Research hotspot and frontier progress of cancer under the background of precision medicine
1. Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China；
2. Department of oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Updated：2020-12-09?DOI：10.12032/TMR20190225101
Highlights
This paper takes stock from five aspects, namely, treatment methods, detection technology, new drug research and development, information data and traditional Chinese medicine, with a view to "from the point to the surface", "from the outside to the inside", and "the combination of Chinese and western", so as to explore the overall picture of cancer treatment and research.
Traditionality
Precision medicine is consistent with the treatment philosophy and thought of traditional Chinese medicine. The three factors of "time, place and people" and the dialectical treatment thought of "different treatment for different diseases and the same treatment for different diseases" all reflect the diagnosis and treatment thought of precision medicine.
Abstract
The timely introduction and rapid development of precision medicine have provided strong theoretical support and technical support for tumor research. The treatment methods have been developed from single to multiple; the research technology has been transformed from macro to micro; the treatment drugs have been updated from systemic chemotherapy to targeted therapy and immunotherapy, and cancer has changed from a highly lethal disease to a "chronic disease". Based on the current international cancer research hotspots and treatment frontiers, this paper takes stock from five aspects, namely, treatment methods, detection technology, new drug research and development, information data and traditional Chinese medicine, with a view to "from the point to the surface", "from the outside to the inside", and "the combination of Chinese and western", so as to explore the overall picture of cancer treatment and research.
Keywords
Background
In January 2015, the US government put forward the?"Precision Medicine Initiative", and the concept of precision medicine quickly entered the public vision and international stage, becoming a hot topic of academic concern. Precision medicine is defined as?"a new approach to disease prevention and treatment that takes into account differences in an individual's genes, environment and lifestyle" by the National Institutes of Health [1]. The purpose of the?"Precision Medicine Initiative" is to transform the concept of precision medicine into scientific evidence for clinical practice, thus ushering in a new era of medicine [1].
The proposal of "Precision Medicine Initiative" is closely related to cancer. Cancer has the highest case-fatality rate in the world, rising with age, and is characterized by "unexplained drug resistance, genetic heterogeneity of tumors, failure to adequately assess efficacy and tumor recurrence.". Precision medicine is a kind of individualized medicine, which can be based on the characteristics of the cancer itself, through the bio-information database, the patient's individualized testing techniques, and the great data analysis techniques, and the big data analysis, to create individualized treatment programs for different patients, which make the tumor treatment appear to be "individualized", "precision" and "optimal".
Precision and innovative tumor treatment methods
In addition to the three main treatment methods of operation, radiotherapy and chemotherapy, the treatment methods of immunotherapy, targeting therapy, hormone therapy and stem cell transplantation have emerged in recent years and has been developed in a single, multi-directional, wide-ranging, and all-round way, in the best of times.
Tumor immunotherapy
Tumor immunotherapy refers to the body by increasing the role of immunity in tumor immune response. The innate immune system produces direct immune cells, which make the body resist tumors, inflammation or other diseases and protect the human body. Adaptive immune system resists specific threats through antigen specific lymphocytes and forms immune memory [2]. Tumor cells can destroy the immune system and turn immune regulation into a favorable mode for tumor cells by influencing the antigen presentation process of the body, destroying the pathways controlling T cell inhibition and activation, collecting immunosuppressive cells and releasing immunosuppressive active factors and other mechanisms [3,?4]. Tumor immunotherapy aims at these mechanisms to develop drugs in the form of antibodies, peptides, proteins, small molecules, cytokines, oncolytic viruses, as well as bispecific molecules and various cellular therapies.
Tumor targeted therapy
Tumor targeted therapy is targeted at specific oncogenic sites at the cellular and molecular level and can be a protein molecule (such as epidermal growth factor receptor [6,7], human epidermal growth factor receptor 2 [8], vascular endothelial growth factor [9-11] and platelet derived growth factor receptor [12,?13] inside tumor cells or a gene fragment (such as cytospecific moroni leukemia toxin insertion site 1 [14]) to design relevant therapeutic drugs. When drugs enter the body, they will specifically select the carcinogenic site to combine with the effect, so that the tumor cells will die specifically without affecting the normal tissue cells around the tumor, thereby improving the efficacy of colorectal cancer, lung cancer, gastric cancer, breast cancer, melanoma, lymphoma and other cancers [15] to reduce toxic and side effects.
Tumor hormone therapy
Tumor hormone therapy (Hormone therapy also called endocrine therapy) refers to a treatment method for slowing or preventing tumor growth. The occurrence and development of tumors are related to the imbalance of hormone secretion in vivo. In the treatment, some hormones or anti-hormone substances can be applied to change the conditions on which tumor growth depends, so as to inhibit the growth of tumors. At present, the clinical application of more hormone treatment options are: (1) thyroid cancer with thyroxine treatment of thyroid cancer [16]; (2) sex hormones and hormone resistance drugs in the treatment of breast cancer [17], prostate cancer [18], endometrial cancer [19]; (3) adrenal cortical hormone and chemotherapy combined application to enhance the effect of chemotherapy, reduce the toxic side effects of chemotherapy. At the same time, endocrine therapy for leukemia [20], malignant lymphoma [21], malignant melanoma [22], ovarian cancer [23] and kidney, seminal vesicle tumor has a certain therapeutic effect.
Stem cell transplantation therapy
Peripheral blood stem cell transplantation has become an effective method to treat solid tumors such as malignant hematopathy, lymphoma and mammary tumor, especially multiple myeloma [24], malignant lymphoma [25] and breast cancer [26]. Stem cell transplantation does not have a direct anti-tumor effect, but can play an anti-tumor role by combining radiotherapy, chemotherapy or concurrent radiotherapy and chemotherapy [27,?28]. Stem cell transplantation includes autologous stem cell transplantation and allogeneic stem cell transplantation [27]. Autologous stem cell transplantation uses the patient's own bone marrow or blood, while allogeneic hematopoietic stem cell transplantation uses bone marrow or blood from a relative donor.
Rapid detection and analysis technology
Clinical detection and analysis of tumors provides strong support and help for the discovery, treatment and prognosis of tumors. Conventional tumor detection and analysis techniques include blood detection, ultrasonic examination, X-ray scanning (including molybdenum target), CT or MRI scanning, endoscopy, radionuclide detection and others, which have been able to provide a strong guarantee for the detection and treatment of clinical tumors. More and more new concepts, technologies and methods have been applied in the detection and analysis of tumors, providing an important technical guarantee for the early detection, diagnosis and treatment of clinical tumors.
Tumor screening technology
Tumor screening refers to the screening of persons with cancer who are actually diagnosed with the disease through simple, convenient and high-throughput screening methods in a large number of?"normal" people. Screening through further examination and diagnosis provides information about early clinical intervention and timely treatment. Screening has become an important method of early detection of cancer. The United States recommends screening for: cervical cancer [29], breast cancer [30], colorectal cancer [31], prostate cancer [32]; Japan leads the world in gastric cancer screening [33]; Screening for esophageal, hepatocellular and nasopharyngeal cancers in China has been characterized [34]. Currently, common and effective tumor screening methods include: molybdenum target screening for breast cancer; HPV detection and screening for cervical cancer; screening colorectal cancer with fecal occult blood and colonoscopy; low-dose spiral CT screening for lung cancer; slpha fetoprotein and abdominal ultrasound; screening for liver cancer; gastroscope screening for gastric cancer and esophageal cancer.
Liquid biopsy technique
Liquid biopsy is a kind of method to monitor the status of the tumor in the body or organs for transplant patients through gathering body fluids, including blood, saliva, sweat, and discharge, etc. to analysis of circulating tumor cells, plasma free DNA or exosome. Liquid biopsy has the characteristics of non-invasive, comprehensive, accurate and real-time, and plays an important role in the clinical treatment and research guidance of lung cancer [35], colorectal cancer [36], gastric cancer [37], liver cancer [38], lymphoma [39], myeloma [40] and other malignant tumors.
Next generation sequencing
The next generation sequencing is characterized by high throughput, including whole genome sequencing, whole exome sequencing and targeted region sequencing, which have the advantages of high throughput, high accuracy and abundant information. It has been applied in noninvasive prenatal screening, tumor gene testing, genetic disease diagnosis, drug guidance and other clinical fields. The FDA had approved Foundation One CDx47, Foundation Focus ? CDx BRCA, Oncomine DX Target Test, Extended the RAS Panel, MSKCC - IMPACT 5 NGS in vitro diagnostic products, to keep up with the latest progress in cancer research, to get more benefit from the latest treatment approaches for patients with tumor.
Genome editing technology
Genome Editing Technology refers to the ability to?"edit" target genes by means of technical means and methods to achieve knockout, addition and transformation of specific gene DNA fragments. The first generation of gene editing technology, represented by ZFN (zinc-finger nucleases) and TALEN (transcription activator-like effector nucleases), has shown great potential in basic research, gene therapy and genetic improvement. The second-generation gene editing technology represented by CRISPR/Cas9 can target and repair tumor suppressor genes, restore the function and activity of tumor suppressor genes, inhibit tumorigenesis, break immune tolerance, and increase the ability of T cells to recognize tumor cells; It is applied to the construction of gene-oriented knockout animal models [53-56]. Gene editing technology has broad prospects in the application, development, treatment and prognosis of tumor treatment, and has far-reaching implications for future cancer treatment research.
Update iterative new drug for cancer treatment
In recent years, a prominent feature of tumor research field is that it is guided by clinical treatment and patient demand. With the continuous update of tumor treatment-related drugs and the continuous iteration of similar drugs, it gradually forms a complete research and development process of new tumor clinical drugs for laboratory research and development, clinical trials, department supervision and clinical application.
Monoclonal antibody-based drug
Antibody (Antibody), is produced by a single B lymphocyte clone highly uniform, only for a specific antigen epitope of Antibody, including monoclonal Antibody and polyclonal Antibody. Clinically, the antibody drugs for tumor treatment are mainly monoclonal antibody (also known as monoclonal antibody), which has gone through four stages: mouse monoclonal antibody, chimeric monoclonal antibody, humanized monoclonal antibody and whole-human monoclonal antibody. Currently, there are mainly immune checkpoint inhibitors (e.g. Ipilimumab [57] [58], Tremelimumab [59], Nivolumab [60], Pembrolizumab [61]), epidermal growth factor receptor inhibitors (cetuximab [62], gefitiinib [63], erlotinib [64], etc.), vascular endothelial growth factor and receptor inhibitors (bevacizumab [65], sunitinib [66], sorafenib [67], etc.), human epidermal growth factor 2 inhibitors (trastuzumab [47], partuzumab [15], etc.), and CD20 inhibitors (rituximab [39], etc.) can be directly used in the diagnosis, prevention, treatment and immune mechanism research of human diseases. It opens up a broad prospect for the immunological diagnosis and treatment of human malignant tumor.
CAR-T based drugs
Chimeric Antigen Receptor t-cell immunotherapy (CAT-T) is a method for the treatment of tumor cells by artificially synthesizing T cells to express Chimeric proteins which can recognize tumor antigens and then delivering them back to the patient for the elimination of tumor cells after in vitro amplification.CAT-T immunotherapy experienced the first generation (with CD8/CD3γ as the extracellular domain) in 2006 [68], the second generation (adding a CD28 or 4-1BB co-stimulation signal on the basis of CD8/CD3 gamma activation) in 2009 [69] and the third generation (more than or equal to three stimulus signals) currently in clinical use [70]. In 2017, as a treatment drug for CAT-T therapy, FDA approved novartis's Kymriah (tisagenlecleucel-T, CTL019) for children and adolescents with recurrent or refractory acute B lymphocytic leukemia (B-ALL). Gilead's Yescarta (Axicabtagene Ciloleucel) was used in adult patients with recurrent or refractory large b-cell lymphoma (LBCL) who had previously received second-line or multiline systemic therapy. Car-t therapy has been widely studied in hematologic tumors, but its application and research in solid tumors are few [71-74]. Therefore, CAT-T therapy has great potential and broad application prospects.
TCR-T based drugs
T Cell Receptor chimeric T Cell therapy (tcr-t) is to transfer tumor antigen-specific TCR genes into autologous lymphocytes through the carrier and then back into the patient's body to kill tumor cells. This TCR chimeric t-cell can produce a large number of tumor antigen-specific CTL cells in vitro culture, exert cytotoxic effects, and enhance the elimination of tumor cells mediated by the immune system after being returned to the body, targeting and killing tumor cells specifically. In 2006, the first clinical trial of tcr-t for melanoma was conducted [75], followed by clinical trials for melanoma [76], colorectal cancer [77], synovial sarcoma [78], metastatic cervical cancer, esophageal cancer and urinary tract epithelial cancer [79], and the rapid progression of tcr-t-cell therapy, could be an important way to treat malignant tumors.
Cancer vaccines
Cancer Vaccines introduce tumor antigens or genes expressing tumor antigens into a patient to activate the immune system and induce cellular and humoral immune responses to control or eliminate tumors [80]. Tumor vaccine includes tumor therapeutic vaccine [81] and preventive vaccine [78]. Provenge was approved by FDA for treatment of advanced prostate cancer in 2010, which is an important milestone in the immunotherapy of tumor vaccines [82] and provides reference for the development of other tumor vaccines [83,?84]. In 2017, Catherine Wu's team at the dana-farber cancer research institute in the United States developed a personalized cancer vaccine that can mobilize the immune system to target tumor mutated proteins in patients, successfully preventing the risk of cancer recurrence in patients with skin cancer [85]. A team of Ugur Sahin, a professor at the university of Johannes Gutenberg medical center in Germany, found similar results in patients with advanced melanoma [86,?87].
Leading the forefront of biological information technology
Cancer research has become an important topic in the field of natural science. Scientists from various fields such as medicine, biology, pharmacy, information science and statistics have conducted a large number of interdisciplinary studies, ranging from animal tissue level to cellular and molecular level, from the stage of clinical treatment to the stage of basic mechanism, from small-scale individual exploration to big data platform analysis. With the highly developed information society and science and technology, various new bioinformatics means and concepts have been gradually introduced into tumor research and treatment application, providing important support and rich connotation for tumor treatment.
Big data
The popularization of the internet leads human beings into the era of big data. The information storm brought by the internet is changing our life, work and thinking. In the field of biomedicine, big data is abstractly defined as?"biomedical big data",?"health and medical big data",?"medical big data" [88]. It provides an important platform for cancer prevention and treatment research, such as?"Human Genome Project" [89-90],?"Human Proteome Project (HPP)",?"Cancer Genome Atlas" [91] and?"The Surveillance, Epidemiology, and End Results of the US national cancer institute" [92] and others. Big data can not only strengthen the integration of clinical information with molecular biology, genomics, metabolomics and other disciplines [93], but also help people discover the secrets behind diseases, improve the research efficiency of targeted drugs, immunotherapy and comprehensive treatment [94], and achieve?"same disease but different treatment" and "same treatment of different diseases" for tumors.
Artificial intelligence
Artificial intelligence (AI) refers to the intelligence shown by machines made by human beings, which enables computers to simulate certain thinking processes and intelligent behaviors of human beings. It has wide applications in psychology, philosophy, linguistics, biomedical fields and other disciplines. IBM's Deep Blue, Google's AlphaGo and IBM's Watson are all applications of artificial intelligence in various aspects. In the field of tumor research, AI technology has been widely used in tumor research. In 2016, Watson was used to study thousands of cases of resistance to cancer drugs, hoping to develop a new generation of cancer drugs and therapies by clarifying how resistance develops [95]. In 2017, the accuracy rate of using AI to diagnose colorectal cancer in Japan was as high as 86% [96], and the use of AI in cancer prevention and treatment has become more and more in-depth.
Mobile health
Mobile health is to provide medical services and information through the use of mobile communication technology. From appointment registration, payment follow-up, post-discharge management to medical information acquisition, more and more mobile medical products have come into our lives. In 2013, researchers evaluated 295 mobile apps for cancer [97] and found that understanding of cancer, education information of cancer, early detection and prevention of cancer have become important contents of mobile cancer medicine. In China, mobile medical applications such as?"cancer doctor",?"tumor chemotherapy assistant" and "tumor chemotherapy manual" provide a very powerful platform for cancer clinicians.
Indispensable traditional Chinese medicine
Traditional Chinese medicine (TCM) refers to the medical science based on the guidance of TCM theory, which has played an important role in safeguarding people's physical health and population reproduction in China's 5,000 years of development. Precision medicine is consistent with the treatment philosophy and thought of traditional Chinese medicine. The three factors of "time, place and people" and the dialectical treatment thought of "different treatment for different diseases and the same treatment for different diseases" all reflect the diagnosis and treatment thought of precision medicine. TCM plays an active role in the comprehensive treatment of malignant tumors and other major and difficult diseases, especially in the prevention of precancerous lesions of tumors, the recuperation of toxic and side effects of chemotherapy, the delay and prevention of postoperative recurrence and metastasis, and postoperative rehabilitation of tumors.
Prevention precancerous lesions
Precancerous lesions is an early stage of cancer, cancer The development process of cancer include precancerous lesions, carcinoma in situ and infiltrating carcinoma three stages. Precancerous lesions are clinically a broad concept, which means to continue to develop certain lesions that are likely to be cancerous, such as lung nodules [98], thyroid nodules [99], chronic atrophic gastritis [100], liver cirrhosis [101], adenomatous intestinal polyps [102], borneas [103], certain benign tumors (hysteromyoma [104], mammary adenoma [105]), and the like. TCM has a good therapeutic effect on the blocking and prevention of precancerous lesions, and can play an all-round, multi-channel and multi-target regulatory role in the treatment of precancerous lesions. It is found that TCM plays an obvious role in preventing the occurrence and development of gastric cancer [106-108], colorectal cancer [109,?110], liver cancer [111], breast cancer [112] and other common malignant tumors. The idea of?"treating the disease before cure" in TCM is the concept of preventing the occurrence and development of diseases, and "preventing the disease before cure, namely preventing the disease from changing" can play an active guiding role in the prevention and treatment of precancerous lesions.
Regulation body immune
Immunotherapy has become the most effective method for curing cancer [113,?114], which mainly means to kill tumor cells by activating the body's own immune system [115]. One of the main functions of TCM in the treatment of tumors is to regulate the body's immunity [116] and enhance the body's autoimmune function to achieve the purpose of anti-tumor [117,?118]. The main mechanisms of TCM in the regulation of the body's immune response to tumor include: (1) TCM regulates the body's anti-tumor immune response, such as regulating major histocompatibility complex, Fas/FasL [119], Bcl-2-associated x protein / B-cell lymphoma 2 [120] and inhibiting of stem cells [121,?122]; (2) TCM reverses the immune suppression of the body and regulates the anti-tumor function of immune cells, such as reversing the immune phenotype of T lymphocytes and tumor-related macrophages and regulating Th1/Th2 factor. TCM plays a dual and multi-target role in regulating the immune microenvironment of tumors in the body. It can improve the immune monitoring and clearance function of the body, enhance the killing ability of the body to tumor cells, break the immune tolerance of the body, reverse the immune escape of tumor cells, and enhance the anti-tumor immune efficiency of the body. It is an important method for the comprehensive treatment of tumors.
Reduce toxic side effects
The non-negligible problems in the integrated treatment of tumor radiotherapy, chemotherapy, immunotherapy, target treatment are the adverse side effects of vomiting, alopecia, hands and hands syndrome, and bone marrow rejection caused by the treatment. The toxic and side effects of the above treatment may become an important factor preventing cancer patients from receiving standard treatment, or even the primary reason for patients not to receive standard treatment. TCM therapy is characterized by?"combination of disease and syndrome and holistic concept". Considering the overall treatment of patients and diseases, it is combined with radiotherapy and chemotherapy, targeted therapy and immunotherapy. While playing its anti-tumor role, TCM has a significant effect on alleviating the toxic and side effects of treatment on patients. It has been reported that Fufang Kushen Injection [123], Kangai Injection [124], Shenqi Fuzheng Injection [125], Xuefu Zhuyu Decoction [126], Fuzheng Kangai Formula [127], Lophatherum and Gypsum Decoction [128], etc., has a significant deceleration on the toxic and side effect of cancer chemotherapy and radiotherapy patient. Therefore, the comprehensive treatment for various toxic and side effects in the precise treatment by TCM is an indispensable and irreplaceable treatment method.
Promoting rehabilitation process
TCM has both drug and non-drug treatment methods, such as acupuncture (including electroacupuncture), moxibustion (including heat-sensitive moxibustion), Gongfu (Qigong, Taijiquan, eighteen methods of practicing Gongfu, Baduanjin, Wuqinxi, etc.) and massage. These non-drug treatment methods also play an important auxiliary role in the process of tumor treatment and rehabilitation process of tumor patients after surgery and drug treatment. Studies have shown that acupuncture combined with different acupoints has a significant effect on nausea and vomiting caused by chemotherapy [129]; acupuncture combined with western medicine has a definite effect on the treatment of polycystic ovary syndrome [130]; meridian balance method can alleviate chronic pelvic pain caused by gynecological tumors [131], electric acupoint stimulation has a preventive effect on lower limb thrombosis in elderly patients with malignant gastrointestinal tumor postoperative patients [132], Qigong has an improved effect on fatigue and sleep quality of non-hodgkinlymphoma chemotherapy patients [133], Taijiquan has an obvious alleviating effect on cancer-related fatigue of lung cancer chemotherapy patients [134]. It is believed that comprehensive treatment for clinical cancer patients has a good therapeutic effect and plays a positive and positive role in the later rehabilitation of cancer patients.
Summary and analysis
The proposal and implementation of the precision medicine initiative has brought modern medicine into an era of large-scale integration of medical data. Genomics, proteomics, metabolomics, epigenetics, microbiology, environment, behavior, clinical examination, TCM and other information have led to exponential growth of medical data. The knowledge system of precision medicine has exceeded the scope carried by individual doctors, and the speed of knowledge update has also exceeded the capacity of traditional medical education system. The clinical treatment of precision medicine for tumors is increasingly dependent on information technology.
In the context of precision medicine, how to effectively process, integrate, analyze and utilize the health data of cancer patients and make appropriate clinical and production decisions has become a problem that doctors, hospitals, pharmaceutical companies and regulatory departments need to think about and face. Under the background of precision medicine, the treatment of tumors still has a long way to go. The development environment of precision oncology is still immature. The development direction is still unclear. The achievements in clinical practice are also limited. It is necessary to understand and grasp the goals and trends of precision medicine for cancer, conduct in-depth research on the mechanism of tumor development and treatment, better serve the academic, clinical and patient needs, and promote the progress of academic research and clinical treatment of cancer under the background of precision medicine.
Acknowledgements
This study is supported by the National Natural Science Foundation of China (Nos.81673784, 81673783, 81520108031, 81830120), the Science Foundation for Shanghai Committee of Science Project (Nos.18QA1404200, 17QA1404100), the Shanghai Health Bureau Science Foundation (No.ZY (2018-2020)-FWTX-4026), and the Xinglin Young Scholar, Shanghai University of Traditional Chinese Medicine.
Conflict of Interest
The authors declare that there is no conflict of interests regarding the publication of this paper.
Abbreviations
symbol——definitionAI——artificial intelligenceTCM——traditional Chinese medicine
Cite this article:
Zhou LH, Li Y, Li Q. Research hotspot and frontier progress of cancer under the background of precision medicine.?Tradit Med Res. 2020;5(1):22–33. doi:10.53388/TMR20190225101