Assistant Professor University of Florida Gainesville, Florida
The gut lumen is filled with bacterial lipopolysaccharide (LPS) produced by the Gram-negative bacteria. When colorectal cancer (CRC) grows in the wall of the colon intestine, LPS can penetrate across the epithelium and enter the tumor. This induces chronic inflammation and strong immune suppression, which favors tumor growth and metastasis. We have developed three different therapy strategies targeting LPS or its receptor TLR4 as effective means to control tumor growth. The first one is simple oral delivery of polymyxin B, a potent antibiotic against Gram-negative bacteria. The second is IV delivery of TAK-242, an antagonist of TLR4, using an emulsion formulation. The third effective approach is to deliver a synthetic fusion protein, called a trap, with high binding affinity (kd = 20 nM) to LPS. Plasmid DNA encoding the LPS trap is encapsulated in the Lipid-Protamine-DNA (LPD) nano-formulation and IV delivered to the tumor for local expression of the trap. All three approaches are effective in slowing down the tumor growth. But the trap approach can be combined with anti-PD-L1 antibody for maximal therapy activity. Supported by NIH grant CA198999.
Understand the role of bacterial lipopolysaccharide in promoting colorectal cancer growth.
Learn different therapy strategies targeting LPS to remodel the tumor microenvironment.
Demonstrate the synergy between quenching tumor LPS and the checkpoint inhibitor therapy.