Molecular target therapies are agents which attempt to disrupt the molecular processes which allow the malignant cells to survive and invade. There are several agents targeted at different processes.
Modulation of Angiogenesis
The most commonly used drug in modulating angiogenesis is the monoclonal antibody bevacizumab, marketed as AVASTIN™. The antibody binds to the Vascular Endothelial Growth Factor A molecule (coded for by the VEGFA gene) and prevents its binding to VEGF receptors present on endothelial cells. VEGFA is produced by normal and tumour cells to stimulate angiogenesis. In studies, bevacizumab has been shown to cause blood vessels to regress and inhibit the formation of new blood vessels.
Modulators of Signal Transduction
There are several steps to signal transuction. A ligand must typically bind to an extracellular receptor, triggering a conformal change. This conformal change then activates an intracellular enzyme, which begins activating a chain of enzymes that eventually causes changes in DNA expression. This presents several sites for targetting malignant cells.
Inhibition of Membrane Receptors
Many signal transduction pathways are initiated through binding of a ligand to a transmembrane protein, which then activates intracellular proteins to generate a signal. Most of these proteins require dimerisation (joining) with a similar protein before they can exert their effect; binding of the ligand to the receptor facilitates this through a structual change. These proteins are often targeted by monoclonal antibodies targeted against their extracellular domain. These antibodies serve two functions:
- They bind to the receptor and prevent it from dimerising with another receptor.
- They target the cell for destruction by cytotoxic T-lymphocytes.
Trastuzumab (Herceptin™) is a monoclonal antibody directed against the ERBB2 (HER2) receptor. It is used in breast cancer to target certain tumour types that overexpress the ERBB2 receptor (usually due to gene amplification).
Cetuximab is a monoclonal antibody directed against the ERBB1 (EGFR) receptor. It is used against squamous cell carcinomas of the head and neck, which frequently overexpress ERBB1.
Inhibition of Tyrosine Kinase
Tyrosine kinases are a group of enzymes that lie within the cell membrane, facing the cytoplasm. They are often activated after a transmembrane receptor is stimulated by its ligand. Once active, these enzymes start a cascade of activation within the cell.
Erlotinib (marked as TARCEVA™) is a small molecule which inhibits the function of the tyrosine kinase associated with the ERBB1 receptor (aka EGFR or HER1 receptor). It functions by blocking the ATP binding site of the tyrosine kinase. This prevents activation of the downstream pathways.
Inhibition of DNA Repair
Methods which block or alter DNA repair can be used as targeted therapies.
In cells with BRCA1 mutations, homologous recombination is unable to take place. DNA damage may be repaired by base excision repair, requiring the PARP molecule. PARP inhibitors may therefore prevent tumour cells from repairing DNA damage at all, leading to cellular death. There are no PARP inhibitors currently available commercially. Inhibition of ATM and/or PRKDC proteins are also potential methods of targeting DNA repair mechanisms.
Stimulation of apoptosis
Apoptosis occurs in response to either external (death receptor) or internal stimuli (hypoxia, excessive oncogene activation). Drugs which effect apoptosis would therefore target:
- Mutated forms of death receptors which can be targeted with antibodies, leading to cell destruction by the autoimmune system
- Pro-apoptotic molecules (similar to the BAX or members of the BH3-only family) which tip the balance in favour of apoptosis
- Inhibitors of anti-apoptotic molecules such as BCL2 which would reduce the stimulus needed for the cell to undergo apoptotis.
Modulation of the Cell Cycle
Many chemotherapy agents are active in a particular phase of the cell cycle.
- Inhibitors of DNA synthesis are most effective in S-phase when the DNA is duplicated (eg. 5-FU, gemcitabine, methotrexate)
- Inhibitors of mitotic spindle formation (taxanes, vinca alkaloids) are most effective in M-phase
Cells which survive exposure to these agents will typically be synchronised as they were not in the susceptible phase.