We are alleviating the toxicity of the anticancer drug CPT-11 by modulating components of the GI microbiome. CPT-11 is essential in treating colorectal and pancreatic cancer, but dose-limiting toxicity severely reduces its efficacy. This toxicity is caused by a bacterial enzyme in enteric microbial symbiotes. The enzyme, beta glucuronidase, removes the inactivating glucuronic acid sugar from CPT-11's key metabolite, which reactivates the drug in the GI and produces epithelial cell death and acute diarrhea. We hypothesized that the selective, non-lethal inhibition of microbial beta glucuronidases would alleviate this side effect. This hypothesis tested true in proof-of-concept molecular-to-animal studies conducted in the previous project period. We will now advance the project in three crucial ways. First, we will characterize the range of active ?-glucuronidases present in the GI microbiome using structural biology and biochemistry. Second, we will create differentially optimized bacterial beta glucuronidase inhibitors via structural and chemical biology. Third, using deep-sequencing and metagenomics, we will unravel how this approach impacts the composition and activity of the GI microbiome. In summary, we seek to advance a novel paradigm - inhibiting specific microbial enzymes for therapeutic gain without harming the bacterial symbiotes essential for human health.

Public Health Relevance

We are alleviating the toxicity of the anticancer drug CPT-11 by modulating components of the GI microbiome. The results will reveal fundamental aspects of mammalian-microbial symbiosis and improve cancer chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA098468-11A1
Application #
8817985
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Fu, Yali
Project Start
2014-09-23
Project End
2019-08-31
Budget Start
2014-09-23
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$263,899
Indirect Cost
$88,633
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Saitta, Kyle S; Zhang, Carmen; Lee, Kang Kwang et al. (2014) Bacterial *-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics. Xenobiotica 44:28-35
Redinbo, Matthew R (2014) The microbiota, chemical symbiosis, and human disease. J Mol Biol 426:3877-91
Mani, Sridhar; Boelsterli, Urs A; Redinbo, Matthew R (2014) Understanding and modulating mammalian-microbial communication for improved human health. Annu Rev Pharmacol Toxicol 54:559-80
Roberts, Adam B; Wallace, Bret D; Venkatesh, Madhu Kumar et al. (2013) Molecular insights into microbial *-glucuronidase inhibition to abrogate CPT-11 toxicity. Mol Pharmacol 84:208-17
Wallace, Bret D; Redinbo, Matthew R (2013) The human microbiome is a source of therapeutic drug targets. Curr Opin Chem Biol 17:379-84
Boelsterli, Urs A; Redinbo, Matthew R; Saitta, Kyle S (2013) Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies. Toxicol Sci 131:654-67
Wallace, Bret D; Redinbo, Matthew R (2013) Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective. Drug Metab Rev 45:79-100
Wallace, Bret D; Betts, Laurie; Talmage, Garrick et al. (2013) Structural and functional analysis of the human nuclear xenobiotic receptor PXR in complex with RXR*. J Mol Biol 425:2561-77
LoGuidice, Amanda; Wallace, Bret D; Bendel, Lauren et al. (2012) Pharmacologic targeting of bacterial ýý-glucuronidase alleviates nonsteroidal anti-inflammatory drug-induced enteropathy in mice. J Pharmacol Exp Ther 341:447-54
Wallace, Bret D; Wang, Hongwei; Lane, Kimberly T et al. (2010) Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330:831-5

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