Optimizing Theranostic Dosimetry and Kidney Biomarkers for Alpha-Emitter Radioligand Therapy in Neuroendocrine Tumors

SUMMARY The somatostatin subtype 2 receptor (SSTR2) is expressed in 80-100% of NETs. SSTR2 targeted alpha-emitter radioligand therapy (α-RLT) is emerging as an exciting alternative to beta-emitter radiopharmaceuticals due to the higher linear energy transfer and dense ionization tracks that result in enhanced formation of double stranded DNA (dsDNA) damage with up to 80% tumor response rates in early clinical studies. However, preclinical studies show that α-RLTs can cause a dose dependent late nephrotoxicity characterized by late tubular injury, fibrosis, and inflammation. Building on recent breakthrough from our group we will test the overall hypothesis that [212Pb]Pb-VMT-α-NET (212Pb-VMT) tumor responses can be maximized through a treatment scheme that incorporates biomarkers of tubular injury, dosimetry, dose fractionation, and a nephroprotective superoxide dismutase mimetic to mitigate nephrotoxicity. In Aim 1, we will develop a detailed understanding of the role of superoxide dismutation in tubular dsDNA repair following [212Pb]Pb-VMT-α-NET treatment. In Aim 2, we will identify [212Pb]Pb-VMT-α-NET dosing regimens to achieve maximal tumor responses and reduce nephrotoxicity using a superoxide dismutase mimetic. We will incorporate the following innovative methods: (1) a novel α-RLT [203Pb/212Pb]Pb-VMT-α-NET theranostic pair targeting SSTR2; (2) innovative SSTR2 expressing tumor models; (3) urine biomarkers for non-invasive detection of tubular injury; (4) dsDNA injury/repair tools to study mechanism of early subclinical tubular dsDNA damage following α -RLT; and (5) a novel nephrotoxicity mitigation strategy based on superoxide scavenging that shows promising tumor response improvement to external beam radiation. If successful, we expect these findings and advances be transferable to a broad range of α-RLTs, not only for pancreatic NETs and neuroblastoma, but also for prostate, breast, melanomas, and other difficult to treat cancers amenable to α-RLT.