Cancer, a formidable adversary in the realm of human health, perseveres as a prominent contributor to global mortality. Through a persistent evolution over recent decades, the multifaceted domain of cancer research has fervently propelled the advancement of novel therapeutic interventions. Among these, the burgeoning prominence of immunotherapy has emerged as a pivotal cornerstone alongside the established pillars of surgical intervention, chemotherapeutic approaches, radiation therapy, and precision-targeted therapies. An article titled 'Nature Milestones in Cancer' was jointly published by Nature Genetics and Nature Medicine. It summarizes 14 significant milestone events in cancer research during the 21st century, showcasing unraveling the intricacies of cancer pathogenesis and the concomitant evolution of transformative treatment modalities.
1. Research Progress on Targeted Therapy Resistance Mechanisms
In contrast to conventional pharmaceuticals, targeted therapies exhibit notable attributes such as minimal toxicity, heightened efficacy, and reduced incidence of adverse reactions. Nonetheless, patients can develop resistance to these targeted drugs, thereby instigating the resurgence of malignant tumors. Addressing this pivotal issue, Mercedes E. Gorre and her team embarked on an extensive inquiry involving tumor cells derived from patients who had encountered relapse subsequent to targeted drug regimens. This meticulous analysis unearthed two distinct modes of resistance, namely, the amplification and overexpression of the BCR-ABL fusion gene, alongside BCR-ABL kinase mutations. The study, along with subsequent analogous research endeavors, indicated that cancer is an evolutionary process with varying degrees of tumor heterogeneity. Moreover, specific genetic elements and mutational patterns persist as pivotal determinants dictating tumor proliferation and sustenance. Consequently, the proposition arises that the development of sophisticated targeted therapeutics targeting these pivotal determinants, or the strategic implementation of combinatorial regimens, holds promise in overcoming the challenging specter of drug resistance.
2. Non-Invasive Diagnosis and Monitoring of Patients Through Liquid Biopsies
Oncologists have long been aware that cancer cells can spread through the bloodstream. Therefore, they have been committed to developing reliable and sensitive detection techniques to detect cancer cells and their components in bodily fluids and determine their clinical utility. In 2004, Cristofanilli et al. first used CellSearch to demonstrate the clinical relevance of circulating tumor cell (CTC) counts for stratifying cancer patients. Subsequently, researchers identified the presence of tumor-derived material in the blood by detecting cancer-related mutations in circulating tumor cells (CTCs). Diehl et al. provided strong evidence for using ctDNA analysis as a cancer biomarker by detecting tumor mutations in colon cancer patients. In 2010, Pantel and Alix-Panabières coined the term "liquid biopsy" for this technique of analyzing circulating tumor material, which has since given rise to various clinical applications. In 2013, Dawson et al. monitored blood samples from metastatic breast cancer patients undergoing treatment and found that ctDNA, as a cancer biomarker, had higher sensitivity than CTCs, and changes in ctDNA levels were closely related to treatment response. In 2014, Bettegowda et al. analyzed blood samples from patients with 14 different types of cancer, confirming that cancer cells and cancer-derived DNA could enter the bloodstream at any stage of disease progression. These studies have led clinicians to increasingly apply liquid biopsies in a range of clinical applications, predicting the risk of disease recurrence and tracking mutations associated with drug resistance. One of the next challenges in this field will be integrating liquid biopsies into routine cancer screening programs to promote early cancer diagnosis.
3. Preventing Cervical Cancer with HPV Vaccines
Cancer prevention strategies are theoretically attractive but often challenging to implement due to the multifactorial nature of most cancers. However, in 1983, Harald zur Hausen and others first discovered a specific subtype of human papillomavirus (HPV-16) in biopsy samples from genital organ cancer patients. Subsequently, in 1999, researchers identified HPV as the primary causative factor of cervical cancer. In 2002, clinical trial results for a VLP-derived vaccine targeting HPV-16 were published, confirming its effectiveness. In 2004, Harper and colleagues confirmed that vaccination with the bivalent vaccine against HPV 16 and 18 (Cervarix) might reduce the risk of cervical cancer. In 2006, the first HPV vaccine to prevent cervical cancer, Gardasil (targeting HPV 6, 11, 16, and 18), was approved by the U.S. FDA, followed by approval for Cervarix by the European Medicines Agency (EMA). The FDA and EMA subsequently approved Gardasil-9 in 2014 and 2015, respectively, which can prevent nine types of HPV infections. Although significant progress has been made in vaccine development, the full potential of HPV vaccination is just beginning to be realized, with challenges such as the lack of widespread vaccination programs and public vaccine hesitancy still existing.
4. Using Synthetic Lethality in Cancer Treatment
In 1946, Theodore Dobzhansky introduced the concept of "synthetic lethality", where the simultaneous mutation of two genes leads to cell death, while a mutation in either gene alone does not produce this result. This strategy became a new direction in cancer drug research. In 1997, Leland Hartwell, Stephen Friend, and colleagues proposed that synthetic lethality relationships could lead to new cancer drug targets. In 2005, Alan Ashworth's team collaborated with KuDOS Pharmaceuticals on two groundbreaking studies, demonstrating that human cancer cells with mutations in the DNA repair tumor suppressor genes BRCA1 and BRCA2 were selectively sensitive to PARP inhibitors. In vitro and mouse experiments showed significant therapeutic benefits. In 2014, the FDA and EMA approved the first PARP inhibitor, olaparib, for targeted treatment of ovarian cancer patients with BRCA1/2 germline mutations. Since then, olaparib and three other PARP inhibitors have been approved for the treatment of various malignancies, including breast cancer, pancreatic cancer, and prostate cancer. Apart from specific gene mutations, drugs may also produce synergistic effects. In 2020, the EMA and FDA approved the combination therapy of BRAF inhibitor encorafenib and EGFR-targeted antibody cetuximab for the treatment of BRAF-mutant metastatic colorectal cancer. Currently, CRISPR-Cas9 is the mainstream technology for synthetic lethality drug screening, boosting cancer drug development. Current exploration areas include intracellular mechanisms (BRCA-PARP and BRAF-EGFR interactions) and the combination of targeted drugs with immunotherapy.
5. Cancer Genes Induce Aging in Precancerous Tissue and Cancer
Cellular senescence can be caused by intrinsic replicative aging or extrinsic factors such as oxidative stress and DNA damage, which can also be driven by activated oncogenes, referred to as Oncogene-Induced Senescence (OIS). In 2005, research teams reported the existence of OIS in both mice and human precancerous tissues, and the pathways of OIS were found to depend on the tumor microenvironment and carcinogenic damage. Senescence-associated beta-galactosidase (SA-β-gal) is one of the most widely used cellular senescence markers. Later, Collado and others identified a set of gene expression profiles associated with the senescent phenotype induced by KRAS-V12, confirming the presence of senescent cells in precancerous adenomas. Senescent cells often exhibit DNA-dense foci of abnormal chromatin. Two subsequent studies in 2006 confirmed interactions between senescence-triggering factors. In 2008, researchers found that the secretion of various chemokines and interleukins, including IL-6 and IL-8, can sustain growth arrest, thereby stabilizing the system. Research in the past decade has revealed the complexity and high dynamism of senescence and its associated secretory phenotype. Currently, researchers are exploring the clinical potential and benefits of applying this therapeutic strategy to cancer patients.
6. Metabolic Adaptation in Cancer
Malignant tumors are not only genetic diseases but also metabolic diseases, as evidenced by the fact that even under conditions of sufficient oxygen supply, malignant tumor cells primarily undergo glycolysis, promoting lactate secretion, a phenomenon known as the "Warburg effect". In 1997, Chi V. Dang and colleagues reported that the glycolytic enzyme lactate dehydrogenase A (LDHA) is a transcriptional target of the cancer protein MYC, providing a molecular basis for the Warburg effect. Paul M. Hwang and Karen Vousden's research team in 2006 discovered that the tumor suppressor protein p53 is involved in controlling the balance between glycolysis and oxidative phosphorylation (OXPHOS) and confirmed the connection between oncogenic driver gene mutations and the Warburg effect at the tumor suppressor level. Subsequently, Thompson and collaborators proposed a model in which cancer cell metabolism is adjusted to optimize nutrient acquisition, providing a growth advantage. Navdeep S. Chandel's research group confirmed that the growth of cancer cells induced by the cancer protein KRAS requires mitochondrial metabolism and other functions in vitro and in vivo, challenging the hypothesis of irreversible mitochondrial damage in cancer proposed by Warburg. A series of studies in the 2010s further deviated from the path set by Warburg, demonstrating heterogeneity in cancer metabolism among different patients, within the same patient, and in different regions of the same tumor, emphasizing that cancer genotype and tissue environment are key determinants. So far, only a limited number of drugs targeting cancer metabolism have been successfully applied clinically (e.g., FDA-approved enasidenib for acute myeloid leukemia). As our understanding of tumors deepens, this situation may change in the future.
7. First Cancer Whole Genome Sequencing
In the first decade of the 21st century, the emergence of next-generation sequencing (NGS) technology provided a new tool for the study of tumor molecular biology and signaled a significant transformation in cancer research. In 2008, American scientists, led by Ley, utilized Solexa technology to determine the complete DNA sequence of the human cancer genome for the first time. They compared it to normal tissues from the same individual and ultimately identified only 8 single-nucleotide variations (SNVs) potentially related to AML (Acute Myeloid Leukemia) in the patient's tumor DNA. This was a true milestone in cancer research. In 2009, they published three additional cancer genome studies from metastatic breast cancer, lung cancer, and melanoma cell lines. These four studies demonstrated substantial genetic heterogeneity in cancer.
Currently, large-scale initiatives like the cancer genome atlas (TCGA) and the pan-cancer analysis of whole genomes (PCAWG) have sequenced tens of thousands of cancer genomes across various tumor types, revealing the complex dynamics of tumor development. However, clinical applications are limited due to the lack of institutions with sufficient resources.
References
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- Cristofanilli, M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 2004, 351, 781–791.
- Harper D. M.; et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. The Lancet. 2004, 364(9447): 1757-1765.
- Bryant H. E.; et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature. 2005, 434(7035): 913-917.
- Ley T. J.; et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008, 456(7218): 66-72.
- Bensaad K.; et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006, 126(1): 107-120.
- Chen Z.; et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005, 436(7051): 725-730.
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