Tumor recurrence and therapeutic resistance: exploring and exploiting the post-radiotherapy brain microenvironment for therapeutic opportunities in malignant brain tumors

Introduction

Gliomas are the most common brain tumors, and the highest-grade glioma, glioblastoma (GBM), is arguably the most aggressive tumor type, with no long-term survivors. Patients with GBM are treated with radiotherapy, chemotherapy, surgery, and tumor treating fields. Despite initial response, all tumors recur as incurable lesions; there is an urgent need for novel therapeutic approaches for this patient group.

Recurrent Tumor Characteristics

The majority of GBMs recur within the treatment field receiving high-dose radiotherapy during the treatment of the primary tumor. The recurrent tumor thus forms in an irradiated microenvironment. Despite the fact that it is the recurrent tumor that ultimately kills the patient, and that the majority of new therapeutic agents for GBM are tested clinically in the recurrent setting, the majority of experimental models and clinical materials for drug discovery are based on primary disease.

Role of the Tumor Microenvironment

Recent advances have established a central role for the tumor microenvironment in determining the therapeutic response of GBM cells. Our lab demonstrated that standard of care radiotherapy of the primary tumor can shape the microenvironment to generate tumor-supportive conditions in the recurrent tumor. These findings suggest that there is untapped potential in targeting the irradiated microenvironment.

Proposal Objectives

This proposal aims to explore and exploit the recurrent brain tumor microenvironment by:

1. Consolidating the contribution of the irradiated brain tumor microenvironment to GBM resistance by integrating:

   • Spatial transcriptomics
   • Single cell RNA sequencing
   • Multiplexed immunohistochemistry from state-of-the-art murine and human models of GBM treatment and recurrence

2. Discovering and targeting novel therapeutic targets unique to the post-radiotherapy brain tumor microenvironment through high-throughput phenotypic screening.

The ultimate goal is to exploit reversible stromal radiation responses and leverage novel therapeutic opportunities unique to the irradiated brain.