Imaging DNA damage response by γH2AX predicts treatment response to Lutetium-177 radioligand therapy and suggests senescence as a therapeutically desirable outcome.

An effective absorbed dose response relationship is yet to be established for Lutetium-177 based radionuclide therapies such as Lu-DOTATATE and Lu-PSMA. The inherent biological heterogeneity of neuroendocrine and prostate cancers may make the prospect of establishing cohort-based dose-response relationships unobtainable. Instead, an individual-based approach, monitoring the dose-response within each tumor could provide the necessary metric to monitor treatment efficacy. We developed a dual isotope SPECT imaging strategy to monitor the change over time in the relationship between Lu-DOTATATE and In-anti-γH2AX-TAT, a modified radiolabelled antibody that allows imaging of DNA double strand breaks, in mice bearing rat pancreatic cancer xenografts. The dynamics of γH2AX foci, apoptosis and senescence following exposure to Lu-DOTATATE was further investigated and in tumor sections. The change in slope of the In-anti-γH2AX-TAT to Lu signal between days 5 and 7 was found to be highly predictive of survival (r = 0.955, P < 0.0001). This pivotal timeframe was investigated further : clonogenic survival correlated with the number of γH2AX foci at day 6 (r = -0.995, P < 0.0005). While there was evidence of continuously low levels of apoptosis, delayed induction of senescence appeared to better account for the γH2AX response to Lu. The induction of senescence was further investigated by analysis and corresponded with sustained retention of Lu within tumor regions. Dual isotope SPECT imaging can provide individualized tumor dose-responses that can be used to predict lutetium-177 treatment efficacy. This bio-dosimeter metric appears to be dependent upon the extent of senescence induction and suggests an integral role that senescence plays in lutetium-177 treatment efficacy.