Hsp90 is a recognized oncogenic signal node whose up regulationactivation is associated with multiple forms of human cancer including 70 percent of all breast cancers. There are 17 Hsp9 inhibitors in clinical development for cancer, including SNX5422, developed by members of our team. In breast cancer, clinical studies have linked activation of Hsp90 and surface expression ectopic of Hsp90 eHsp90 with poor outcomes in malignant breast tumors. We therefore hypothesized that selective targeting of eHsp90 on breast tumors presents an opportunity to not only discriminate indolent tumors from metastatic disease, but also offers a molecularly targeted radiotherapy approach for body wide tumor ablation with low normal tissue toxicity. To test this hypothesis, our laboratories developed a series of PET Positron Emission Tomography enabled tethered Hsp90 inhibitors Ti90s that demonstrate exquisite selectivity in vivo for metastatic breast tumor cells. We also discovered that eHsp90 is rapidly internalized and can carry radionucleotide labeled Ti90 specifically into the breast cancer cell. In this proposal we will optimize conditions that enable two PET enabled Ti90s HS-113 andHS-227 carrying radioiodine 124I and 131I or 211Astatine to be effectively delivered to malignant breast tumors using mouse models of triple negative, ERand HER2 breast cancer. These studies will provide essential proof of concept data to move one or more PET enabled Ti90 into first in human clinical trials. Ultimately, we envisage a process in which a patient, after standard of care breast exam, is first evaluated for malignancy vs. indolent disease by PET imaging using 124I-labeled Ti90. Then, in patients with malignancies detected in high contrast to normal tissues, targeted radiotherapy would be performed at patient-optimized doses of inhibitor labeled with the Beta-emitter 131I or the alpha-emitter 211At.