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

Project Information

RESISTANCEPROGRAMS

Grant agreement ID: 101043587

DOI

10.3030/101043587

EC signature date 11 April 2022

Start date 1 September 2022

End date 31 August 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 999 444,00

EU contribution

€ 1 999 444,00

Coordinated by

LUNDS UNIVERSITET
Sweden

Periodic Reporting for period 1 - RESISTANCEPROGRAMS (Tumor recurrence and therapeutic resistance: exploring and exploiting the post-radiotherapy brain microenvironment for therapeutic opportunities in malignant brain tumors)

Reporting period: 2022-09-01 to 2025-02-28

Summary of the context and overall objectives of the project

This research project centers on glioblastoma (GBM), the most severe and aggressive form of brain cancer, with very limited treatment success and no cure. The study identifies the critical need for new treatment approaches for GBM, especially given that most current therapies, including surgery, radiotherapy, chemotherapy, and tumor treating fields, ultimately fail as tumors invariably recur in an aggressive, incurable form. Interestingly, most recurrent GBMs re-emerge in the same areas that received high-dose radiotherapy, creating a unique post-treatment, irradiated tumor microenvironment (TME) that potentially influences the recurrence and progression of the disease.

This project aims to address the gap in GBM research by focusing specifically on the irradiated microenvironment of recurrent tumors, rather than the primary tumor state that has traditionally been the main focus of drug discovery and testing. Recognizing that the TME plays a central role in how GBM cells respond to treatments, this research proposes two primary objectives. The first goal is to delineate the specific cellular elements within the irradiated TME that contribute to GBM resistance by using advanced techniques like single-cell RNA sequencing, spatial transcriptomics, and multiplexed immunohistochemistry. This approach seeks to identify both supportive and restrictive cellular interactions within the irradiated brain environment. The second objective is to discover novel therapeutic targets within this irradiated TME through mapping cellular interactions and conducting high-throughput screening of drug repurposing libraries, aiming to find interventions that could modify or reverse radiation-induced support structures within the TME.

The anticipated impact of this research is substantial, as it proposes a unique therapeutic strategy by focusing on the post-radiotherapy TME, which could lead to the development of treatments specifically targeting the recurrent tumor’s supportive environment. By understanding and manipulating the irradiated TME, this project hopes to pave the way for therapies that can overcome resistance mechanisms in recurrent GBM, potentially offering a significant advancement in treating this otherwise lethal cancer.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have developed a detailed protocol to grow tumors in mice, irradiate them, and then collect samples from healthy brain tissue, primary tumors, and recurrent tumors. By analyzing these samples at the single-cell level, we are mapping out the unique cell types within each type of tissue. This includes comparing the makeup of immune cells in healthy brains, primary tumors, and recurrent tumors. Notably, immune cells seem to play a major role in making the GBM environment suppressive to the immune system, which may drive tumor regrowth. The team has also begun to identify where specific cell interactions occur within the tumor, using spatial mapping techniques. This will help pinpoint which cell types work together in ways that could contribute to the tumor’s resistance to treatment. We are also setting up methods to analyze these spatial relationships more closely.

To advance treatment options, we have developed a new way to test drugs that can affect astrocytes, cells that become more reactive following radiation. A promising discovery from these tests was that flunarizine, an anti-migraine drug, improved the survival of mice with GBM post-radiotherapy. However, it had no impact on mice that did not receive radiation, suggesting it specifically affects cells altered by radiation.

Moving forward, we plan to continue studying flunarizine’s effects on GBM in detail, with the goal of potentially repurposing it as a treatment for human patients with recurrent GBM. The data gathered from this study will eventually be shared as a public resource, providing insights into how radiotherapy changes the tumor environment and guiding future GBM treatments.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This research holds the potential to transform glioblastoma (GBM) treatment by targeting the changes that occur within the tumor microenvironment following radiotherapy. By examining the unique interactions between tumor cells and other cells in this irradiated environment, the study could uncover mechanisms driving GBM resistance and recurrence, ultimately paving the way for new therapies that might prolong survival and improve quality of life for patients facing this aggressive cancer. Specifically, the discovery that flunarizine, a common anti-migraine medication, may extend survival in irradiated GBM models is particularly promising. If validated, this finding could lead to a cost-effective, readily available therapeutic option, significantly broadening treatment possibilities for GBM patients who currently have very limited options.

Furthermore, the comprehensive cellular mapping and spatial analysis generated by this research will be valuable resources for the wider scientific community, fostering additional studies on the radiotherapy-induced tumor microenvironment in GBM and other cancers. This work could stimulate research into similar radiation-focused treatment strategies across multiple cancer types, potentially leading to new avenues for combating recurrence.

However, before this approach can reach clinical application, further preclinical validation is essential to confirm both the effectiveness and safety of potential therapeutic candidates like flunarizine. Comprehensive studies are needed to better understand its mechanisms of action within the irradiated tumor environment, ensure it can cross the blood-brain barrier effectively, and assess its impact in varied and more complex GBM models. This additional preclinical work will be crucial in preparing for eventual clinical trials and translating these promising findings into tangible treatments for GBM patients.