Novel bacteria-based delivery system for TACE (ADAM17) selective biological inhibitor
2molecular cell biology, Weizmann Institute of Science, Israel
Non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancer cases, needs to be treated effectively urgently. Overexpression of tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) is associated with poor clinical outcomes. This led to the generation of a highly selective anti-TACE biological inhibitor called the TACE Pro Domain (TPD). Due to low drug penetration into tumors, TPD treatment had a moderate effect on NSCLC tumor progression. Antitumor treatments with cellular vehicles are an efficient solution for selective and local treatment. As a delivery system for TPD, we have engineered attenuated Salmonella Typhimurium (STM). The STM-TPD system colonizes Lewis Lung Carcinoma (LLC) and improves the treatment outcome of NSCLC model in-vivo and in-vitro as compared to TPD alone. By overexpressing and secreting tumor specific TPD, engineered Salmonella can efficiently deliver fresh TPD to tumors and inflammatory tissues. In-vitro functional assays demonstrate inhibition of pro-TNFα secretion, reduction in cell proliferation and attenuation of metastasis. Treatments in- vivo have a significant impact on the growth and progression of tumors. Overall, STM-TPD provides a general, yet novel, drug delivery system to administer anti-matrix biological inhibitors e.g., TPD directly into the TME.