Radioligand therapy (RLT) is rapidly expanding as a systemic radiation modality for metastatic cancer, yet the radiobiology of the FDA-approved radionuclide lutetium-177 and the genetic basis of resistance remain poorly defined. Emerging clinical ctDNA studies suggest that resistance can arise without new canonical driver mutations and may instead involve shifts in chromosome copy number, but current assays often cannot resolve how Lu shapes karyotypic evolution over treatment. This ASPIRE Award addresses the overarching question of how prolonged, low-dose-rate Lu exposure drives chromosomal instability and aneuploidy, and whether these genome-level changes promote tumor cell fitness and therapeutic escape, a critical need given the frequency of progression within months of treatment.
The team will model Lu selection in androgen-sensitive and -insensitive prostate cancer cells, tracking emerging resistant populations over multiple radionuclide half-lives and performing single-cell and clone sequencing to map recurrent copy number alterations, benchmarked against patient ctDNA trajectories. In parallel, they will run pooled, barcoded gain-of-function screens spanning ~2,100 oncogenic alterations in genetically defined epithelial models to identify mutations and pathways that confer Lu sensitivity or resistance, followed by focused validation with clonogenic assays and DNA damage-response readouts. Together, these complementary approaches aim to deliver mechanistic insight and candidate biomarkers to guide patient selection and combination strategies, with broad relevance as new Lu-based RLTs enter trials across tumor types.