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PubMed2003

Characterization of renal allograft rejection by urinary proteomic analysis.

OBJECTIVE: To develop a diagnostic method with no morbidity or mortality for the detection of acute renal transplant rejection. SUMMARY BACKGROUND DATA: Rejection constitutes the major impediment to the success of transplantation. Currently available methods, including clinical presentation and biochemical organ function parameters, often fail to detect rejection until late stages of progression. Renal biopsies have associated morbidity and mortality and provide only a limited sample of the organ. METHODS: Thirty-four urine samples were collected from 32 renal transplant patients at various stages posttransplantation. Samples were collected from 17 transplant recipients with acute rejection and 15 patients with no rejection. Samples from patients less than 4 days posttransplant were omitted from data analysis due to the presence of excessive inflammatory response proteins. Rejection status was confirmed by kidney biopsy. Specimens were analyzed in triplicate using SELDI mass spectrometry. The obtained spectra were subjected to bioinformatic analysis using ProPeak as well as CART (Classification and Regression Tree) algorithms to identify rejection biomarker candidates. These candidates were identified by their molecular weight and ranked by their ability to distinguish between nonrejection and rejection based on receiver operating characteristic (ROC) analysis. The candidates with the highest area under the ROC curve (AUC) exhibited the best diagnostic performance. RESULTS: The best candidate biomarkers demonstrated highly successful diagnostic performance: 6.5 kd (AUC = 0.839, P <.0001), 6.7 kd (AUC = 0.839, P <.0001), 6.6 kd (AUC = 0.807, P <.0001), 7.1 kd (AUC = 0.807, P <.0001), and 13.4 kd (AUC = 0.804, P <.0001). A separate analysis using the CART algorithm in the Ciphergen Biomarker Pattern Software correctly classified 91% of the 34 specimens in the training set, giving a sensitivity of 83% and specificity of 100% using two separate biomarker candidates at 10.0 kd and 3.4 kd. CONCLUSIONS: Biomarker candidates exist in urine that have the ability to distinguish between renal transplant patients with no rejection and those with acute rejection. These biomarker candidates are the basis for development of a noninvasive method of diagnosing acute rejection without the morbidity and mortality associated with needle biopsy. The combination of biomarkers into a panel for diagnosis leads to the possibility of enhanced diagnostic performance.

Acute Disease↗
PubMed2025

IGCN: integrative graph convolution networks for patient level insights and biomarker discovery in multi-omics integration.

MOTIVATION: Developing computational tools for integrative analysis across multiple types of omics data has been of immense importance in cancer molecular biology and precision medicine research. While recent advancements have yielded integrative prediction solutions for multi-omics data, these methods lack a comprehensive and cohesive understanding of the rationale behind their specific predictions. To shed light on personalized medicine and unravel previously unknown characteristics within integrative analysis of multi-omics data, we introduce a novel integrative neural network approach for cancer molecular subtype and biomedical classification applications, named Integrative Graph Convolutional Networks (IGCN). RESULTS: To demonstrate the superiority of IGCN, we compare its performance with other state-of-the-art approaches across different cancer subtype and biomedical classification tasks. Our experimental results show that our proposed model outperforms the state-of-the-art and baseline methods. IGCN identifies which types of omics data receive more emphasis for each patient when predicting a specific class. Additionally, IGCN has the capability to pinpoint significant biomarkers from a range of omics data types. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/bozdaglab/IGCN.

Humans↗
PubMed2025

Target and biomarker exploration portal for drug discovery.

MOTIVATION: The discovery of novel drug targets and precision biomarkers remains a major challenge in drug development, with traditional differential expression analysis often overlooking key regulatory proteins. Here, we present a novel, web-based bioinformatics tool, the Target and Biomarker Exploration Portal (TBEP), designed to accelerate the drug discovery process by integrating large-scale biomedical data with network analysis techniques. RESULTS: TBEP harnesses machine-learning approaches to mine and combine multimodal datasets, including human genetics, functional genomics, and protein-protein interaction networks, to decode causal disease mechanisms and uncover novel therapeutic targets and precision biomarkers for specific phenotypes. A unique feature of the tool is its ability to process large-scale data in real-time, facilitated by an efficient cloud-based architecture. Additionally, the tool incorporates an integrated large language model (LLM), which assists researchers in exploring and interpreting complex biological relationships within the generated networks and multi-omics data using natural language (English). By offering an intuitive, interactive interface, the LLM enhances the exploration of biological insights, making it easier for scientists to derive actionable conclusions. This powerful integration of network analysis, multi-omics data, and LLM provides a robust framework for accelerating the identification of novel drug targets. AVAILABILITY AND IMPLEMENTATION: The tool is publicly available at https://tbep.missouri.edu. The source code, documentation and installation instructions are available at GitHub repository: https://github.com/mizzoudbl/tbep.

Drug Discovery↗
PubMed2005

Biomarkers in osteoarthritis.

PURPOSE OF REVIEW: Biomarker discovery and validation for osteoarthritis have accelerated over the past several years, coincident with an evolving understanding of joint tissue molecules and their complex interactions, and the compelling need for improved osteoarthritis outcome measures in clinical trials. This review highlights advances in osteoarthritis-related biomarker research within the past year. RECENT FINDINGS: The studies in the past year involving biochemical markers in humans can be assigned to one of four categories: new approaches and new biomarkers, exploratory studies in specialized disease subsets, large cross-sectional validation studies, and longitudinal studies, with and without an intervention. SUMMARY: Most these studies have examined the association of a biomarker with some aspect of the natural history of osteoarthritis. As illustrated by the six studies reviewed here that included therapeutic interventions, however, several biomarkers are emerging that display credible association with disease modification. The expanding pool of informative osteoarthritis-related biomarkers is expected to positively impact the development of therapeutics for this disease and, it is hoped, ultimately clinical care.

Biomarkers↗
PubMed2001

Effects of uncertainties on exposure estimates to methylmercury: a Monte Carlo analysis of exposure biomarkers versus dietary recall estimation.

This article presents a general model for estimating population heterogeneity and "lack of knowledge" uncertainty in methylmercury (MeHg) exposure assessments using two-dimensional Monte Carlo analysis. Using data from fish-consuming populations in Bangladesh, Brazil, Sweden, and the United Kingdom, predictive model estimates of dietary MeHg exposures were compared against those derived from biomarkers (i.e., [Hg]hair and [Hg]blood). By disaggregating parameter uncertainty into components (i.e., population heterogeneity, measurement error, recall error, and sampling error) estimates were obtained of the contribution of each component to the overall uncertainty. Steady-state diet:hair and diet:blood MeHg exposure ratios were estimated for each population and were used to develop distributions useful for conducting biomarker-based probabilistic assessments of MeHg exposure. The 5th and 95th percentile modeled MeHg exposure estimates around mean population exposure from each of the four study populations are presented to demonstrate lack of knowledge uncertainty about a best estimate for a true mean. Results from a U.K. study population showed that a predictive dietary model resulted in a 74% lower lack of knowledge uncertainty around a central mean estimate relative to a hair biomarker model, and also in a 31% lower lack of knowledge uncertainty around central mean estimate relative to a blood biomarker model. Similar results were obtained for the Brazil and Bangladesh populations. Such analyses, used here to evaluate alternative models of dietary MeHg exposure, can be used to refine exposure instruments, improve information used in site management and remediation decision making, and identify sources of uncertainty in risk estimates.

Algorithms↗
PubMedDate not supplied

Chronic nephropathy in ad libitum overfed Sprague-Dawley rats and its early attenuation by increasing degrees of dietary (caloric) restriction to control growth.

The early development and progression of chronic nephropathy and its amelioration by moderate and marked dietary restriction (DR) was determined in Sprague-Dawley (SD) rats at 20, 33, 60, and 113 weeks of age. Both sexes of SD rats were overfed ad libitum (AL) or DR-fed at 72-79%, 68-72%, or 47-48% of the adult AL intake. The AL-fed rats rapidly developed increased body and kidney size, increased glomerular area (GA) and urinary protein loss, followed by declining creatinine clearance. Early increased kidney growth and glomerular hypertrophy by 20 weeks preceded increases in glomerular sclerotic index (GSI), 7-day BrdU tubular labeling index (TLI), and the lesions associated with chronic nephropathy. The glomerular number (GN) or the number of nephrons did not differ between the groups over the course of the study. Moderate DR (68-79% of AL) prevented the increased kidney size and GA at 20 weeks and delayed increases in GSI and TLI until 60 weeks of age. Marked DR (47-48% of AL) prevented increases in kidney size, GA and TLI at 20 weeks, and GSI at 60 weeks of age. In AL-fed rats, the early increase in GA predicted the early onset of proteinuria and the later decrease in creatinine clearance, and increased GSI, TLI, and mortality from severe nephropathy. The temporal and dose-related effects of increasing degrees of DR demonstrated that while nephron numbers were unchanged with age, the early development of glomerular hypertrophy was the critical morphological biomarker predicting the progression and severity of chronic nephropathy. Caloric restriction by DR prevented or delayed the development of glomerulosclerosis, tubulointerstitial damage, functional changes, morbidity, and mortality associated with chronic nephropathy in AL-overfed SD rats by controlling initial body and kidney growth, glomerular size, and nephron hypertrophy. These results indicate that control of body and renal growth by DR may be essential to prevent the development and progression of glomerulosclerosis in spontaneous nephropathy of laboratory rats.

Aging↗
PubMed2006

Identification and confirmation of increased fibrinopeptide a serum protein levels in gastric cancer sera by magnet bead assisted MALDI-TOF mass spectrometry.

Gastric cancer is the second most common malignancy and prognosis remains dismal. The reasons for the poor prognosis are the lack of sensitive serum markers for early detection and screening of high-risk individuals as well as the limited treatment options in advanced cancer stages. Using MALDI-TOF mass spectrometry after prefractionation of sera with magnet hydrophobic C8 coated beads sera from 14 patients with gastric cancer and 14 healthy controls mass spectra were generated. A peptide fragment was found to be highly elevated in cancer sera and was identified as fibrinopeptide A. To confirm proteome analysis of gastric cancer sera, we then screened a larger series of patients with gastric cancer (n = 99), high-risk individuals (n = 13) and normal controls (n = 111) for fibrinopeptide A serum levels. Interestingly, the mean logarithmic concentrations of serum fibrinopeptide A levels were significantly higher in cancer patients (mean 3.636 +/- 0.3738; p < 0.0001) and high-risk individuals (mean 3.569 +/- 0.4722; p < 0.05) compared to normal controls (mean 3.303 +/- 0.4012). In contrast, we observed no association of fibrinopeptide A levels with tumor stage, tumor location, presence of regional or distant metastasis, and Lauren type of gastric cancer. In conclusion, MALDI-TOF mass spectrometry of prefractionated gastric cancer sera allows the identification of potential biomarkers that may lead to the development of serum based tests for screening of high-risk individuals.

Aged↗
PubMed1996

Neurotransmission and the ontogeny of human brain.

The early appearance of neurotransmitters in brain tissue refers to their regulative functions on the neuronal circuits. Many neurotransmitters have direct effects on neuronal outgrowth and differentiation during brain development, which precede their role in synaptic information coding. Both the neurotrophic and neurotoxic properties of excitatory amino acids (EAAs) have focused special interest on glutamatergic neurotransmission during brain development. Therefore, this work intends to review and discuss developmental alterations of the EAA neurotransmitter system in the human brain, their relation to human brain maturation and implications for pathological processes during early human brain development.

Aging↗
PubMed2005

Ductal pancreatic cancer in humans and mice.

Pancreatic ductal adenocarcinoma (PDA) eludes early detection and resists current therapies, earning its distinction as the most lethal malignancy by organ site in the western world. This dire reality prompted extensive yet generally disappointing efforts to generate transgenic mouse models of this malignancy. Recently, mutant mice that develop pancreatic intraepithelial neoplasms (PanIN), the presumed preinvasive stage of PDA, were produced by conditionally expressing an endogenous oncogenic Kras allele in the developing murine pancreas. Mice with PanIN demonstrated promise in the pursuit of biomarkers of early pancreatic cancer, and, importantly, such mice eventually developed and succumbed to PDA after a long latency, establishing PanINs as true precursors to the invasive disease. Furthermore, the incorporation of conditional mutations in tumor suppressor alleles known to be altered in human PDA synergized with oncogenic Kras to produce advanced PDA with a short latency, recapitulating central pathophysiological events in human PDA. These models facilitate a variety of biological and clinical investigations such as explorations of the cellular origins of PDA and the development of treatment strategies for advanced PanIN and PDA. In addition, lessons from modeling PDA may be applicable to other tumor types and illuminate general principles of carcinogenesis.

Animals↗
PubMed2005

Utilisation of human pharmacology studies with biomarkers for new drug applications in Japan.

OBJECTIVE: This study evaluated the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation conducted for new drug applications (NDAs) submitted to the Japanese regulatory authority, the Ministry of Health, Labour and Welfare (MHLW). METHODS: A total of 50 new chemical entities (NCEs) posted on the Websites, which were approved from June 2000 to November 2001, were evaluated by investigating their approval information. The utilisation of human pharmacology studies with biomarkers was evaluated by focusing on the classification referred to biomarkers for either efficacy or safety estimation and timing of studies. RESULTS: The human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted in 20 compounds classified by utilising measures of either efficacy (17 compounds) or safety (seven compounds). In 4 of 17 NCEs, some of the biomarkers in human pharmacology studies were similar to the clinical endpoints for efficacy assessment in therapeutic exploratory and/or therapeutic confirmatory studies. For safety assessment in therapeutic exploratory and/or therapeutic confirmatory studies, clinical endpoints rather than biomarkers in human pharmacology studies were used in all seven NCEs. The timing of each type of clinical study could only be obtained for 15 NCEs. Of these 15 NCEs, human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted on six compounds. There were only two compounds for which human pharmacology studies with biomarkers for efficacy estimation were conducted before pivotal studies such as a therapeutic exploratory study or a bridging study. CONCLUSION: Our survey suggests that with Japanese NDAs, human pharmacology studies with biomarkers for either efficacy or safety estimation do not play a key role in accelerating drug development and maximising the knowledge gained from confirmatory trials. The relationship between a biomarker and a clinical endpoint should be investigated appropriately for accelerating drug development. We think that the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation in the regulatory review process for NDAs should be encouraged with the advancements of drug evaluation research using an appropriate biomarker based on clinical pharmacology.

Biomarkers↗
PubMed1999

Nondestructive biomarkers of exposure to endocrine disrupting chemicals in endangered species of wildlife.

This paper explores the problem of endocrine disrupting chemicals (EDCs) from the ecotoxicological point of view, focusing on nondestructive biomarkers of exposure to EDCs for risk assessment of endangered species of wildlife. Several EDCs, such as polyhalogenated aromatic hydrocarbons and toxic metals, tend to be biomagnified in the terrestrial and particularly the marine food chains. Top predators tend to accumulate high concentrations of these contaminants which places them in a situation of high toxicological risk. Hence, there is a need to develop nondestructive techniques, such as nondestructive biomarkers, for hazard assessment, protection, and conservation of endangered species exposed to EDCs. The biological materials proposed for this approach (for example blood, faeces, fur, skin biopsy specimens) are easily obtained with minimal stress for individuals and populations. Some validation data are reported on porphyrins in sea bird excreta (Larus dominicanus, Phalacrocorax olivaceus, Pelecanus occidentalis thagus), as nondestructive biomarkers of exposure to organochlorines, and on benzopyrene monooxygenase activities in marine mammal skin biopsy specimens (Stenella coeruleoalba, Balaenoptera physalus), as early indicators of exposure to p,p'-DDE and other endocrine disrupting organochlorines.

Animals↗
PubMed2004

Red wine polyphenolic compounds inhibit atherosclerosis in apolipoprotein E-deficient mice independently of effects on lipid peroxidation.

BACKGROUND: Lipid peroxidation is thought to play an important role in the pathogenesis of atherosclerosis. Fatty acid peroxidation products such as hydroxyeicosatetraenoic acids and F(2)-isoprostanes have been found in advanced human atherosclerotic plaques. However, little is known about the formation of these products during lesion development. OBJECTIVE: This study examined stable biomarkers of lipid oxidative damage in relation to atherosclerotic disease progression in apolipoprotein E-deficient (Apoe(-/-)) mice and retardation of the disease by red wine polyphenols. DESIGN: One hundred male Apoe(-/-) mice and 50 male control (C57BL/6J) mice were given a high-fat, high-cholesterol diet for 20 wk. To examine the effect of the polyphenolic compounds on lesion development, 50 of the Apoe(-/-) mice were also given dealcoholized red wine for the duration of the study. RESULTS: Aortic lipid deposition was significantly greater in the Apoe(-/-) mice than in the control mice (P < 0.01). Plasma and aortic F(2)-isoprostanes did not differ between the treatment groups. Plasma concentrations of monocyte chemoattractant protein 1, which has been implicated in the development of atherosclerosis, were significantly higher in the Apoe(-/-) mice than in the control mice up to 16 wk (P < 0.05). Hydroxyeicosatetraenoic acid concentrations increased significantly over time in all groups (P < 0.05). Red wine polyphenols had no effect on markers of lipid peroxidation or monocyte chemoattractant protein 1 concentrations, but lipid deposition in the aorta at age 26 wk was significantly less in the mice given red wine than in those not given red wine. CONCLUSION: These results suggest that lipid deposition is independent of lipid oxidation and that the protective action of red wine polyphenols is independent of any antioxidant action of these compounds.

Animals↗
PubMed1997

Breast cytology and biomarkers obtained by random fine needle aspiration: use in risk assessment and early chemoprevention trials.

In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 224 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women had a first-degree relative with breast cancer (74%), prior biopsy indicating premalignant breast disease (25%), a history of breast cancer (13%), or some multiple of these risk factors (12%). Median ages of the high- and low-risk groups were 44 and 42, respectively. Seventy percent of high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 27, 37, and 29% of high-risk subjects but only 0, 3, and 3% of low-risk subjects (P < .0023). Overexpression of ER and HER-2/neu occurred in 7 and 20% of high-risk women but in none of the low-risk subjects. Biomarker abnormalities were more frequent with increasing cytologic abnormality. Restricting the analysis to those 3 biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 19% of high-risk women with epithelial hyperplasia, and 49% of high-risk women with hyperplasia with atypia had abnormalities of 2 or more of these 3 biomarkers (P = .00004). At a median follow-up of 32 months, four women have been diagnosed with invasive cancer and two with ductal carcinoma in situ (DCIS). Later detection of these neoplastic conditions was associated (P < or = .016) by univariate analysis with prior FNA evidence of hyperplasia with atypia; overexpression of p53 and EGFR; the modified Gail risk of breast cancer development at 10 years; and multiple biomarker abnormalities. By multivariate analysis, later detection of cancer was primarily predicted by the number of biomarker abnormalities in the 3-test battery (P = .0005) and secondarily by the Gail risk at 10 years (P = .0049). In turn, hyperplasia with atypia was associated with multiple biomarker abnormalities, particularly p53 and EGFR overexpression. Thus, hyperplasia with atypia and cytologic markers in breast FNAs have promise as risk predictors and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.

Adult↗
PubMed2001

Ultraviolet radiation-induced photoproducts in human skin DNA as biomarkers of damage and its repair.

We have developed a 32P-postlabelling method for quantifying ultraviolet irradiation (UV)-induced cyclobutane dimers and 6-4 photoproducts in human skin in situ. We review the application of the method in studies with human volunteers, demonstrating dose-response relationships over a wide range of administered doses, repair kinetics of UV-damaged DNA among healthy individuals and melanoma patients, and modulation by sunscreens, tan and constitutive pigmentation of damage induction. A notable finding is the wide interindividual variation in DNA damage immediately after irradiation and in its repair. Moreover, the protective effects of sunscreens against erythema and DNA damage also show wide interindividual variation. These results cannot be explained by variation in the experimental methods used. The worst-case scenario is that the differences between individuals are multiplicative, resulting in 1000-fold differences in sensitivity in the population, which would be likely to translate into differences in risk of skin cancer.

Biomarkers, Tumor↗
PubMed2004

Investigation of volatile biomarkers in lung cancer blood using solid-phase microextraction and capillary gas chromatography-mass spectrometry.

In the present work, solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) was developed for investigation of lung cancer volatile biomarkers. Headspace SPME conditions (fiber coating, extraction temperature and extraction time) and desorption conditions were optimized and applied to determination of volatiles in human blood. To find the biomarkers of lung cancer, investigation of volatile compounds in lung cancer blood and control was performed by using the present method. Concentrations of hexanal and heptanal in lung cancer blood were found to be much higher than those in control blood. The two molecules of hexanal and heptanal were regarded as biomarkers of lung cancer. By comparison of volatiles in breath and in blood, it is demonstrated that hexanal and heptanal in breath were originated from blood and screening of lung cancer by breath analysis be feasible. These results show that SPME/GC-MS is a simple, rapid and sensitive method very suitable for investigation of volatile disease markers in human blood.

Adult↗
PubMed2005

Development of a sensitive and specific enzyme-linked immunosorbent assay for thymosin beta15, a urinary biomarker of human prostate cancer.

OBJECTIVES: In tissue-based assays, thymosin beta15 (Tbeta15) has been shown to correlate with prostate cancer (CaP) malignancy and with future recurrence. To be clinically effective, it must be shown that Tbeta15 is released by the tumor into body fluids in detectable concentrations. Toward this end, we have worked to develop a quantitative high-throughput assay that can accurately measure clinically relevant concentrations of Tbeta15 in human urine. DESIGN AND METHODS: Sixteen antibodies were raised against recombinant Tbeta15 and/or peptide conjugates. One antibody, having stable characteristics over the wide range of pH and salt concentrations found in urine and minimal cross-reactivity with other beta thymosins, was used to develop a competitive enzyme-linked immunosorbent assay (ELISA). Urinary Tbeta15 concentration was determined for control groups; normal (N = 52), prostate intraepithelial neoplasia (PIN, N = 36), and CaP patients; untreated (N = 7) with subsequent biochemical failure, radiation therapy (N = 17) at risk of biochemical recurrence. RESULTS: The operating range of the competition ELISA fell between 2.5 and 625 ng/mL. Recoveries exceeded 75%, and the intra- and inter-assay coefficients of variability were 3.3% and 12.9%, respectively. No cross-reactivity with other urine proteins was observed. A stable Tbeta15 signal was recovered from urine specimens stored at -20 degrees C for up to 1 year. At a threshold of 40 (ng/dL)/mug protein/mg creatinine), the assay had a sensitivity of 58% and a specificity of 94%. Relative to the control groups, Tbeta15 levels were greater than this threshold in a significant fraction of the CaP patients (P < 0.001), including 5 of the 7 patients who later experienced PSA recurrence. CONCLUSIONS: We have established an ELISA that is able to detect Tbeta15 at clinically relevant concentrations in urine from patients with CaP. The assay will provide a tool for future clinical trials to validate urinary Tbeta15 as a predictive marker for recurrent CaP.

Amino Acid Sequence↗
PubMedDate not supplied

Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker.

Many genes become transcriptionally silenced during the development of cancer. As well as affecting disease progression, gene silencing has the potential to influence drug resistance and clinical outcome following therapy. In addition to silencing due to gene mutations, covalent epigenetic modifications such as DNA hypermethylation and histone post-translational modifications are associated with transcriptional inactivation of many genes and are an important early event during carcinogenesis and tumour development. Aberrant methylation of CpG islands in promoters is associated with transcriptional inactivation of genes involved in all aspects of tumour development. Genes involved in key DNA damage response pathways, such as cell cycle control, apoptosis signalling and DNA repair, can frequently become methylated and epigenetically silenced in tumours. This may lead to differences in intrinsic sensitivity of tumours to chemotherapy, depending on the specific function of the gene inactivated. Furthermore, it is proposed that chemotherapy itself can exert a selective pressure on epigenetically silenced drug sensitivity genes present in subpopulations of cells, leading to acquired chemoresistance. Since the DNA sequence of epigenetically inactivated genes are not mutated but rather subject to reversible modifications via DNA methyltransferases (DNMTs) or histone modification, it is possible to reverse silencing using small molecule inhibitors. Such compounds show anti-tumour activity and can increase the sensitivity of drug resistant preclinical tumour models. Clinical trials of epigenetic therapies are now underway. Epigenetic profiling, using DNA methylation and histone analysis, will provide guidance on optimisation of these therapies with conventional chemotherapy and will help identify patient populations who may particularly benefit from such approaches.

Animals↗