Personalized Medicine and Epigenetic Drug Development
Epigenetic modifications have had an important function in the evaluation of potential biomarkers for patient cancer diagnostics . The goals have been to identify patient populations likely to respond to specific anticancer therapies and to define reasonable dosages for investigational anticancer drugs. The profiles of genetic and epigenetic alterations were characterized for gastric cancer . Analysis of DNA methylation by a bead array with 485,512 probes revealed that genes involved in cancer-related pathways were more frequently affected by epigenetic modifications than by genetic alterations. This knowledge will be useful for selection of patients likely to benefit from specific drug treatment.
Application of stem cell technology for epigenetic reprogramming of tumor cells isolated from cancer patients can aid in the creation of self-evolving personalized translational platforms. The generated stem cell population is immediately available for experimental manipulations including pharmacological screening for personalized “stemotoxic” cancer drugs. A cell-based epigenetic assay system (EPISSAY) has been designed based on a silenced triple-mutated bacterial nitroreductase, TMnfsB, fused with red fluorescent protein expressed in the nonmalignant human breast cell line MCF10A . The potency of the epigenetic drug decitabine was evaluated for the naked drug and a PEGylated liposome-encapsulated formulation showing a 50% higher potency for the encapsulated version. The EPISSAY assay system provided rapid comparison of novel drug formulations to existing drugs.
Epigenetic aberrations can influence drug treatment by key gene expression modulations related to metabolism and distribution of drugs and drug targets . The interindividual variation in drug response, the epigenetic alterations, and the epigenetic profiles of circulating nucleic acids present great potential for the application of biomarkers for personalized drugs. Moreover, the pharmacoepigenetic results provide information for the regulation of ADME (adsorption, distribution, metabolism, and excretion) genes and drug targets, which can be used for interindividual variations in drug response.
Furthermore, in addition to inactivation of tumor suppressor genes, epigenetics may play an important role in the development of drug resistance . Epigenetic mechanisms triggering resistance to the colorectal cancer drugs 5-fluorouracil, irinotecan, and oxaliplatin have been investigated to aid in the stratification of cancer patients and to develop tailored personalized therapy. Also, preclinical studies on DNA methyltransferase and histone deacetylase inhibitors have suggested that they may provide reversible chemoresistance in colorectal tumors.
DNA methylation of a number of genes involved in DNA repair (MGMT, hMLH1, WRN) and cell cycle regulation (CHFR, CDK10, p73) influence the sensitivity to chemotherapeutic drugs. Therefore, DNA methylation should be explored to discover molecular markers for the prediction of the tumor responsiveness of chemotherapy by applying genome-wide analysis of DNA methylation using microarrays and next-generation sequencing. Furthermore, epigenetic-based agents may help in ameliorating chemoresistance or enhancing tumor cytotoxicity.
Journal of Clinical Research and Bioethics
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