Reversing the advantage of cancers with Hypoxia and Homologous Recombination Defect (HRD) by using a pan-cancer, composite, lesions-specific biomarker

Project Information

ReverseTheAdvantage

Grant agreement ID: 101082238

DOI

10.3030/101082238

Project closed

EC signature date 8 July 2022

Start date 1 August 2022

End date 31 January 2024

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

UNIVERSITEIT MAASTRICHT
Netherlands

Periodic Reporting for period 1 - ReverseTheAdvantage (Reversing the advantage of cancers with Hypoxia and Homologous Recombination Defect (HRD) by using a pan-cancer, composite, lesions-specific biomarker)

Reporting period: 2022-08-01 to 2024-01-31

Summary of the context and overall objectives of the project

Deficiencies in certain DNA repair pathways ensure that anti-cancer treatments become more effective. This is exemplified by our previous research showing that tumors with a deficiency in homologous recombination (HR) DNA repair react much better to hypoxia activated prodrug CP-506 targeting the therapy-resistant hypoxic tumor areas. It is therefore key to identify these patients for which this treatment has higher chances of success.

The objective of this project is:
1) to develop a biomarker combining levels of hypoxia (a key requisite for CP-506 efficacy) and HR Deficiency (HRD) based on whole genome sequencing
2) test this combined biomarker preclinically in an independent tumor dataset for different anti-cancer treatments
3) develop a strong IP portfolio
4) make a business plan and perform a market

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

- As whole genome sequencing did not stratify properly tumors with or without HRD, a different strategy was applied in order to stratify HRD tumors. Based on previous experience, we developed a combined handcrafted radiomics and deep learning model showing high performance in predicting HRD (AUC 0.87). See technical report for details and figures.
- Currently we are looking to validate this HRD signature in clinical datasets before starting the development of the combined biomarker. Levels of hypoxia are available for the models used for the design of the HRD signature.
- Any other activities described in the project proposal are delayed until clinical validation.

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)

The decision to develop an HRD signature will have huge impact in the future at an economical and societal level. All cancer patients undergo a diagnostic CT before their treatment, therefore this information is available without any additional cost to predict HRD using our developed signature. Total costs will be significantly lower in order to predict HRD compared with the currently validated whole genome sequencing method. In addition, as the model can predict HRD very fast, time between cancer diagnosis and HRD confirmation (currently, a biopsy has to be taken, shipped to genomic centers to execute sequencing and analysis) will be shortened significantly. Patients can be stratified for a certain anti-cancer treatment much faster, possibly resulting in better treatment outcome.