Therapy-Associated Lineage Plasticity in DIPG Following Combined CDK4/6 Inhibitor, Temozolomide, and Radiation

Area of Science:

• Oncology
• Pediatric Neuro-oncology
• Cancer Therapeutics

Background:

• Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor with limited treatment options.
• Understanding treatment response and cell plasticity in distinct DIPG backgrounds is crucial for therapeutic advancement.

Purpose of the Study:

• To evaluate the efficacy of a triple therapy (abemaciclib, temozolomide, radiation) in patient-derived DIPG models.
• To investigate therapy-associated residual cell-state changes and identify potential resistance mechanisms.

Main Methods:

• Utilized two patient-derived orthotopic xenograft (PDOX) models of DIPG, one treatment-naïve and one previously treated.
• Assessed treatment activity in PDOX-derived organoids and conducted randomized PDOX studies.
• Employed survival analysis, immunohistochemistry, and single-cell RNA sequencing (scRNA-seq) for comprehensive evaluation.

Main Results:

• The triple therapy demonstrated synergistic antitumor effects and significantly prolonged survival in both DIPG PDOX models.
• scRNA-seq revealed alterations in cell populations, including reduced oligodendrocyte-progenitor-like (OPC-like) cells and distinct therapy-tolerant states.
• Identified a radiation-resistance-associated subpopulation with potential radiosensitization targets (NPAS3, TBC1D15, INPP4B).

Conclusions:

• Combined abemaciclib, temozolomide, and radiation therapy offers survival benefits in clinically distinct DIPG models.
• Therapy-induced cell-state changes provide insights into residual disease and resistance mechanisms.
• Findings may guide future strategies for achieving durable DIPG tumor control.