LRRC15-targeted theranostics – A new treatment modality for pancreatic ductal adenocarcinoma (PDAC) targeting tumor cells and the tumor microenvironment (TME)

• Applicants: Professorin Katharina Lückerath, Ph.D.; Marija Trajkovic-Arsic, Ph.D.
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552440240

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies; new, more effective treatment options are urgently needed. Here, we propose a new concept in PDAC treatment; we will explore efficacy of a new radioimmunotherapy (RIT), and the mechanistic determinants of its effectiveness. Our approach to RIT is unique: It is targeted to the tumor microenvironment (TME), which has emerged as a critical factor for treatment resistance, and may exert anti-PDAC efficacy through both, tumor cell kill and stromal reprogramming. Together with our collaboration partners we developed a radiolabeled antibody targeting LRRC15. LRRC15 is expressed on and is a biomarker for cancer-associated fibroblasts (CAF) that surround PDAC cells. Preliminary data indicate that our 177Lu-LRRC15-antibody specifically binds to LRRC15, is internalized into cells upon binding, and retained in tumors for at least 14 days, resulting in reduced tumor burden and prolonged survival in sarcoma and breast cancer mouse models. In syngeneic PDAC mouse models with LRRC15+ CAF, 177Lu-LRRC15 specifically enriched in PDAC tissue and exhibited anti-tumor effects in a pilot study. The overarching hypotheses of the proposal are that LRRC15-targeted RIT (i) effectively delivers ionizing radiation specifically to tumors to induce PDAC cell death, without significant healthy organ toxicity; (ii) acts as in situ vaccine to enhance immunogenicity; and (iii) reduces immunosuppressive and pro-tumorigenic signals from stromal cells by reprogramming CAF. Profiling these adaptations will enable identification of PDAC liabilities that can be exploited in rationally designed, clinically viable RIT-combination regimens (e.g., with new KRAS (G12D)-inhibitors) to improve PDAC outcome. We will address these hypotheses in 2 specific aims using orthotopic and genetic PDAC mouse models. We will: (1) establish LRRC15-RIT as treatment option for PDAC by assessing biodistribution, tumor and healthy organ doses, and efficacy as monotherapy; and (2) elucidate the complex interplay between tumor and its microenvironment by profiling the molecular and cellular outcome of LRRC15-RIT in tumor cells, CAF and immune cells using flow cytometry, multiplexed immunofluorescence and single cell RNA-sequencing. Together, we propose to investigate a new immunotheranostic that targets tumor cells and the TME. We expect LRRC15-RIT to have systemic effects that might allow to overcome barriers to therapeutic efficacy posed by PDAC heterogeneity. Our mechanistic analyses will contribute to the understanding of PDAC biology, and identify determinants of response/non-response to this therapy as well as tumor liabilities that can be exploited in future, synergistically acting RIT-combination regimens. Successful completion of proposed studies will aid the clinical translation of LRRC15-theranostics, and thus, benefit the patient and scientific community.

• DFG Programme: Research Grants