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Pharmacogenomic Study for Individual Response to CPT-11 in Colorectal Cancer Patients (Step 2)

ABSTRACT: Interventions: Intravenous adminstration of CPT-11 100 mg/m2 on Days 1, 8, and 15, every 4 weeks Primary outcome(s): 1)Tumor response rate 2)Genotype-phenotype association (CYP3A4,CES1,2, UGT1A1, ABCG2, ABCB1, and ABCC1,2 vs toxicity), mutation -phenotype association (TOP1A, ABCG2 vs tumor response), and expression-phenotype association (TOP1A, ABCG2 vs tumor response) Study Design: Single arm Non-randomized

DISEASE(S): Stage Iv Colorectal Cancer After Palliative Operation

PROVIDER: 2609520 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:In drug development, a system for predicting drug metabolism and drug-induced toxicity is necessary to ensure drug safety. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is an important drug-metabolizing enzyme expressed in the liver and small intestine, and predicting CYP3A4-mediated drug metabolism and drug-induced toxicity is essential. We previously developed procedures to differentiate human induced pluripotent stem (iPS) cells into hepatocyte-like cells (HLCs) or intestinal epithelial-like cells (IECs) with a fetal phenotype as well as a highly efficient genome editing technology that could enhance the homologous recombination efficiency at any locus, including CYP3A4. By using human iPS cells and our genome editing technology, we generated CYP3A4-knockout (KO) iPS cell-derived HLCs and IECs for the evaluation of CYP3A4-mediated drug metabolism and drug-induced toxicity. CYP3A4 deficiency did not affect pluripotency and hepatic and intestinal differentiation capacities, and CYP3A4 activity was entirely eradicated by CYP3A4 KO. Off-target effects (e.g., inhibition of bile acid excretion) were hardly observed in CYP3A4-KO cells but were observed in CYP3A4 inhibitor-treated (e.g., ketoconazole) cells. To evaluate whether drug-induced hepatotoxicity and enterotoxicity could be predicted using our model, we exposed CYP3A4-KO HLCs and IECs to acetaminophen, amiodarone, desipramine, leflunomide, tacrine, and tolcapone and confirmed that these cells could predict CYP3A4-mediated toxicity. Finally, we examined whether the therapeutic effects of an anti-hepatitis C virus (HCV) drug metabolized by CYP3A4 would be predicted using our model. CYP3A4-KO HLCs were treated with asunaprevir (antiviral drug metabolized by CYP3A4) after HCV infection, and the anti-viral effect was indeed strengthened by CYP3A4 KO. Conclusion: We succeeded in generating a novel evaluation system for prediction of CYP3A4-mediated drug metabolism and drug-induced toxicity.

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Pharmacogenomic Study for Individual Response to CPT-11 in Colorectal Cancer Patients (Step 2)

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