Somatostatin receptor 2 (SSTR2)

Class

targeted radiopharmaceutical (radioligand therapy); actinium-225 (Ac-225)-labeled DOTATATE, an alpha-particle-emitting radioisotope chelated (via DOTA) to the somatostatin analog octreotate (TATE); developed by RayzeBio (Bristol Myers Squibb)

Pathway

binds with high affinity and selectivity to SSTR2 on the tumor cell surface, is internalized, and the alpha-particle emission from Ac-225 causes lethal double-strand DNA breaks less amenable to cellular repair than beta-emitter radioligands; in HR+/HER2- breast cancer the TRACY-1 study targets tumors that co-express SSTR2 and have progressed after antibody-drug conjugates and/or chemotherapy

Somatostatin receptor 2 (SSTR2) is a G protein–coupled receptor normally activated by the hormone somatostatin, which regulates secretion of growth hormone and other peptides. Many neuroendocrine tumors, and some other cancers, display unusually high SSTR2 density on their cell surface, making the receptor a convenient handle for tumor-selective drug delivery. This mechanism exploits that biology: a somatostatin-mimicking peptide (octreotate) is chemically linked, through a metal-binding cage called DOTA, to a radioactive atom. When the peptide binds SSTR2, the receptor-ligand complex is drawn inside the cell, carrying the radioisotope with it. The isotope used here emits alpha particles, a form of radiation that travels only a few cell widths but deposits its energy densely, producing DNA damage that is difficult for cells to repair. Because normal tissue exposure is limited mainly to cells that also express SSTR2, this approach aims to concentrate cytotoxic radiation in tumor tissue while sparing much of the rest of the body. This mechanism is broadly relevant to neuroendocrine tumors, where SSTR2 expression is a defining feature, and is being explored in other cancers where SSTR2 is present alongside standard tumor markers.