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

Informations projet

ReverseTheAdvantage

N° de convention de subvention: 101082238

DOI

10.3030/101082238

Projet clôturé

Date de signature de la CE 8 Juillet 2022

Date de début 1 Août 2022

Date de fin 31 Janvier 2024

Financé au titre de

• European Research Council (ERC)

Coût total

Aucune donnée

Contribution de l’UE

€ 150 000,00

Coordonné par

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)

Période du rapport: 2022-08-01 au 2024-01-31

Résumé du contexte et des objectifs généraux du projet

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

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

- 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.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

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.