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 Table of Contents  
MINI REVIEW
Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 17-21

Research and development of anticancer agents under the guidance of biomarkers


1 Department of Chemical Drug and Traditional Chinese Medicine, Lanzhou Institutes for Food and Drug Control, Lanzhou, Gansu, China
2 Department of Medicine, The Fifth People's Hospital of Zhuhai, Zhuhai, Guangdong, China
3 Department of Food, Gansu Province Product Quality Supervision and Inspection Research Institute, Lanzhou, Gansu, China
4 Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou, Gansu, China

Date of Submission18-Feb-2019
Date of Acceptance03-Mar-2019
Date of Web Publication28-Mar-2019

Correspondence Address:
Assoc. Prof. Guoyu Qiu
Department of Chemical Drug and Traditional Chinese Medicine, Lanzhou Institutes for Food and Drug Control, No 988, Peng Jia Ping Town, Lanzhou 730050, Gansu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_2_19

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  Abstract 


At present, cancer ranks first as the cause of death in the world, necessitating the need to develop new anticancer agents. As a probe, biomarkers can indicate the biological and pharmacological activity of anticancer agents and are thus valuable in predicting their effectiveness during the research and development phase. This paper reviews the research on the biomarker-guided prediction of the efficacy of anticancer agents. We infer that, in the process of the development of anticancer agents, reasonable selection of biomarkers can improve the accuracy of the development of anticancer agents.

Keywords: Anticancer agents, biomarkers, research and development


How to cite this article:
Xu X, Qiu G, Ji L, Ma R, Dang Z, Jia R, Zhao B. Research and development of anticancer agents under the guidance of biomarkers. Cancer Transl Med 2019;5:17-21

How to cite this URL:
Xu X, Qiu G, Ji L, Ma R, Dang Z, Jia R, Zhao B. Research and development of anticancer agents under the guidance of biomarkers. Cancer Transl Med [serial online] 2019 [cited 2019 Apr 22];5:17-21. Available from: http://www.cancertm.com/text.asp?2019/5/1/17/255121




  Introduction Top


Now, more than half of all cancer patients live in low- and middle-income countries, and that number is expected to rise to 70% by 2030, according to a report by the International Union against Cancer.[1] Cancer has become the first cause of death in urban and rural residents in China. The incidence of cancer is rising rapidly, with about 2.6 million people suffering from cancer and 1.8 million dying every year in China. Currently, there are about 130–150 types of approved anticancer drugs in the market around the world.[2],[3] Anticancer drugs are the primary mode to fight against cancer and represent the highest level of research in cancer therapeutics. As shown in [Figure 1],[4] the failure in the process of development of anticancer agents is due to wrong drug target, wrong molecule, wrong conclusion, and wrong patient. However, under the guidance of biomarkers, the success rate of developing anticancer agents can be three times higher than those without biomarkers. The development of anticancer agents is still slow, expensive, and inefficient. One way to solve this problem is to use predictive biomarkers. During the research, biomarkers are involved in a wide range of disciplines, models, and developmental stages, from the identification and evaluation of drug targets to solving the problem during the clinical trials. Biomarker can be used as the probe to play an important role in determining drug target, drug action mechanism, and other aspects, which is of great significance in predicting the accuracy of the anticancer molecule.[4] In the context of preclinical drug development, biomarker can objectively measure and evaluate the normal biological process, pathological process, and process of drug reaction, which is helpful to monitor the effectiveness of the drug on the disease. [Figure 2] shows the research designs of anticancer agents, differentiated by the presence or absence of biomarkers. With the completion of human genome sequencing and the development of metabonomics technology, biomarkers are more and more widely used in drug development. Major organ systems where biomarkers are reliably applied are the hepatobiliary system, renal system, cardiac system, muscle system, reproductive system, nervous system, and immune system. This paper reviews the biomarker-guided screening of anticancer agents, which we hope to be assistance in further research and development of new anticancer agents.
Figure 1: Comparison of success rate of drug research under the guidance of the presence or absence of biomarkers

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Figure 2: Two designs of anticancer agent research; (a) without the guidance from biomarkers and (b) under the guidance of the biomarkers[4]

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  Biomaker Top


Biomarkers that are based on immunology and molecular biology technology, relating to cell growth and proliferation, are being developed. Many molecules, including proteins, nucleic acids, and metabolic derivatives, can be potential biomarkers. Cancer biomarkers can be the molecules that are directly secreted by the cancer tissues or secreted by the body in response to cancer. The presence of these molecules indicates the presence of cancer in the human body.[5],[6],[7],[8] Identification and detection of these cancer biomarkers are of great importance in understanding the activity and mechanism of action of the drug, which aids in better prediction of the pharmacological activity of the test drug, thus reducing the time and cost of drug research and clinical trials. Drug activity screening is the first step in the discovery of new anticancer agents,in vitro and in vivo. Common biomarkers include cytotoxic biomarkers,[9],[10],[11],[12],[13],[14],[15],[16] gene biomarkers,[17] protein expression biomarkers, and imaging biomarkers.[18] At present, most of the studies on anticancer agents use biomarkers to study the pharmacological activity. Based on the type of biomarkers studied, it is either upregulated or downregulated posttreatment, aiding in prediction of the pharmacological effects of the studied anticancer agent.[19],[20] Metabolomics offer the opportunity to identify endogenous biomarkers and are applicable to the drugs that produce urinary metabolite. However, the protocol is not applicable to the drug that cannot be metabolized or eliminated through different pathway. In a study, stable isotope labeling and unlabeled drug administration were performed on mice, and urine samples were collected, and on the basis of principal component analysis (PCA), nontargeted mass spectrometric metabolomic analysis was performed.[21] Currently, the methods used to find and identify biomarkers include second-generation genome sequencing, bioinformatic mutation analysis, PD marker identification in vivo and in vitro, quantitative Western Blot, FACS analysis, immunohistochemical detection, and DNA sequencing.


  Studying Anticancer Agent Based on Biomarker Top


The search for biomarker includes two key processes. One is to find the biomarker and establish an applicable detection method for it, while the second is to establish the correlation or causal relationship between biomarker and anticancer agent. Only the biomarker that meets both the processes is eligible to be used in the research of anticancer agent.[19] [Table 1] lists the highly cited literature on the research of anticancer agents based on prediction and prognostic biomarkers in recent years.[22] At present, the cost of developing new drugs is rising, technology is improving, but the declaration of new drug is on the decline. In the face of this situation, it is important to identify few biomarkers based on computer design for specific classes of anticancer agent with both biosafety and efficacy. Under the guidance of biomarker, pharmacological activity of anticancer agents, including pharmacokinetic and pharmacodynamic properties and drug efficacy, can also be predicted.
Table 1: Highly cited references about recent studies on anticancer agents by prediction and prognostic biomarkers[23],[24],[25],[26],[27],[28],[29],[30],[31]

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Predict pharmacological activity

A compound must undergo a series of bioactivity screening in vitro and in vivo before it can be considered as a candidate for anticancer agent. In the early stage of screening such a candidate agent, the related specific biomarker plays an important role in its evaluation. Currently, the targets of anticancer agent screening mainly include microtubulin, telomerase, DNA topoisomerase, and those regulating cell signal transduction pathways. The primary research objective of anticancer agents is to find the target, while the application of biomarker discovery is to predict and evaluate the efficacy of anticancer agents and their targets.[33] [Table 2] lists such examples where biomarkers were used to screen anticancer agents.[22]
Table 2: Examples of screening anticancer agents with biomarkers

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Studying pharmacokinetics and pharmacodynamics

The relationship between targets and diseases was confirmed by the biomarkers understanding pharmacodynamic combined with pharmacokinetics. The expression of biological effects was studied and correlated at several levels, including tissue, organ, and whole animal, which were targeted by anticancer agent receptors, to elucidate the pharmacodynamic basis and mechanism of anticancer agents. At the same time, based on the comprehensive and systematic research results, biomarkers closely related to the expression of medicinal properties were found for quality control and guiding the selection of dosage. Pharmacodynamic results of therapeutic anticancer agent are often used to confirm targeted biological reactions, and its analytical methods range from mass spectrometry to immunohistochemistry. So far, detection of antigen-specific antibody was widely used.[34] Membrane transporters, belonging to two superfamilies of ATP-binding cassette transporter (ABC) and solute transporters, play a core role in homeostasis regulation of the body. The drug carriers that can associate with these membrane proteins are widely studied. Drug transporters involve all aspects of drug absorption, distribution, and excretion. Several ABC transporters are highly expressed in a variety of cancers and play an important role in the formation of multidrug resistance phenotypes. Some polymorphisms of transporter have been shown to alter the pharmacokinetic characteristics of clinical drug. Therefore, drug transporters are reliable biomarkers of pharmacokinetics and pharmacodynamics. In the meantime, when the function of transporter is impaired, the substrates of transporter can also serve as a biomarker.[35] Due to the environmental factors and genetic factors of cancer heterogeneity, the response of anticancer drug varies among individuals. Genetic factors may influence the pharmacokinetics and pharmacodynamics of anticancer drug, which results in systemic drug exposure or changes in the function of drug targets that alter drug response. Therefore, some pharmacogenetic biomarkers have been applied in the practice of pharmacodynamics or pharmacokinetics of anticancer agents. However, many genetic biomarkers are in the stage of discovery, and some problems need to be solved to improve the translation of genetic biomarkers, which will involve a multidisciplinary approach using standardized phenotypic and genotyping strategies to work together to identify and replicate associations.[25]

Predicts and prognosis drug efficacy

The function of combination and inhibition of targeted anticancer agents plays a role as molecular targets that are vital in the development and progression of cancer and intracellular signaling pathways. So far, hundreds of different cancer-targeting drugs are approved for clinical use in different countries. Compared with previous chemotherapy, recent anticancer-targeted drugs have fewer side effects, higher efficiency, and higher cost. However, the therapeutic efficiency of the targeted anticancer drugs against advanced cancer is still insufficient. Different targeted anticancer drugs have different mechanisms of action and show curative effect in different patients. Therefore, a personalized approach is needed to select the best candidate of targeted anticancer drugs for individual patients. Now, researchers have developed a new generation of biomarkers, which are molecular pathway activators that can predict the response of individual cancer to targeted anticancer drugs. The successful application of high-throughput gene expression profiles and the emergence of new biological information tools have promoted the rapid development of the fields related to molecular pathways.[36] Predictive biomarkers for cancers are necessary to accurately identify patients who will benefit from such cancer treatment. Approved anticancer drugs target discrete molecular aberrations or pathways in tumor cells, active in a subset of the patient population, but clinical studies have shown that not all patients showed positive response to biomarkers. To predict the emerging resistance mechanism of biomarkers, it is necessary to not only to guide the selection of patient subgroups in specific treatments but also to identify new therapeutic targets. Beyond the “one marker, one drug” model, the integration of genomics transcriptome and receptor status assessment into the joint development of biomarker will contribute to the successful application of molecular marker in cancer therapy.[31] On the other hand, the intrinsic or acquired drug resistance, adverse drug reactions, and heterogeneity between cancer and patients limit the clinical efficacy of anticancer drugs in the treatment of advanced cancer. To overcome these obstacles, the application of predictive biomarkers was used to guide medical oncologist to choose a variety of anticancer treatment for cancer patients and improve the efficiency against toxicity. However, for some anticancer agents from natural sources, such as tribetidine, carbamazepine, and alvocidib, the application of biomarkers to predict the clinical therapeutic effect is still slow.[22]


  Discussion Top


Biomarkers have received extensive attention due to their importance in anticancer agent research as they can be used to screen anticancer agent of high efficiency and low toxicity. However, the mechanism of action of anticancer agent is mostly established in cell line and animal model. Human body is a highly complex system with many cells and organs, where different diseases involve multiple biological signaling pathways and different organs have different mechanisms, which are very difficult to simulate in the preclinical drug development system. In addition, biological signal transduction pathways often involve multiple genes other than the one target, which makes it very limited to use a single original drug target as a biomarker. On the other hand, the majority of anticancer agents has in common DNA-damaging properties and affects not only target cells but also nontumor cells. Its genotoxicity has been demonstrated in experimental models and in cancer patients treated with chemotherapy. This phenomenon makes that some anticancer agents can fail in the latter stages of development because of toxicity and lack of efficacy. To improve anticancer agent safety during its developmental phase, new biomarkers are needed, which can reduce the time-consuming process and cost of drug development. Therefore, it is essential to develop anticancer agent under the guidance of few biomarkers and verify with each other.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Studying Antican...
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