(Irinotecan) is a widely used chemotherapeutic prodrug that exhibits curtailed clinical utility due to its intense dose-limiting side-effect, diarhea. Several approaches have failed to adequately reduce this toxicity. The pharmacology of CPT-11-induced diarrhea implicates the in situ production of the active metabolite, SN- 38, from inactive SN-38-glucuronde by microbial ?-glucuronidase residing within the gut lumen. We recently elucidated the crystal structure of E. coli ?-glucuronidase and discovered several high potency inhibitors effective in living bacterial strains. Subsequent studies in mice showed that one such inhibitor, Inh1, protected mice from CPT-11 induced toxicity (Wallace et al., Science 2010, in press). The central hypothesis for this proposal is that CPT-11 anti-tumor activity can be improved using novel gastrointestinal (GI) bacteria-targeted lead compounds. This hypothesis has been formulated on the rationale that reduced GI toxicity will result in the ability to administer escalated doses of CPT-11, thereby improving exposure and anti-tumor activity. The long- term objectives stemming from this discovery are to understand the roles microbial ?-glucuronidases play in xenobiotic and endobiotic metabolism, toxicity and carcinogenesis.
The aims of this proposal are to complete the essential preclinical in vivo pharmacology and efficacy studies of the promising lead compound, Inh1, as it relates to CPT-11 (Aims 2 &3). In addition, other novel bacterial ?-glucuronidase inhibitors will be examined and characterized in in vitro, cell- and mouse-based studies (Aim 1). The methodologies used to complete these aims include an understanding of the pharmacokinetics and pharmacodynamics of Inh1 as its relates to CPT-11 metabolism in rodents. Novel heterotransplanted human colon tumors in mice will be used to determine the effect of Inh1 on CPT-11 dose-intensification and anti-tumor activity. Finally, novel uncharacterized ?-glucuronidase inhibitors we have already discovered will be evaluated in vitro and in vivo. New compound synthesis may be necessary to optimize delivery while preserving potency.
These aims and goals are in keeping with the mission of NCI, which is focused on mechanistic approaches towards improving cancer therapies. Our objective is to improve CPT-11 efficacy by alleviating its dose-limiting side effect.
The dose-limiting side effect of the widely used anticancer drug CPT-11 (Irinotecan) is acute diarrhea caused by the reactivation of a drug metabolite in the GI. We have eliminated this toxicity in mice by inhibiting a specific enzyme in bacterial GI symbiotes. Here we outline the necessary preclinical studies to develop our lead compounds into novel drugs to improve the efficacy and systemic tolerance of this proven chemotherapeutic agent. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page
|Huang, Kezhen; Mukherjee, Subhajit; DesMarais, Vera et al. (2018) Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis. Pediatr Res 83:1031-1040|
|Stepankova, Martina; Bartonkova, Iveta; Jiskrova, Eva et al. (2018) Methylindoles and Methoxyindoles are Agonists and Antagonists of Human Aryl Hydrocarbon Receptor. Mol Pharmacol 93:631-644|
|Pollet, Rebecca M; D'Agostino, Emma H; Walton, William G et al. (2017) An Atlas of ?-Glucuronidases in the Human Intestinal Microbiome. Structure 25:967-977.e5|
|Hudson, Grace M; Flannigan, Kyle L; Erickson, Sarah L et al. (2017) Constitutive androstane receptor regulates the intestinal mucosal response to injury. Br J Pharmacol 174:1857-1871|
|Garg, Aditya; Zhao, Angela; Erickson, Sarah L et al. (2016) Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation. J Pharmacol Exp Ther 359:91-101|
|Pasquel, Danielle; Doricakova, Aneta; Li, Hao et al. (2016) Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity. Biochim Biophys Acta 1859:1155-1169|
|Ranhotra, Harmit S; Flannigan, Kyle L; Brave, Martina et al. (2016) Xenobiotic Receptor-Mediated Regulation of Intestinal Barrier Function and Innate Immunity. Nucl Receptor Res 3:|
|Pondugula, Satyanarayana R; Pavek, Petr; Mani, Sridhar (2016) Pregnane X Receptor and Cancer: Context-Specificity is Key. Nucl Receptor Res 3:|
|Daillère, Romain; Vétizou, Marie; Waldschmitt, Nadine et al. (2016) Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects. Immunity 45:931-943|
|Wallace, Bret D; Roberts, Adam B; Pollet, Rebecca M et al. (2015) Structure and Inhibition of Microbiome ?-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity. Chem Biol 22:1238-49|
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