Abstract A107: A novel theranostic approach targeting ATM-deficient pancreatic ductal adenocarcinoma (PDAC) using 177Lu-labeled anti–TRA-1-60

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest cancers, with over 80% diagnosed at advanced stages and a 5-year survival rate below 12%. Current treatments are largely ineffective, and even patients who undergo surgery often experience early relapse, highlighting the urgent need for better therapeutic strategies. Approximately 20–40% of PDACs harbor defects in DNA damage response (DDR) pathways, including mutations in ATM. ATM is a central kinase involved in repairing DNA double-strand breaks, and its loss promotes genomic instability and tumorigenesis. However, ATM deficiency also increases tumor sensitivity to DNA-damaging agents. In this context, cells become more dependent on the related DDR kinase ATR, presenting a promising target for synthetic lethality-based therapies. TRA-1-60 (TRA), a key cell-surface antigen involved in the reprogramming of inducible pluripotent stem cells, is overexpressed in PDAC, and correlates with poor survival. Tumor samples derived from our PDAC models showed differential TRA-1-60 expression, with BxPC-3-derived tumors exhibiting high levels and AsPC-1-derived tumors low levels. TRA expression increases before or during metastasis and decreases with cell differentiation, making it a promising biomarker for targeted radiopharmaceutical therapy (RPT) in PDAC. We developed a beta-emitting RPT by attaching 177Lutetium (t1/2 ∼ 6.67 d) to the antibody Bstrongomab, which targets TRA on PDAC cells and induces DNA strand break damage. Considering PDAC’s complex mutational profile, including DNA repair defects in 20–40% of cases, we evaluated TRA RPT alone and its combinations with PARP and ATR inhibitors in ATM- deficient and wild-type (WT) PDAC cell models. The in vitro analysis of PANC1 ATM knockout (KO) and AsPC1 ATM KO cells revealed increased sensitivity to non-targeted [177Lu] LuCl3 treatment compared to WT cells. This suggests that DDR-deficient PDAC cells may be more susceptible to DNA damage induced by the radionuclide. In vivo, treatment of these DDR-deficient models with TRA RPT significantly delayed tumor growth compared to WT, particularly in AsPC1 ATM KO xenografts, despite their low TRA expression. TRA RPT alone (p = 0.001) significantly suppressed tumor progression in the AsPC1 ATM KO model compared to WT xenografts. While the combination of TRA RPT with olaparib (PARPi) (p = 0.00025) also suppressed tumor growth compared to WT, it did not provide a statistically significant benefit over TRA RPT treatment alone. Notably, combining TRA RPT with the ATR inhibitor berzosertib resulted in a pronounced delay in tumor growth in AsPC1 ATM KO models, showing a significant improvement compared to TRA RPT alone. These results highlight the promise of combining TRA RPT with DDR-targeted therapies to improve treatment in DDR-deficient PDAC. Identifying effective drug combinations may be key to better patient outcomes and advancing personalized therapies, especially for cases with DDR mutations. Citation Format: Nasrin Movahhedin, Jacob Lindquist, Istri Ndoja, Chris Yunker, Nerissa T. Viola, Steve M. Patrick. A novel theranostic approach targeting ATM-deficient pancreatic ductal adenocarcinoma (PDAC) using 177Lu-labeled anti–TRA-1-60 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A107.