A Novel Syndecan-1 Targeted Therapeutic Antibody Inhibits Macropinocytosis and Induces Anti-Tumor Immunity in Pancreatic Cancer

<p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with an overall 5-year survival rate of only 13%. Given the prevalence of oncogenic <em>KRAS</em> mutations (<em>KRAS*</em>) and their role in PDAC development and growth, therapeutic strategies to quench KRAS*-driven malignant progression are urgently needed to improve the clinical outcome for this disease. Our previous work identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical downstream effector protein of KRAS*, which promotes cancer progression by mediating macropinocytosis. Moreover, SDC1 plays an essential role for the acquired resistance to KRAS* inhibition in PDAC, making it an attractive new therapeutic target, as allele-specific and pan-KRAS* inhibitors continue progressing through pre-clinical and clinical development.</p> <p>However, despite the great potential of targeting SDC1 for cancer therapy, SDC1-targeted therapies have largely been explored in the context of multiple myeloma, while its potential in solid tumors is underestimated. More importantly, most of currently anti-SDC1 agents function by exploiting SDC1 as a surface target to deliver cytotoxic payload or facilitate immune cell-mediated killing, while the direct functional inhibition of SDC1 itself is frequently overlooked during the development of SDC1-targeted approaches.</p> <p>To explore the potential of targeting SDC1 in solid tumors, especially in the context of pancreatic cancer, we developed a monoclonal antibody with remarkable sensitivity and specificity for human SDC1 (anti-SDC1 mAb). Anti-SDC1 mAb robustly inhibited PDAC cell proliferation <em>in vitro</em> and exhibited potent tumor inhibitory effects across multiple PDAC models. Mechanistically, we revealed that anti-SDC1 mAb directly inhibits macropinocytosis to block nutrient salvage as well as induces antibody-dependent cellular cytotoxicity (ADCC) to eliminate PDAC cells. Notably, <em>in vivo</em>, our anti-SDC1 mAb exhibited synergistic anti-tumor effects in combination with first-line chemotherapy, KRAS* inhibitors, and immunotherapies, resulting in robust tumor suppression. In summary, our findings support the anti-SDC1 mAb as a promising therapeutic strategy for PDAC and potentially other solid tumors characterized by aberrant SDC1 expression.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Author dc:creator

• Yang, Zecheng

Contributors dc:contributor

• Wantong Yao
• Haoqiang Ying
• Laura Bover

• Pancreatic Cancer
• Therapeutic Antibody
• Macropinocytosis
• Syndecan-1
• Biotechnology
• Medical Immunology
• Medical Pharmacology
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1494

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2551