– Hi-ROC

Hypoxia in tumors and their microenvironments significantly contributes to resistance against photon-
based radiotherapy in many solid cancers. In this context, heavy ion RT, especially carbon ion RT (CIRT), is
becoming increasingly a pivotal approach due to its superior efficacy in targeting hypoxia tumors compared
to photon RT. However, RT protocols typically prioritize factors like tumor stage and histotype over specific
traits such as hypoxia when selecting treatments. While this approach streamlines therapeutic decisions, it
falls short of achieving the best therapeutic results for patients. A significant challenge hindering
personalized approaches in selecting patients for CIRT is the lack of a comprehensive non-invasive
diagnostic/predictive biomarker. Our collaborative translational project (Hi-ROC) focuses on establishing a
multimodal and comprehensive non-invasive biomarker/signature for identifying hypoxia at the individual
level. This will involve comparing genetic, transcriptomic, microbiota, cellular, microcirculation, and imaging
features of patients with unresectable locally advanced lung cancer, high-risk head and neck cancer, and
large operable retroperitoneal soft tissue sarcoma who were either cured or not cured by photon RT. The
biomarker will be used in a pilot study to select patients for either CIRT or photon RT, assessing the viability
of the potential for future clinical trials. Additionally, we will develop a Beta-Prototype for an in vitro
medical device for non-invasive determination of clinically relevant hypoxia. Our project also entails
deepening our understanding of hypoxia mechanisms through in vitro experiments and optimizing an in-
silico platform to assess the potential of advanced RT techniques and technologies (beyond C-ions) in
overcoming hypoxia. Finally, we will explore the use of feasibility and potential of digital twins in
personalized radiation oncology, representing a new generation of biomarkers.