Cancer Research

Cancer is driven by genetic and epigenetic changes that allow cells to hyperproliferate and evade the mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in broader signaling networks that promote cancer progressions. Mutations that convert cellular proto-oncogenes into oncogenes can lead to the overactivation of these signaling pathways, while the inactivation of tumor suppressors eliminates key negative regulators of these signaling. After a tumor expands, the central part of the tumor loses access to oxygen and nutrients, often leading to the growth of new blood vessels (angiogenesis), which restores access to nutrients and oxygen. Subsequently, tumor cells can develop the ability to invade the tissue beyond their normal boundaries, enter the circulation, and seed new tumors at other locations (metastasis).

Fig. 1 Cancer progression

• The Hedgehog (Hh) Signaling Pathway, regulates embryonic development. Major pathway targets include Hh signal peptides (Shh, Ihh, Dhh), transmembrane receptors (Ptch, Smo), and downstream transcription factors (Gli).
• The Wnt Signaling Pathway, plays a key role in embryonic development and the formation of the central nervous system, and also involves in regulating cell growth, migration as well as differentiation, main pathway targets include β-catenin, RhoA protein, Jun kinase, etc.
• The Tyrosine Kinase Receptor Pathway, regulates many target molecules in cells, including Ras/MAPK, STAT, JNK, P13K, and regulates the activity of transcription factors, which can promote cell proliferation, inhibit cell apoptosis, directly related to tumor development. Activation of protein kinases such as EGFR also accelerates tumor metastasis and promotes tumor angiogenesis.
• TGF-β Signaling Pathway, plays an important role in early embryonic development, organ formation, immune supervision, tissue repair and homeostasis. TGF-β has two distinct roles in tumor initiation and progression. In the early stages of tumorigenesis, it acts as a tumor suppressor due to its effects on cell cycle arrest; in the latter stages, TGF-β acts as a tumor promoter by stimulating angiogenesis, cell dissemination, immunosuppression, in addition to extracellular matrix synthesis.
• The Integrin Transduction Pathway, regulates adhesion between cells and/or between cells and the extracellular matrix (ECM), also mediates interactions between tumor cells and the ECM, which affects tumorigenesis, invasion, along with the capacity of metastasis to other organs.

Cancer Research and Drug development

The intersection of signaling pathways will form a complex network, moreover, the same protein or gene can participate in different pathways in different roles. Exploring the molecular mechanism is an important part of tumor research. Through the exploration of cancer biomolecular mechanisms and signal transduction pathways, the changes in DNA and proteins that lead to cancer can be well discovered, which helps explore the key targets along with their druggability, assisting in the development of targeted anti-tumor drugs.

Types of Targeted Drugs:

• Small Molecule Drugs

Small-molecule drugs are often used to target intracellular targets (mainly multikinase inhibitors), such as sorafenib, sunitinib (inhibit VEGFR1, VEGFR2, KIT, PDGFR-α, etc.), and bevacizumab (anti-VEGF monoclonal antibody).

• Monoclonal Antibodies

Monoclonal antibodies, for example, trastuzumab (anti-HER 2) and rituximab (anti-CD20), can label cancer cells by recognizing cell surface markers so that the immune system can better observe as well as destroy these cancer cells, or directly prevent them from growing or cause them to die by blocking relevant pathway sites.

• ADC

ADCs, such as Moxetumomab pasudotox and loncastuximab tesirine, are monoclonal antibodies used in combination with cell-killing substances such as toxins, or chemotherapy drugs. These monoclonal antibodies attach to their targets on the surface of cancer cells, as a guide of cell-killing substances to cancer cells.

• Immune Checkpoints Inhibitors

Immune checkpoint molecules constitute inhibitory and stimulatory pathways that maintain self-tolerance as well as assist immune responses. Approved immune checkpoint inhibitors include Ipilimumab (anti-CTLA-4), pembrolizumab and nivolumab (anti-PD-1), and Atezolizumab (anti-PD-L1), etc. In addition, drugs targeting the novel immune checkpoint LAG-3 are being actively researched.

Detection of cancer biomarkers can be used for auxiliary diagnosis of cancer and differentiation of cancer subtypes, which helps provide more precise medical treatment strategies. Another application is for prognosis. Detection and ongoing monitoring of relevant biomarkers can assist in determining the aggressiveness of the tumor, the feasibility and the efficacy of given treatment, along with predicting or monitoring cancer recurrence.