Development and validation of novel drug for medulloblastoma recommended by artificial intelligence
- Abstract
- Medulloblastoma sequencing studies have highlighted the intertumoral molecular heterogeneity underpinning this malignancy, revealing very few recurrently mutated driver genes. Together with the previous study that identified genomic rearrangements in association with mutually exclusive PRDM6 activation in a pediatric patient (PD2107) with medulloblastoma, we investigated whether PRDM6 is a driver gene worthy of pursuit as a candidate for molecular targeted therapy in a significant portion of medulloblastoma patients.
Expression of PRDM6 in the human DAOY Sonic Hedgehog medulloblastoma cell line results in malignant growth and protection from cell death. This capability was revealed based on engineered gene knockdown of the PRDM6 and aberrant up-regulation of the PRDM6 gene in human neuroepithelial stem cells. Loss of PRDM6 results in decreased cell proliferation, and increased apoptosis in DAOY cells. PRDM6 overexpression reverses experimentally induced apoptosis, indicated by the decreased TP53 mRNA levels. In light of the oncogenic potential of PRDM6 reported in our study, its inhibition may be of benefit in PRDM6-activated medulloblastomas. Additionally, as PRDM6 expression is shut off postnatally, which would make it an attractive drug target as PRDM6-selective inhibition should not affect the homeostasis of normal tissues.
As PRDM6 was identified a highly ‘druggable’ target that occurs in a minority of cases, we aimed to discover a high affinity inhibitor using AI-based screening of clinically approved drugs. We found S2181 among the suggested compounds demonstrated superior anti-medulloblastoma activity that mimicked the PRDM6 siRNA-induced cellular responses. Overall, our findings have the potential to increase the percentage of patients amenable to targeted therapy for medulloblastoma.
- Author(s)
- 성현지
- Issued Date
- 2025
- Type
- Thesis
- URI
- https://scholar.gist.ac.kr/handle/local/19104
- Alternative Author(s)
- Seong Hyeonji
- Department
- 대학원 생명과학부
- Advisor
- Williams, Darren
- Table Of Contents
- Abstract
Contents
List of Tables
List of Figures
I. Introduction
II. Materials and Methods
2.1. Cell culture
2.2. siRNA reverse transfection
2.3. Reverse transcription polymerase chain reaction (RT-qPCR)
2.4. Cell proliferation and viability assay
2.5. Immunofluorescent staining
2.6. Western blot
2.7. CRISPR (clustered regularly interspaced short palindromic repeats) activation plasmid transfection
III. Data Availability
IV. Results
4.1. PRDM6 expression across MB subgroups.
4.2. Loss of PRDM6 blocks malignant growth in DAOY cell line.
4.3. Loss of PRDM6 blocks triggers apoptosis in DAOY cell line.
4.4. PRDM6 overexpression provides partial protection from dell death.
4.5. PRDM6 overexpression promotes the growth of DAOY cell line and protects DAOY cell line from apoptosis
4.6. Artificial intelligence (AI) based screen identifies potential therapeutics targeting PRDM 6
4.7. S2181 demonstrates superior anti-MB activity compared to MB clinical drugs
4.8. S2181 mimics siRNA-induced cellular responses
V. Discussion
VI. References
VII.Abstract in Korean (국문요약)
Acknowledgment
- Degree
- Master
-
Appears in Collections:
- Department of Life Sciences > 3. Theses(Master)
- 공개 및 라이선스
-
- 파일 목록
-
Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.