Imaging biomarkers for the modulation of the hypoxic tumor microenvironment

Hypoxia, a frequent phenomenon in solid tumors, is associated with chemoradiotherapy resistance. However, most efforts to target or overcome tumor hypoxia have yielded equivocal results due to the lack of biomarkers for appropriate patient selection. The use of non-invasive molecular imaging such as positron emission tomography (PET) may have some advantages over traditional tissue-based biomarkers, such as the capacity to follow up the entire tumor mass longitudinally and evaluate drug efficacy early in the course of therapy. Thus, radiotracers that specifically accumulate in hypoxic cells have been developed, such as [18F]fluoromisonidazole ([18F]FMISO) and [18F]flortanidazole ([18F]HX4). A hypoxia PET scan could not only be used to image hypoxia and assess a patient’s prognosis, it also holds potential as a predictive marker for patient selection and therapy response, thereby enabling personalized medicine. Therefore, our aim is to validate [18F]FMISO and [18F]HX4 PET as imaging biomarkers for hypoxia-targeting therapy combinations in preclinical studies that simulate the concept of precision medicine. We investigated [18F]FMISO PET as a biomarker for a combination therapy of the hypoxia-inducible factor 1 (HIF-1) inhibitor PX-12 and standard 5-fluorouracil chemotherapy in a colorectal cancer xenograft model. In this study, [18F]FMISO could predict that more hypoxic tumors were resistant to chemotherapy and that this resistance could be alleviated by PX-12. We also investigated metformin as a radiosensitizer in a lung cancer xenograft model. Using [18F]HX4 PET, we showed that metformin could decrease tumor hypoxia with 10%, thereby sensitizing tumors to the effects of radiotherapy. These radiosensitizing effects depended on the baseline degree of hypoxia as assessed with [18F]HX4, which validated this hypoxia tracer as a predictive biomarker within this setup. Remarkably, this predictive potential of [18F]HX4 could not be observed in a similar study in a colorectal cancer model, which is most probably due to metformin’s cell-line dependent working mechanisms. Importantly however, regardless of its predictive properties, [18F]HX4 PET could be validated as a prognostic biomarker in both the colorectal cancer and lung cancer model. Our translational experimental results add to the ongoing validation of hypoxia PET as a predictive and prognostic biomarker. Although further research is warranted, we are optimistic that the investigated molecular imaging tools, which are currently also under investigation in different clinical trials, have the potential to eventually become a standard part of drug research or even routine clinical practice, in this way leading to precision medicine and improved quality of life for cancer patients.

Jaar van publicatie:2019

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open