressive Complex 1 - antagonists & inhibitors / Polycomb Repressive Complex 1 - genetics / Recurrence (Disease) / Small Molecule Libraries - administration & dosage / Small Molecule Libraries - pharmacology / Stem cell research / Stem cell transplantation / Stem cells / Surgery / Survival / Therapeutic applications / Treatment Outcome / Tumors / Up-Regulation - drug effects / Vincristine / Xenograft Model Antitumor Assays / Xenografts