Co-treatment of taxane with mesothelin targeted immunotoxin improves pancreatic cancer cell killing

Authors

• EA Kolyvas
• K Hollevoet
• I Pastan
• C Alewine

Abstract

Pancreatic cancer (PDAC) kills more than 40,000 Americans each year, with incidence nearly equal to mortality since there are few effective therapies. Mesothelin (MSLN) is a cell surface glycoprotein expressed by most PDACs. RG7787 (aka Ro6927005) is an immunotoxin that uses an anti-MSLN antibody Fab fragment for targeting a conjugated deimmunized Pseudomonas exotoxin A (PE) to MSLN expressing cancers. When RG7787 is internalized by cancer cells, PE irreversibly modifies Elongation Factor-2. This inhibits protein synthesis and decreases levels of the anti-apoptotic protein mcl-1, resulting in cell death. Previously, we have shown that combination of RG7787 with paclitaxel improves anti-tumor efficacy against KLM1 pancreatic tumor xenografts. Here, we demonstrate that co-treatment with RG7787 and NAB-paclitaxel results in durable complete regression in this model. Our investigations demonstrate that RG7787/ taxane enhancement of cell killing can also be observed in vitro. The effect is toxin-dependent, since neither an anti-MSLN Fab alone nor substitution of immunotoxin with a chemical protein synthesis inhibitor can replicate the synergistic cytotoxicity. Addition of taxane to RG7787 does not change the depth, rate of onset or recovery from protein synthesis inhibition. Additional studies are currently in progress to further delineate the mechanism for the enhanced efficacy. A clinical trial of RG7787 with standard gemcitabine and NAB-paclitaxel for pancreatic cancer patients is planned.

Scientific Focus Area: Molecular Biology and Biochemistry

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