[177Lu]Lu-PSMA-617

Recent Findings on [177Lu]Lu-PSMA-617 — latest 30 papers

These five publications span preclinical platform development, biomarker discovery, and safety management, with [177Lu]Lu-PSMA-617 serving primarily as the clinical benchmark or reference therapy against which new agents and assays are measured.

Two preclinical studies used [177Lu]Lu-PSMA-617 as a head-to-head comparator for novel PSMA-targeted radioligand designs. A programmable outer membrane vesicle platform displaying lanmodulin (TRT@LnOMVs), derived from attenuated Salmonella typhimurium, enabled chelator-free radiolabeling of diverse isotopes and, when PSMA-targeted, produced a 90% survival rate in a prostate cancer model versus 25% for [177Lu]Lu-PSMA-617; single-cell RNA sequencing and transcriptomic profiling attributed the gain to remodeling of the tumor immune microenvironment through reprogramming of immunosuppressive myeloid cells 42263768Jun. A separate medicinal-chemistry effort conjugated the oral absorption enhancer SNAC to PSMA ligands bearing quinoline or naphthalene linkers, yielding three candidates radiolabeled with 68Ga and 177Lu at greater than 98% radiochemical purity; the lead compound PDB3-1 showed the highest PSMA affinity (IC50 19.1 nM), and [177Lu]Lu-PDB3-1 achieved tumor inhibition and survival benefit comparable to [177Lu]Lu-PSMA-617 at a reduced 9.25 MBq dose, with 111 MBq tolerated without notable histopathologic findings 42126983May.

The clinical work centers on the problem of response heterogeneity in metastatic castration-resistant prostate cancer (mCRPC), where the survival benefit established in the VISION trial is not uniformly realized and resistance mechanisms remain poorly characterized 42054640Apr. A prospective, longitudinal multicenter observational protocol was designed to evaluate liquid biopsy — particularly circulating tumor DNA — as a minimally invasive means of assessing tumor heterogeneity, monitoring response, and detecting emerging resistance during PSMA radioligand therapy 42054640Apr.

Complementary biomarker results came from a prospective cohort of 100 mCRPC patients treated with [177Lu]Lu-PSMA-617, in which shotgun proteomics of plasma-derived extracellular vesicles identified 5,137 proteins alongside enumeration of PSMA-positive circulating tumor cells 42013849Apr. High levels of the cell-surface targets PSMA, B7-H3, Trop-2, and STEAP1 on extracellular vesicles associated with worse overall survival, and all four correlated positively with molecular tumor volume on PSMA-PET, serum PSA, and alkaline phosphatase. Circulating tumor cell subpopulations, including PSMA+/EpCAM+ and PSMA−/EpCAM+ cells, associated with worse progression-free and overall survival, while pathway analysis linked p53 upregulation to poor outcomes and, unexpectedly, an activated E2F pathway to better progression-free and overall survival — findings positioned as support for embedding liquid biopsy proteomics into biomarker-driven trials 42013849Apr.

Administration safety was addressed through a dosimetric analysis of extravasation, an uncommon but potentially injurious complication of therapeutic radioligands including [177Lu]Lu-PSMA-617 and [177Lu]Lu-DOTATATE, for which no standardized management guidelines exist 41985532Apr. Two patients managed conservatively with manual massage, warmth, and arm elevation were assessed by quantitative SPECT/CT with three to four early acquisitions within six hours plus imaging at 24 and beyond 48 hours; absorbed doses were computed in threshold-based sub-volumes using mono-exponential fitting, with a pipeline combining deep learning–based CT segmentation, anatomy-guided partial volume correction, and Monte Carlo dose computation. Systemic dosimetry of organs at risk and metabolic tumor volume was evaluated in both patients and, in one, compared between extravasated and uneventful cycles, supporting an evidence-based case for conservative management 41985532Apr.