Cancer

Cancer targeted therapy is the foundation of precision medicine; it uses drugs or other substances to target specific genes and proteins that control cancer cells’ growth, division and spreading. Compared to traditional chemotherapy drugs, targeted-drugs can specifically act on cancer cells with high efficacy without damaging normal cells. Drugs used in cancer targeted therapy mainly includes small molecules and macromolecules (e.g., monoclonal antibodies), which can target cancer cells and constituents in the tumor microenvironment to activate the immune system. Anti-angiogenesis drugs, such as those targeting vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), transforming growth factor (TGF)-α, TGF-β, Tumor necrosis factor (TNF)-α, and platelet-derived endothelial growth factor (PDGFR) inhibit the proliferation and metastasis of cancer cells. In recent years, the proportion of antibody drugs in cancer treatment has gradually become prominent. Antibody-drug conjugates (ADCs) are a new type of targeted drugs that are composed of monoclonal antibody, cytotoxic drug and linker. ADCs can deliver drugs to tumor cells and minimize the toxicity to normal tissues. Proteolysis-targeting chimera (PROTAC) is a useful technology for targeted protein degradation. PROTAC exploits the ubiquitin-proteasome system and forms a ternary complex with a hijacked E3 ubiquitin ligase and target protein, leading to polyubiquitination and degradation of the target protein.

Cancer immunotherapy (CIT) is a type of biological therapy, aiming to improve anti-tumor immune responses with fewer off-target effects than chemotherapy. Several types of immunotherapy include: oncolytic virus therapies, cancer vaccines, cytokine therapies, adoptive cell transfer (ACT), and immune checkpoint inhibitors (ICIs). In particular, ICIs and ACT have obtained immense clinical response, but their efficacy varies from person to person. Immune cells can be harnessed to eliminate tumor cells, such as T cells, B cells, NK cells, and myeloid cells. T cells have potent tumor-killing capability, therefore, a plethora of cancer immunotherapy research have focused on inducing T-cell-mediated anti-tumor responses. CTLA-4 and PD-1 are found on the cell surface of T cells as co-inhibitory receptors. The breakthrough in cancer immunotherapy results from the identification and subsequent targeting of checkpoint mechanisms in T cells with monoclonal antibodies against CTLA-4 and programmed death-ligand 1/programmed death-1 (PD-L1/PD-1).

Cancer stem cells (CSCs) are populations of cancer cells that have the properties of stem cells i.e. self-renewal and ability to generate differentiated progenies. CSCs have high plasticity, which changes their phenotypic and functional appearance. They have important roles in tumor development, expansion, resistance, relapse and metastasis. Multiple studies have shown that CSCs originate from non-malignant stem or progenitor cells. Inhibition of developmental signaling pathways that are critical for stem and progenitor cell homeostasis and function has important implications in strategies to target CSCs in cancer research.

Drug resistance in chemotherapy, radiotherapy, molecular targeted therapy and immunotherapy is one of the main causes of death due to cancer. Gene mutations, non-genetic and epigenetic mechanisms to evade drug actions can promote the occurrence of drug resistance and treatment failure. Simultaneous resistance to multiple drugs with different chemical structures, different mechanisms of action and different targets is known as multidrug resistance (MDR). MDR can be related to a variety of mechanisms, including overexpression of drug efflux pumps(ABC transporter family), decreased drug uptake, mutation/loss of receptors, altered apoptotic pathway, enhanced DNA repair and drug metabolism(glutathione S-transferase, CYP450).

Metabolic abnormalities are a major feature of cancer, such as increased substance anabolic pathways and aerobic glycolysis. Cancer metabolism shows flexibility and plasticity, which are crucial for the survival and growth of cancer cells. Cancer metastasis is completed in five steps i.e. invasion, dissemination, circulating tumor cells, colonization, and secondary tumor formation. Recently, metabolic adaptation mechanism of cancer metastasis has been proposed to reveal the extensive relationship between cancer metabolism and cancer metastasis. Metastasizing cancer cells selectively and dynamically adapt their metabolism during the complex multistep cascade.