Using Whole Genome Bisulfite Sequencing to Identify Novel Therapeutic Targets in DIPG and ATRT

Email Principal Investigator
Ongoing
Specimen
Atypical teratoid/rhabdoid tumor (AT/RT)
DIPG
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Eric Raabe

Johns Hopkins Medicine
Baltimore, MD, USA
71

CBTN Participants

CBTN Pre-clinical Models Used

About this

Project

DIPG and ATRT are epigeneitcally driven diseases with poor outcomes. New therapies are desperately needed. The lack of drugable mutations and intra and intertumoral heterogeneity as well as the cancer stem cell characteristics of these tumors are barriers to target identification and deployment of novel drugs. Recent work in a variety of cancer types, including ATRT and DIPG, has pointed to a critical role of epigenetic dysregulation such as altered DNA methylation. Furthermore, recent evidence suggests that increased epigenetic variation in cancer may underlie phenotypic plasticity and resistance to therapy. Feinberg and colleagues have recently formalized a novel framework for analyzing variability of DNA methylation directly from whole-genome bisulfite sequencing data by modeling stochastic Markov processes, allowing rigorous computation of DNA methylation entropy at precise genomic locations (Jenkinson et al, Nature Genetics 49: 719-29, 2017). The degree of methylation variation (entropy) at key promoters predicts the degree to which a cancer relies on a given gene. Our preliminary evidence confirms increased DNA methylation entropy as a fundamental property ATRT and DIPG. We hypothesize that dissection of the genomic targets and biological pathways affected by methylation entropy will identify gene regulatory networks responsible for the aggressive and therapy resistance phenotypes of ATRT and DIPG, thereby identifying new targets for therapy.

Ask The

Scientists

Ask the scientists

What are the goals of this project?

The goals of this project are to perform WGBS at single base resolution on ATRT tumors and to perform WGBS at single base resolution on DIPG tumors.

What is the impact of this project?

Hopkins is a member of both CBTN and PNOC and the PI is a member of the DMG-ACT and ATRT pre-clinical and clinical trial groups. Data discovered in this effort will be available to CBTTC and PNOC partners and we anticipate will inform the PNOC clinical trials for DIPG and ATRT.

Why the CBTN request is important to this project?

CBTN has the largest collection of these specimens in the world to our knowledge. Access to CBTN specimens and data will allow us to propel target discovery and validation in these two diseases.

Specimen Data

The Children's Brain Tumor Network contributed to this project by providing tumor DNA and cell lines.