PROJECT SUMMARY/ABSTRACT We propose to evaluate a novel αvβ6 integrin molecularly targeted theranostic approach for the detection and treatment of metastatic cancers. The αvβ6 integrin is a cell surface receptor that is low or undetectable in normal adult epithelium but is widely expressed on numerous carcinomas. There is a statistically significant association between the high expression of the αvβ6 integrin, distant spread, and poor survival. We previously developed an αvβ6 -Binding Peptide (BP) with nanomolar affinity and high selectivity for the integrin αvβ66. Our prior clinical data demonstrates that using [18F]-αvβ6 -BP PET/CT imaging we can detect both primary tumors and metastases. PET images showed low background uptake in normal brain, lungs, liver, and osseous skeleton which are common sites of metastatic disease. Furthermore, sub-centimeter metastases to these organs were detected using [18F]αvβ6 -BP PET/CT. We further developed our αvβ6-BP into a novel theranostic pair, [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G in which [68Ga]Ga DOTA-5G is being developed as a diagnostic and [177Lu]Lu DOTA-ABM-5G is being developed as a radiotherapy. We now propose a prospective clinical trial to test the [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G in patients with metastatic disease. Patients will undergo [68Ga]Ga DOTA-5G PET/CT scans to confirm eligibility for the [177Lu]Lu DOTA-ABM-5G therapy and follow up [68Ga]Ga DOTA-5G PET/CT scans to evaluate treatment response. We hypothesize that a) [68Ga]Ga DOTA-5G will detect lesions in patients with metastatic cancers b) the theranostic pair [68Ga]Ga DOTA-5G/ [177Lu]Lu DOTA-ABM-5G will be safe and well tolerated; and c) a therapeutic response will be achieved with a single dose of [177Lu]Lu DOTA-ABM-5G. This proposal leverages the complimentary expertise of Dr. Sutcliffe to develop and translate the theranostic agents, and Dr. Foster to treat patients and interpret images for treatment response. The ability of the Sutcliffe lab to generate the theranostic agents in this study for patients treated at UC Davis maximizes existing resources and a well-established successful collaboration between the PIs, increasing the speed of translation of these theranostic agents from research to Phase II trials and ultimately, a standard of care option for patients with metastatic disease. Given the role of the αvβ6 integrin receptor in the processes of invasion and metastasis, αvβ6 is a very attractive target for the detection and treatment of metastatic cancers and could have broad impact across multiple cancers. [68Ga]Ga DOTA-5G will more accurately and non-invasively detect disease and the promising pharmacokinetic profile of the theranostics proposed suggests that off-target toxicity of this [177Lu]Lu DOTA-ABM-5G therapy is not expected. This poses a major improvement over current treatments that are known to cause bone marrow toxicity, hepatobiliary toxicity, and cardiotoxicity. Collectively, this proposal will s...