# Small Molecule Cocktail DLC79 Suppresses Gliomagenesis by Activating Ascl1 and Remodeling Transcriptome

## TL;DR

A drug cocktail called DLC79 reprograms glioma cells into neuron-like cells, reducing tumor growth and offering a new therapy approach for glioblastoma.

## Contribution

DLC79 is a novel small-molecule cocktail that pharmacologically reprograms glioma cells via ASCL1 activation, suppressing tumor growth and promoting neuronal differentiation.

## Key findings

- DLC79 activates ASCL1 and reprograms glioma cells into neuron-like cells with upregulated neuronal markers.
- DLC79 treatment inhibits glioma cell proliferation, migration, invasion, and clonogenicity in vitro.
- In a xenograft model, DLC79 pretreatment reduced tumor bioluminescence by 56% and tumor mass by 47%.

## Abstract

What are the main findings?
A small molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) activates endogenous Ascl1 as a key drug target and remodels transcriptional identity, inducing the pharmacological reprogramming of glioma cells to neuron-like cells.DLC79 suppresses oncogenic behaviors (proliferation, migration, and invasion) and tumorigenicity in vivo.

A small molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) activates endogenous Ascl1 as a key drug target and remodels transcriptional identity, inducing the pharmacological reprogramming of glioma cells to neuron-like cells.

DLC79 suppresses oncogenic behaviors (proliferation, migration, and invasion) and tumorigenicity in vivo.

What are the implications of the main findings?
By suppressing tumorigenicity while promoting neuronal differentiation, this approach may open new avenues for glioma therapy.As a small-molecule-based cocktail, DLC79, exemplifies a feasible pharmacological strategy for reprogramming-based therapy, contributing to drug discovery.

By suppressing tumorigenicity while promoting neuronal differentiation, this approach may open new avenues for glioma therapy.

As a small-molecule-based cocktail, DLC79, exemplifies a feasible pharmacological strategy for reprogramming-based therapy, contributing to drug discovery.

Glioblastoma (GBM) remains incurable due to its invasive growth and therapeutic resistance. While the neurogenic transcription factor-mediated reprogramming of glioma cells has been reported, pharmacological reprogramming offers a promising alternative due to its potential advantages for clinical translation. Using phenotype-driven screening, we identified a multi-target small-molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) that effectively reprograms human glioma cells into neuron-like cells by activating endogenous ASCL1 (174.4-fold) and remodeling the transcriptional landscape. This conversion led to the strong upregulation of neuronal markers (e.g., MAP2 and GAD67) and suppression of glial identity. Functionally, DLC79 treatment inhibited glioma malignancy in vitro, impairing proliferation, migration, invasion, and clonogenicity. In a subcutaneous xenograft model, brief pretreatment with DLC79 significantly attenuated the tumorigenic potential of glioma cells, reducing tumor bioluminescence by 56% and tumor mass by 47%. Our study establishes pharmacological reprogramming as a promising anti-glioma strategy that leverages neuronal conversion to reduce oncogenic properties, thereby initiating a novel therapeutic paradigm.