Systematic Testing of a TGFβ Targeted Theranostic in Preclinical Cancer - ABSTRACT Radiopharmaceutical therapy (RPT) has received approval for the treatment of thyroid (131I), neuroendocrine (177Lu-Dotatate), neuroblastoma (131I-MIBG), lymphomas (90Y-antiCD20, 131I-anti-CD20), and prostate cancers (223Ra, 177Lu-PSMA). The efficacy of targeted RPT for these cancers has motivated RPT approaches that broaden its use in other patient populations. A tumor-agnostic theranostic in which the patient selection is based on validated target by positron emission tomography (PET) would be highly desirable. Transforming growth factor β (TGFβ) is controlled by a highly regulated process of extracellular activation, which is tightly controlled in normal tissue and highly dysregulated in cancer, thus providing a favorable tumor to tissue differential that can be exploited for the delivery of a therapeutic isotope. We propose that TGFβ activity is a promising target for a tumor-agnostic theranostic. We demonstrated specific detection of TGFβ activation in breast, brain, and lung cancer modus using 89Zr-labeled TGFβ neutralizing antibody for PET imaging. Here, we aim to leverage our deep knowledge of TGFβ biology and the clinical benefit of RPT to understand the biological basis for TGFβ- targeted RPT efficacy. Our multi-principal investigator team of a radiobiologist, radiochemist, and imaging physicist will collaborate to label a clinically validated human neutralizing TGFβ antibody with an imaging isotope, 89Zr, and a therapeutic isotope, 177Lu, to evaluate pharmacokinetics and dosimetry in five mouse models that differ in TGFβ activity, tissue origin, and radiosensitivity. Our goal is to assess the relative biological effectiveness of TGFβ RPT by comparing the delivered dose as a function of the level of TGFβ activation, TME composition, radiosensitivity and immunity. Aim 1 will radiolabel fresolimumab with 89Zr for PET imaging to ascertain TGFβ activity differentials in vivo and with 177Lu to assess dose delivered to 5 isogenic cancer models in which TGFβ activity is engineered or induced to be high versus low. Aim 2 will test TGFβ RPT compare cellular mechanisms of radiation response between isogenic pairs and across mouse models to establish the basis for its relative biological effectiveness for tumor control. Our highly innovative project will employ diverse preclinical breast, brain, and lung cancer models, measure key cellular mechanisms of radiation response and ascertain integrated total dose to delineate the interaction between dose and biological mechanisms as determinants of TGFβ RPT response. The resulting foundational data on tumor response and cellular radiobiology as a function of the delivered dose will also illuminate how RPT dynamically impacts cancer biology processes, which is a primary goal of STRIPE (PAR-22-139).
