Is a PARP1 targeted imaging agent a predictive marker for radiotherapy success and how does it perform in comparison to 18F-FDG imaging?

• Applicant: Professorin Susanne Kossatz, Ph.D.
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265100635

Tumor monitoring by the assessment of glucose uptake using FDG-PET is an established standard methods in clinical practice. However, in a certain subpopulation of patients a decrease in glucose uptake after radiotherapy is followed by a fast relapse. We believe that these tumors have become invisible for FDG-PET in course of radiotherapy and the associated reduction of tumor metabolism, although they continue to exist. A termination of therapy at this point would be fatal for the patient, therefore we want to investigate the responsible mechanism to improve the chances to identify this subpopulation of patients and be able to assign them to their most appropriate treatment group. Radiotherapy leads to the expression and activation of the enzyme PARP1, which is important for the repair of the radiotherapy related DNA damage in cancer cells. According to our hypothesis, subsequently an under-supply of the cofactor NAD can occur leading to the inhibition of glucose uptake without inevitably leading to cell death. Hence, cells become undetectable for FDG-PET, because FDG, equally to glucose, needs NAD to be trapped inside of cells. Our investigations aim to verify and characterize these processes in vitro and in vivo to improve therapy monitoring after radiotherapy in the future. Furthermore, we want to elucidate if PARP1 targeted tracers are suitable to assess the outcome of radiotherapy. Subject of the investigations will be the PARP1 inhibitor iPARP, which is derived from Olaparib, a PARP1 inhibitor which momentarily is investigated in clinical studies as therapeutic molecule. In our study, PARPi will be subjected to fluorescence imaging after conjugation of the fluorochrome Bodipy Fl (iPARP) and PET (18F-iPARP) as high affinity, small molecule imaging agent. The decisive processes will first be investigated in vitro, where we will assess the influence of radiotherapy of cells on FDG uptake, PARP1 expression, iPARP uptake and the availability of NAD, to find the exact correlations of these parameters. In the vivo investigations tumor bearing animals will be treated will intensity modulated radiotherapy. Subsequently, we will conduct real time fluorescence microscopy of the tumors using the dorsal window chamber model after injection on iPARP to assess the PARP1 expression and find correlations to the corresponding FDG uptake (FDG-PET) and the availability of NAD (hyperpolarized magnetic resonance imaging). We believe that PARP1 tracers are ideal tools to ultimately determine during clinical imaging, if tumor cells are active or not following radiotherapy.

• DFG Programme: Research Fellowships
• International Connection: USA