Abstract B032: Targeting Lipid Rafts in Hypoxic Pancreatic Ductal Adenocarcinoma: Preclinical Evaluation of [225Ac]CLR 121225, a Novel Actinium-Based Radio-Conjugate

Pancreatic ductal carcinoma (PDAC) has a 5 year survival of <10%. One hallmark of PDAC’s tumor microenvironment is dense desmoplasia, due to abnormal accumulation of extracellular matrix and proliferative fibroblasts, resulting in desmoplasia hypovascularity and a hypoxic environment requiring the tumor cells to use lipids from the microenvironment. Lipid rafts (LR) are highly ordered cell membrane regions composed of cholesterol, sphingolipids and transmembrane signaling receptors and transporters that transport lipids into the cell. LRs are generally enriched in tumor cell membranes versus normal cells (at least 10-fold higher) and even more so in hypoxic environments. Here, we disclose [225Ac]CLR 121225 (CLR 225), a novel actinium-based radio-conjugate uniquely designed to target LRs and enter the tumor cell. CLR 225 safety and efficacy was tested in three mouse subcutaneous xenograft models of human pancreatic cancer: MIA PaCa-2 (MP), PANC-1 (P), and BxPC-3 (BP). Assessments included tumor volume calculation using caliper measurements, body weight measurements, and clinical observations. Animals were euthanized if tumor burden reached >2000 mm3. The single-dose, multiple-level IV plasma pharmacokinetics of unlabeled CLR 225 was determined in mice, rats and dogs. A GLP multiple-dose IV toxicity study of unlabeled CLR 225 at three dose levels in excess of the anticipated human equivalent dose was performed in dogs. Single IV doses of CLR 225 were used in MP and P models at total radioactive amounts of 100, 250, or 500nCi. In the BP model, single IV doses of CLR 225 were given at 250, or 500nCi, and two IV doses of 500nCi on Days 0 and 14. In all models, dose-dependent inhibition of tumor growth was observed as were significant increases in time to progression/survival. In the MP and P models tumor growth was significantly suppressed at all doses with statistically significant tumor volume reduction occurring at doses of 250 and 500 nCi (single doses). This resulted in a survival benefit and reduced growth rate post-decay of the isotope in all treated dose groups. Exponential growth rates were significantly reduced in all treatment groups in BP model with increased growth inhibition occurring with two doses of 500nCi compared to a single dose and resulting in a further survival benefit. This suggests that multiple doses may provide enhanced long-term outcomes. All doses were safe and tolerated based upon body weight and clinical observations. The plasma IV single dose PK of unlabeled CLR 225 was dose-proportional in all three species. Allometric scaling was linear. The multiple-dose toxicity study of unlabeled CLR 225 in dogs was safe with no effects or changes in the measured endpoints. CLR 225 demonstrated in multiple PDAC models significant tumor volume reduction and inhibition of growth resulting in survival benefit, predictable pharmacokinetics, and good safety. Unlabeled CLR 225 exhibited predictable PK and safety in all species, including multiple doses in dogs. These preclinical results support further development. Citation Format: Jarrod Longcor, Randall Hoover, Maria Banach. Targeting Lipid Rafts in Hypoxic Pancreatic Ductal Adenocarcinoma: Preclinical Evaluation of [225Ac]CLR 121225, a Novel Actinium-Based Radio-Conjugate [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): nr B032.