Targeting the undruggable: Leveraging neomorphic DNA-binding preferences of chimeric fusion oncogenes to promote cancer suicide

Project Information

Cancer-Harakiri

Grant agreement ID: 101122595

DOI

10.3030/101122595

EC signature date 8 December 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 992 235,00

EU contribution

€ 1 992 235,00

Coordinated by

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

Periodic Reporting for period 1 - Cancer-Harakiri (Targeting the undruggable: Leveraging neomorphic DNA-binding preferences of chimeric fusion oncogenes to promote cancer suicide)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

Children, teenagers, and young adults with aggressive bone and soft-tissue cancers, like Ewing sarcoma (EwS), still have poor chances of survival, especially when the cancer has spread. Current treatments are very harsh, often causing long-term side effects, yet survival rates have barely improved for decades. There are almost no effective therapies for patients with metastatic disease. Safer and more effective treatments are urgently needed. Many of these cancers are driven by abnormal fusion transcriptin factors. These are unique to cancer cells and act as a permanent “on” signal, forcing the tumor to grow uncontrollably. This makes them excellent targets for treatment, but directly blocking these fusion genes has not worked and can sometimes even make the cancer more aggressive.

For our new approach, instead of trying to block these fusion genes, we use their unusual behavior against the cancer itself. We have developed a strategy using a specially designed virus that: only becomes active in cancer cells, not healthy cells. This virus will kill cancer cells from the inside and help the immune system recognize the tumor more effectively. The virus is programmed so that it can only function when the cancer-specific fusion genes are present. Once inside the tumor, it produces a protein that allows doctors to use an already approved antiviral drug to selectively kill cancer cells. Nearby cancer cells are also affected, even if the virus does not enter every single cell.

In early studies in mice, this approach:
• Effectively destroyed EwS and other fusion-gene cancers
• Did not harm healthy tissues
• Worked even when given through the bloodstream
• Used drugs that are already safe and approved

This project will:
• Prepare the therapy so it can be safely produced for use in patients
• Identify additional weaknesses in these cancers to improve treatment
• Expand the approach to other aggressive fusion-gene cancers and prepare for early clinical trials

This is a completely new approach of treating pediatric fusion-driven cancers: using the tumor’s own unique genetic signature to trigger a highly targeted therapy. If successful, it could lead to safer, more effective treatments for children and young adults with deadly cancers like EwS, who currently have very limited options.

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

WP1: Conceptually advance an innovative, highly specific, and versatile virus-based therapy
We have created a new reporter system based on an already published and proven method. This system is specially adapted to EwS. It uses short DNA sequences that attract the cancer-specific fusion gene and activate the system only inside cancer cells. We succesfully tested several versions of this reporter and found the most effective design. This included adjusting factors such as the type of genetic “on switch” used and the number of activating DNA repeats. In addition, we tested different types of virus serotypes to identify the one that works best and most efficiently in killing cancer cells.

WP2: Comprehensively map the oncogenic transcription factor-regulome to identify novel therapeutic vulnerabilities
Five reporter EwS cell lines have been generated to better understand how the oncogenic fusion transcription factor is regulated by other genes. This in vitro model was designed to be applicable across multiple EwS cell lines and use a precise molecular biology technique that enables specific and reliable measurement of transcription factor activity.

WP3: Translate regulome-data into an improved GMP-compliant vector and to other cancers
Building on the reporter system developed in WP1, we are currently expanding this strategy to additional pediatric cancers that are also driven by cancer-specific fusion genes. Similarly as before, different promoters (DNA sequences that activate the genes) and virus serotypes have been tested in additional pediatric sarcomas. Using insights gained from our detailed analysis of gene regulation, we are refining the design of the viral vectors to ensure they meet good manufacturing practice (GMP) standards required for clinical use. The goal of this work package is to improve the safety, reliability, and scalability of the therapy, while demonstrating that this highly targeted approach can be applied beyond EwS to other aggressive childhood cancers.

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)

WP1: Conceptionally advance an innovative, highly specific, and versatile virus-based therapy
We designed and are currently developing a virus that can precisely detect and attack cancer cells in EwS, while leaving healthy cells unharmed. We have already shown that this approach can use the cancer’s own unique signals to turn on the virus only in tumor cells. We are also adding features that help the immune system recognize and fight the tumor, making the therapy stronger and more versatile than traditional virus-based treatments.

WP2: Comprehensively map the OTF-regulome to identify novel therapeutic vulnerabilities
We are mapping exactly how the cancer-driving fusion genes control tumor growth. The molecular biology techniques using for this objective to improve the develop and modify the virus are stable and more reliable than others. By doing this, we can find new points where the cancer is vulnerable and could be safely targeted with therapy. We use a careful, precise method to study these genes in the lab, ensuring our results are reliable and safe.

WP3: Translate regulome-data into an improved GMP-compliant vector and to other cancers
We are working to turn our lab findings into a real, safe therapy that can be produced for clinical use. We also aim to show that this approach could work for other aggressive childhood cancers, not just EwS. By proving its safety, effectiveness, and broader applicability, we hope to attract partners to bring this therapy into clinical trials and eventually to patients.