Nature Milestones: 14 milestones in human cancer research in the past 20 years!

Nature Milestones: 14 milestones in human cancer research in the past 20 years! In recent decades, people’s understanding of cancer has continued to deepen, such as genetic and epigenetic aberrations related to tumor development, and tumor genome sequencing.

Introduction

Cancer is still one of the biggest killers of humans in the world. Recently, Nature Genetics and Nature Medicine jointly published an article “Nature Milestones in Cancer”, which summarized 14 important milestones in the cancer research journey to demonstrate the significant progress made in understanding cancer and developing new therapies.
In recent decades, people’s understanding of cancer has continued to deepen, such as genetic and epigenetic aberrations related to tumor development, and tumor genome sequencing. These discoveries have promoted the development of new cancer therapies, especially immunotherapy, which has become an important treatment alongside surgery, chemotherapy, radiotherapy and targeted therapy. It is hoped that these breakthrough events can stimulate people’s optimism about cancer research and actively develop new methods to combat cancer.
timeline

Brief introduction

01 Routes to resistance (Research progress of targeted therapy drug resistance mechanism)

At the turn of the century, molecularly targeted drugs targeting driver genes were continuously developed and applied, such as tyrosine kinase inhibitor-imatinib. Compared with traditional drugs, targeted drugs have the characteristics of low toxicity, high efficiency, and fewer adverse reactions. However, clinical trials have shown that patients will develop drug resistance after receiving the targeted drugs, leading to tumor recurrence. To this end, Mercedes E.Gorre and his collaborators studied tumor cells in patients who relapsed after the drug treatment and discovered two different resistance mechanisms (amplification and overexpression of the BCR-ABL fusion gene; BCR-ABL Kinase mutation). This study and similar follow-up studies have shown that cancer is an evolutionary process with varying degrees of tumor heterogeneity; and certain genes and mutations are still important driving factors for tumor growth and survival. Therefore, higher-level targeted drugs can be developed for these driving factors, or combined with other drugs to avoid drug resistance.

02 Tracking cancer in liquid biopsies (non-invasive diagnosis and monitoring of patients by liquid biopsy)

Oncologists have long realized that cancer cells will spread through the bloodstream, so they are committed to developing reliable and sensitive detection technologies to detect cancer cells and their components in body fluids and determine their clinical utility. In 2004, Cristofanilli et al. used CellSearch for the first time to prove the clinical relevance of circulating tumor cell counts to stratify cancer patients; later, researchers detected tumor-related mutations in circulating tumor cells (CTCs) to identify the presence of tumor-derived substances in the blood. Diehl et al. used the detection of tumor mutations in colon cancer patients to provide strong evidence for ctDNA analysis as a tumor biomarker; in 2010, Pantel and Alix-Panabières derived this analysis of circulating tumor substances into a variety of clinical applications. Named “liquid biopsy”; in 2013, Dawson and others monitored blood samples from women with metastatic breast cancer undergoing treatment and found that as a cancer biomarker, ctDNA is more sensitive than CTCs and changes in ctDNA levels It is closely related to treatment response; in 2014, Bettegowda and others tested and analyzed the blood of patients with 14 different types of cancer, which confirmed that cancer cells and cancer-derived DNA can enter the blood at any stage of disease development. These studies have prompted clinicians to increasingly apply liquid biopsy to a range of clinical applications, predict the risk of disease recurrence and track mutations associated with resistance. One of the next challenges in this field will be to incorporate liquid biopsy into routine cancer screening programs to promote early cancer diagnosis.

03 When cancer prevention went viral (HPV vaccine to prevent cervical cancer)

Cancer prevention strategies are theoretically attractive, but they are often difficult to implement because the pathogenesis of most cancers involves multiple factors. In 1983, Harald zur Hausen et al. first discovered the presence of a specific subtype of human papillomavirus (HPV-16) in biopsy samples from patients with cancer of the reproductive organs; then in 1999, researchers determined that HPV is cervical cancer The main pathogenic factor of HPV; the results of clinical trials of a VLP-derived vaccine against HPV-16 were published for the first time in 2002, confirming its efficacy; in 2004, Harper et al. confirmed that vaccination against HPV 16 and 18 bivalent vaccine (Cervarix) is possible Will reduce the risk of cervical cancer; in 2006, Merck’s first HPV vaccine Gardasil (for HPV 6, 11, 16 and 18) successfully developed to prevent cervical cancer was approved by the US FDA, and Cervarix was subsequently approved by the European EMA; FDA and EMA followed Gardasil-9 was approved in 2014 and 2015. The vaccine can prevent 9 types of HPV infections. Despite a series of successes in vaccine research and development, the potential of HPV vaccination has just begun to be realized. There are still some challenges, such as the lack of extensive implementation of the HPV vaccination plan, and public distrust of the vaccine.

04 A licence to kill (Using synthetic lethality for cancer treatment)

In 1946, Theodore Dobzhansky proposed “synthetic lethality”, which refers to the co-mutation of two genes to cause cell death, and the mutation of any one of the genes alone will not cause such a result. This strategy is one of the research on anticancer drugs. New direction; in 1997, Leland Hartwell, Stephen Friend and colleagues proposed that synthetic lethal relationships may lead to new anticancer drug targets; in 2005, Alan
The Ashworth team conducted two landmark studies in collaboration with KuDOS Pharmaceuticals, which showed that human cancer cells with mutations in the DNA repair tumor suppressor genes BRCA1 and BRCA2 are selectively sensitive to PARP inhibitors, and both in vitro and mouse experiments have shown A larger therapeutic index;
In 2014, the FDA and EMA approved the first PARP inhibitor olaparib for targeted therapy of BRCA1/2 germline mutant ovarian cancer patients. Since then, Olapaparib and three other PARP inhibitors have been approved for several other malignancies Tumor (breast cancer, pancreatic cancer and prostate cancer) treatment.
In addition to being related to specific gene mutations, drugs may also produce synergistic enhancement effects. In 2020, EMA and FDA approved the combined use of the BRAF inhibitor encorafenib and the EGFR-targeting antibody cetuximab to treat BRAF mutant metastatic colorectal cancer .
At present, CRISPR-Cas9 is the mainstream technology for screening synthetic lethal drugs to help the development of anti-cancer drugs. The current exploration areas mainly include the internal mechanism of the cell (the interaction of BRCA-PARP and BRAF-EGFR), and the combination of targeted drugs and immunotherapy Combine.

05 Sitting on the fence (senescence induced by oncogenes in precancerous tissues and cancer)

Cellular senescence is caused by internal replicative senescence or external oxidative stress and DNA damage. The latter can also be driven by activated oncogenes and is called oncogene-induced senescence (OIS). In 2005, a research team reported the existence of OIS in mouse and human precancerous tissues, and the pathway of OIS action depends on tumor tissue and carcinogenic damage; senescence-related β-galactosidase is the most widely used cell senescence One of the markers. Later, Collado et al. identified a set of expression profile genes related to the KRAS-V12-induced senescence phenotype, proving that senescent cells exist in precancerous adenomas; senescent cells usually show abnormalities of tightly packed DNA Chromatin lesions; two follow-up studies in 2006 confirmed the interaction between aging triggers; in 2008, researchers found that the secretion of a variety of chemokines and interleukins (including IL-6 and IL-8) can be maintained Growth is stagnant, thereby stabilizing the system. Research in the past ten years has revealed the multifaceted and highly dynamic nature of aging and its related secreted phenotypic factors, and researchers are currently exploring the clinical potential and benefits of this treatment strategy for cancer patients.

06 Not a simple switch (metabolic adaptation in cancer)

Malignant tumor is not only a genetic disease, but also a metabolic disease. It is embodied in that even in the case of sufficient oxygen supply, malignant tumor cells mainly undergo glycolysis to promote lactic acid secretion. This phenomenon is called the “Warburg effect” .

• In 1997, Chi V. Dang and colleagues reported that the glycolytic enzyme lactate dehydrogenase A (LDHA) is the transcription target of the oncoprotein MYC, which provides the molecular basis for the Warburg effect; Paul M. Hwang and Karen Vousden’s research team In 2006, it was discovered that the tumor suppressor protein p53 is involved in controlling the balance between glycolysis and oxidative phosphorylation (OXPHOS), which confirmed the connection between oncogenic driver gene mutations and the Warburg effect at the level of tumor suppressor;
• Subsequently, Thompson and his collaborators proposed a model in which the metabolism of cancer cells was adjusted to optimize the acquisition of nutrients and produce growth advantages; the Navdeep S. Chandel research team confirmed that cancer cells induced by the oncoprotein KRAS in vitro and in vivo Growth requires mitochondrial metabolism and other functions, which shakes Warburg’s hypothesis of irreversible damage to mitochondria in cancer;
• A series of studies in the 2010s made the field further deviate from Warburg’s path, showing the heterogeneity of cancer metabolism among different patients, within the same patient, and between different regions within the same tumor, and emphasized that cancer genotype and tissue environment are The key determinant.

So far, only a limited number of drugs targeting cancer metabolism have been successfully applied in clinical practice (enasidenib approved by the FDA for acute myeloid leukemia). With the in-depth understanding of tumors, this situation may change in the future.

07 Sequencing the secrets of the cancer genome (first cancer genome sequencing)

In the first decade of the 21st century, the emergence of second-generation sequencing technology (NGS) provides new methods for the research of tumor molecular biology, and also heralds a major change in cancer research.

In 2008, American scientists Ley et al. used Solexa technology to determine the complete DNA sequence of the human cancer genome for the first time, and compared it with the normal tissues of the same individual. In the end, only 8 tumor DNAs that may be related to AML were found in the patient’s tumor DNA. Nucleotide Variation (SNV), which is a real milestone in cancer research;

In 2009, three other cancer genomes from metastatic breast cancer, lung cancer and melanoma cell lines were published.

These four studies show that cancer has substantial genetic heterogeneity.

At present, large-scale studies such as the Cancer Genome Atlas (TCGA) and Whole Genome Pan-Cancer Analysis (PCAWG) have sequenced tens of thousands of cancer genomes of various tumor types, revealing the complex dynamics of tumor development, but due to lack of adequate Institutions with sufficient resources limit clinical applications.

08 Unleashing the immune system against cancer (immune checkpoint inhibitor)

The earliest use of the immune system to treat cancer can be traced back to more than 100 years. The immune system has an immune surveillance function. However, cancer cells can evolve multiple mechanisms to evade the body’s immune surveillance and attacks in some cases.

• In 1996, James Allison and colleagues demonstrated that antagonistic antibodies targeting CTLA-4 can induce tumor rejection in mice. This discovery revealed the therapeutic potential of immune checkpoint inhibitors (ICIs);
• In 2003, Allison and his collaborators conducted the first human study on the CTLA-4 antibody ipilimumab, which provided clinical evidence for the treatment concept. At the same time, the discovery of the immune checkpoint ligand PD-L1 and its receptor PD-1 Promote the development of new ICIs;
• In 2010, the first human study on PD-1 antibody nivolumab revealed the persistent regression of several tumor types;
• In 2011, the FDA approved the first ICI—ipilimumab; in 2014, the FDA approved the first PD-1 inhibitor—pembrolizumab for the treatment of ipilimumab-refractory melanoma, and subsequently nivolumab was also approved;
• In 2015, PD-1 inhibitors were gradually approved for the treatment of other tumor types;
• In 2016, the FDA approved the first PD-L1 inhibitor—atezolizumab;
• The 2018 Nobel Prize in Physiology or Medicine was awarded to Allison and Honjo for their outstanding contributions in the field of cancer immunotherapy.

At present, ICIs have been included in the treatment of at least 17 advanced malignant tumors, bringing the possibility of long-term survival for patients, and may even cure some patients. In addition, these drugs are used in combination with other treatments and have been approved for chemotherapy and anti-angiogenic drugs. However, ICIs are not a panacea. There is a risk of immune-related adverse events (irAEs). Important issues must be addressed to further improve patient prognosis and alleviate irAEs.

09 Engineering armed T cells for the fight (engineering T cells to kill cancer cells)

T cells are the main weapon of the immune system, which can effectively identify and kill infected cells. If they recognize cancer cells, they will also be killed. Adoptive cell therapy (ACT) uses this cytotoxic ability of T cells to eradicate tumors.

• In the 1980s, ACT was successfully applied to cancer treatment for the first time. Steven Rosenberg isolated tumor infiltrating lymphocytes (TIL) from melanoma patients, activated and expanded them, and injected them into the patients. This study showed that modified T cells after metastasis It can still survive for several months, which is a key condition for ACT;
• In 1989, Zelig Eshhar combined the variable region of the antibody with the constant region of the T cell receptor (TCR) chain to produce chimeric antigen receptors (CARs), which provide T cells with antibody type specificity;
• In 2002, Michel Sadelain and colleagues optimized the CAR design, integrating the intracellular domain of TCR and the key costimulatory receptor CD28 into a single molecule to help maintain the expansion, function and persistence of T cells;
• In 2010, James Kochenderfer and his colleagues made an important breakthrough in CAR-T cell therapy and found that CAR-T cells are active in patients;
• In 2017, CD19 CAR T cell therapy was approved by the FDA for the treatment of children with ALL and adults with aggressive lymphoma.

In addition, another type of ACT is to engineer T cells to express TCRs that recognize tumor-associated antigens. This method can target antigens that are not present on the cell surface. Despite the success of T cell immunotherapy, there are still important obstacles, such as: disease recurrence caused by antigen loss, acquired drug resistance, and toxic effects. Currently, new CAR constructs are being developed to address these limitations.

10 Oncohistones: epigenetic drivers of cancer (epigenetic drivers of tumor occurrence and development)

The genetic and biological characteristics of pediatric cancers are different from those of adult cancers. The repeated histone mutations found in childhood cancers indicate that “oncogenic histones” are the root cause of many aggressive pediatric cancers.

• In 2012, two groundbreaking studies revealed high-frequency somatic mutations in high-grade gliomas in children. These mutations mainly affect the histone H3 gene. Oncogenic histones interfere with chromatin remodeling and accessibility. Transcription regulation, thereby promoting the occurrence and development of tumors;
• In 2013, a number of studies reported that EZH2 can be used as a therapeutic target and confirmed that the loss of H3K27me3 is related to the up-regulation of many genes involved in developmental neurogenesis;
• A report in 2017 indicated that some sites (such as CDKN2A) retain H3K27me3, leading to selective gene silencing procedures, promoting tumorigenesis, while retaining the identity of tumor cell origin;
• In 2019, studies have shown that oncogenic proteins are not limited to gliomas and sarcomas. Somatic mutations of all core histones have been found in different types of tumors, but it is impossible to determine whether it is a driver mutation or a passenger mutation, and the underlying underlying mechanisms are also still not clear.

Currently, some histone deacetylase inhibitors and tyrosine kinase inhibitors are in clinical trials. According to tumor genetic screening, therapeutic intervention in clinical trials should increase the chance of success.

11 Tumour evolution: from linear paths to branched trees (the clonal diversity of tumor cells is the basis for tumor progression and treatment resistance)

The emergence of second-generation sequencing technology has achieved the characterization of cancer genomes with unprecedented resolution. The study of cancer genome maps is expected to make cancer treatment develop in a genotype-oriented direction.

• In 1976, Peter Nowell proposed that cancer is an evolutionary process. Subsequently, James Goldie and Andrew Coldman proposed that tumor gene heterogeneity increases resistance to treatment;
• In 2000s, several studies proved the complexity of clonal evolution and supported that clonal diversity is the basis of disease progression and treatment resistance;
• In 2011, Anderson and Notta et al. traced the evolutionary path of different subclones in the progression of acute lymphoblastic leukemia, and found that the degree of genetic heterogeneity of the initial cell subsets of leukemia and the genetic heterogeneity of the leukemia cell population in the sample The degree is similar, and the branch evolution trajectory does not conform to the linear model of cancer evolution;
• In 2012, Gerlinger et al. confirmed that cancer is a highly dynamically evolving entity, which promoted the transformation of people’s thinking about tumors—from linear cancer evolution to tree-like cancer evolution, and showed that cancer genomes are extremely heterogeneous.

Genetic heterogeneity exacerbates treatment resistance. Therefore, a comprehensive understanding of the dynamics of cancer evolution and evaluation of tumor heterogeneity are essential for prediction, drug development, and treatment.

12 Undruggable? Inconceivable (targeting “undruggable” non-kinase proteins)

At the beginning of the 21st century, dozens of kinase inhibitors are constantly moving into the clinic, and the research progress of key non-kinase targets in oncology is relatively scarce. The RAS gene is one of the most widespread cancer-causing mutations. Since its discovery in 1982, a drug for RAS has not been successfully developed. Therefore, RAS has become an “undruggable” target.

In 2013, Shokat reported for the first time the feasibility of using small molecules to covalently bind to KRAS-G12C mutants (one of the most common RAS mutations in non-small cell lung cancer). This discovery caused a sensation. Two drugs (AMG510, MRTX849) was developed and showed efficacy in early clinical trials.

However, not all RAS mutations are G12C, and compounds targeting KRAS subtypes other than G12C are also being developed. These subtypes are commonly found in NCSLC, pancreatic cancer, and colorectal cancer. Compared with RAS, the development of other non-kinase target inhibitors has not been successful, such as p53 inhibitors, which failed in the phase III trial of acute myeloid leukemia in 2020; MYC, there is still no medicine currently available.

In addition, proteolytic targeted chimera technology (PROTACs) may liberate these drugless targets. The first PROTAC successfully completed the phase I trial in 2020, showing some signs of anti-tumor effects. Therefore, it is feasible to develop therapeutic compounds targeting proteins.

13 Good bacteria make for good cancer therapy (the influence of intestinal microbiota on anti-tumor immune response)

At present, many cancer treatments rely on the stimulation of anti-tumor immune response, but it is not clear whether the gut microbiota will influence the host’s response to cancer treatment through the immune system.

• In 2013, two pioneering studies by the team of Laurence Zitvogel and Giorgio Trin Chieri proved that a complete gut microbiota to activate the innate immunity and adaptive immune system is very important for the effectiveness of the three anti-cancer programs;
• The research results of Iida et al. also showed that tumor-bearing mice lacking intestinal microbes respond to CpG oligodeoxynucleotide (ODN), oxaliplatin chemotherapy and interleukin 10 receptor (IL-10R) blockade Weaken
• In 2015, two studies were conducted to further identify different types of bacteria that regulate anti-tumor immune responses under treatment pressure, such as: Bifidobacterium spp. and B. fragilis;
• In 2018, Zitvogel, Gajeski and Jennifer Wargo published three parallel studies, showing that intestinal symbiotic bacteria determine the efficacy of anti-PD-1 ICIs for patients with melanoma and epithelial tumors.

In addition, the composition of the gut microbiota may be a factor leading to the primary resistance of ICIs. In summary, recent studies have shown that the gut microbiota can affect the efficacy of immunotherapy, but strict clinical trials are required to confirm its credibility, and there are still some challenges that need to be resolved, such as: gut microbiota prediction Is the efficacy of immunotherapy related to cancer species, race, and drugs? How does the gut microbiota affect the immune system’s response to cancer treatment?

14 The AI ​​revolution in cancer (the potential of artificial intelligence in cancer diagnosis and monitoring)

At present, histopathology is still the “gold standard” for cancer diagnosis. The emergence of clinical genomics helps to improve patient stratification and clinical decision-making by identifying operable tumor weaknesses, but histological evaluation and sequencing methods are relatively time-consuming and Expensive, and often produce inconsistent results in different institutions, artificial intelligence (AI) + medical can achieve clinical-level automated diagnosis and simplify the work process of clinicians.

In the past decade, the amount of digital clinical data has exploded, including electronic health records, genomics, and digital biomedical images.

• In 2017, Esteva et al. published a landmark study on applying computer vision to cancer detection. The author used a large number of data sets of digital images of skin conditions to train and verify a deep convolutional neural network, so that the network can accurately distinguish between good Malignant lesions;
• Bejnordi and others pioneered the accurate detection of breast cancer lymph node metastasis by deep learning models;
• Prospective clinical trials conducted by Hollon et al. show that artificial intelligence-driven systems can provide accurate diagnosis for patients undergoing brain cancer surgery;
• Esteva et al. used conventional mobile phone cameras to pave the way for AI-assisted differential classification of skin injuries in an economical way.

These are just the beginning. The integration of big data and artificial intelligence in the oncology field provides a unique interface, and we look forward to groundbreaking discoveries in this research field in the next 10 years.

~~~ Nature Milestones: 14 milestones in human cancer research in the past 20 years! In recent decades ~~~

~~~ Nature Milestones: 14 milestones in human cancer research in the past 20 years! In recent decades ~~~

~~~ Nature Milestones: 14 milestones in human cancer research in the past 20 years! In recent decades ~~~

(source:chinanet, reference only)

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