Year: 2019
Type: dissertation
Abstract: Pineoblastoma is a WHO IV tumour of the pineal gland affecting primarily children. Five-year overall survival (OS) is 54%, and this level significantly drops to 15% in children ≤ 5 years old. Thus, there is an urgent need to understand the biology of pineoblastoma and identify therapeutic targets to improve OS and quality of life. Germline mutations in RB1 have been implicated in the etiology of pineoblastoma. Patients with familial retinoblastoma, which carry RB1-germline mutation, develop pineoblastoma, termed “trilateral retinoblastoma”. Here, I used a WAP-Cre transgenic line to inactivate murine Rb and p53 in the pineal gland, and showed that WAP-Cre:Rbflox/flox:p53flox/flox and WAP-Cre:Rbflox/flox:p53LSLR270H/flox mice develop pineoblastoma with 100% penetrance. These tumours readily metastasized to leptomeningeal surfaces of brain and spinal cord. Rb/p53-deficient pineoblastomas exhibited features of human pineoblastoma including pleomorphic nuclei, scant cytoplasm and rosettes structures. Furthermore, transcriptome analysis revealed that Rb/p53-deficient pineoblastomas clustered close to human pineoblastoma. In silico drug screens using Connectivity map drug perturbation signatures identified several cationic amphiphilic drugs including nortriptyline as top candidate drugs against Rb/p53-deficient pineoblastomas. Nortriptyline suppressed tumour growth in vitro and in vivo, and synergized with gemcitabine, an anti-neoplastic drug currently used in clinics to effectively kill pineoblastoma in preclinical models. Nortriptyline induced lysosomal membrane permeability leading to secretion of cathepsin B into cytosol and inhibition of autophagic flux. This study describes novel mouse models that spontaneously form pineoblastoma and identifies nortriptyline as a potential new therapeutic for patients with pineoblastoma.
Source: TSpace (University of Toronto)
Author: Eu Ddeum Chung
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3141664285