The Development of Radiotherapeutic Paradigms for Desmoplastic Small Round Cell Tumor - Abstract Desmoplastic small round cell tumor (DSRCT) is an extremely rare soft tissue sarcoma that forms within the abdominal and pelvic peritoneal cavity. DSRCT predominantly affects male children and young adults, and metastases are usually present at diagnosis due to the delayed onset of symptoms. Most critically, there is no current standard-of-care for the treatment of DSRCT, and the prognosis for patients with the disease is very poor: the 5-year survival rate is under 15%. As a result, the development of novel therapeutics for the disease is an urgent clinical need. This proposal describes the synthesis, characterization, in vitro validation, and in vivo evaluation of 177Lu-, 225Ac-, and 212Pb-labeled radiotherapeutics for DSRCT. We have selected two targets for these probes ¾ fibroblast growth factor receptor 4 (FGFR4) and leucine rich repeat containing 15 (LRRC15) ¾ that are highly expressed by DSRCT cells but not healthy tissues. The former is a transmembrane tyrosine kinase that has roles in cell proliferation, migration, and differentiation. The latter is a transmembrane protein involved in cell-cell interactions, cell-extracellular matrix interactions, and cell adhesion. In Specific Aim 1, we will leverage two clinically validated mAb ¾ samrotamab (LRRC15) and U3-1784 (FGFR4) ¾ and a pair of sdAb derived from these IgG (i.e. sdAbSAM and sdAbU3) to create a series of FGFR4- and LRRC15-targeting radioimmunotherapeutics. We will use a site-specific approach to bioconjugation to modify the mAb with CHX-A²-DTPA (for 177Lu3+) and macropa (for 225Ac3+) and append these two chelators as well as PSC (for 212Pb2+) to the sdAb, and the resultant immunoconjugates will be comprehensively characterized. Protocols will then be developed to radiolabel these immunoconjugates with 177Lu, 225Ac, and 212Pb in high yield and specific activity, and the purity, stability, and antigen-binding properties of the radioimmunoconjugates will be interrogated. Next, in Specific Aim 2, we will first perform biodistribution experiments with these 177Lu-, 225Ac-, and 212Pb-labeled radiotherapeutics in an orthotopic murine model of DSRCT using both intravenous and intraperitoneal administration routes. These data will be used for dosimetry calculations that will inform the selection of probes and choice of doses for systemic and intracompartmental radioimmunotherapy studies in three orthotopic models of the disease. Throughout the aim, the radioimmunoconjugates will be evaluated using several metrics, including radiation dose rates to tumor lesions, therapeutic indices for healthy tissues, hematoxicological parameters, nephrotoxicological parameters, tumor growth inhibition, and median survival time. In the end, we contend that this investigation could have a transformational impact on the clinical care of patients with DSRCT. Indeed, it is our hope that this work could yield safe and effective tools for the radiopharmaceutical therapy of a recalcitrant malignancy for which very few treatment options exist.
