Therapeutic Eradication of Cancer-associated Fibroblasts Inhibits in vivo progression of Pancreatic Cancer

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ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with an unmet medical need. therapeutic elimination of cancer associated fibroblasts (CAFs), key drivers of tumor aggressiveness, has been the focus of recent studies. However, the inherent heterogeneity and plasticity of CAFs have hampered the development of CAF-targeted therapies. Clemastine, an FDA-approved cationic amphiphilic drug, is known to elicit cytotoxic lysosomal membrane permeabilization in solid tumors. We evaluated its efficacy in patient derived PDAC organoids and patient avatars. In vitro, half of the organoids responded to clemastine, although sensitivity did not predict in vivo outcomes. In vivo , clemastine treatment led to CAF depletion, halted cancer progression and delayed disease progression . To assess potential synergy with standard-of-care therapy, clemastine was combined with gemcitabine. The combination enabled dual targeting—clemastine effectively eliminated all CAF subtypes, while gemcitabine eradicated cancer cells - leading to inhibition of metastatic dissemination. These findings support clemastine as a promising companion therapy in PDAC, targeting the tumor-supportive microenvironment.

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