Bio therapy and Targeted Therapy Flashcards
What is the basic principle of targeted therapies?
- The growth, regulation, angiogenesis and cell death of both normal and cancer cells are regulated by signals
- Signals by growth factor receptors allow the inside and outside of the cell to communicate
- These proteins are essential for normal cell growth
- Alterations in genes that create variations result in either malfunction or too many receptors
- These proteins are called oncoproteins, since they can turn healthy cells into Ca cells
What are the two families of growth factors that have clinical significance in the treatment of Ca?
1) Epidermal growth factor receptors (EGFR)
2) Vascular endothelial growth factor (VEGF) receptors
Blocking these growth factors is the focus of targeted therapy treatments. There is now some new protein pathways discovered in research for developing new drugs
What is another term for growth factor?
Ligand
How does signal transduction work?
- Is a communication process used by regulating molecules for processes like cell growth, differentiation and survival
- Begins with activating a receptor on the cell membrane by a ligand (growth factor) > ligand binding activates > activating is a signal that crosses the cell membrane from the outside to inside > tyrosine kinase is activated > downstream cascade of signals that influence cell activity
- Cell signaling affected by both intracellular and extracellular events
What are the three cellular-signally pathways that are utilized in targeted therapy?
1) Receptor kinase pathways
2) Intracellular signalling kinase pathways
3) Angiogenesis pathways
What are receptor tyrosine kinases?
- Some cell membrane receptors also double as enzymes
- If a receptor is also an enzyme, the binding of signal molecules will activate that specific enzyme activity
- Receptor tyrosine kinases are the largest class of enzyme receptors
- Important role in regulating cell growth, differentiation (gene transcription) and survival (eg. growth factors and hormones bind to RTK’s)
- Many cancers appear to be d/t mutations in RTK’s
- There is both extra-cellular and intra-cellular components to the tyrosine kinase receptor (extra cellular where growth factors like VEGF attach) and intra-cellular, which when activated communicates directly to the nucleus
Describe the basic process of activating an RTK:
1) Signal molecules (ligand) will bind to an RTK
2) Neighboring RTK’s that both have signal molecules will bind to each other by cross-links
3) Cross-linking activates the tyrosine kinase activity within the cell by phosphorylation (taking the phosphorus group from ATP and adding it to itself, the protein/receptor site)
4) A protein with an extra phosphorus group will act as an on/off switch for the cell
How do RTK inhibitors work?
Blocks ATP from binding to to a tyranise kinase active site, preventing phosphorylation, and therefore keeping the cell ‘turned off’
- Groups of cancer occur when specific tyrosine kinase receptors that will act as an ‘on switch’ for cancer if they are activated and have an error in the gene, making them an oncogene and oncoprotein
What is the suffix for RTK inhibitors?
- tinib
What are the side effects of RTK inhibitors?
- Nausea/vomiting
- Fluid retention (CHF, periorbital edema)
- Prolonged QT interval
- GI and liver toxicity
- Bone marrow suppression
What is the intracellular signalling kinase pathway?
- When a chain of reactions transmits a signal from the surface of the cell to different places within the cell (this is intracellular signal transduction)
- These different pathways are tyrasine kinase pathways
- This connects the cell surface to the nucleus
- If connected to the nucleus, can change gene expression
- These pathways can be proto-oncogenes
What is one of the most potent proteins that signals for angiogenesis (both normal and abnormal)
- Vascular endothelial growth factor (increased levels are found in multiple types of tumors)
- Promotes vascular permeability = creates new blood vessels
- Binds to tyranise kinase intracellular receptors, transmitting signals from the receptor to the nucleus
The three cell-signalling pathways used in targeted therapies involve tyranise kinase. What are the key differences between these pathways and their use of TK?
1) Receptor kinase pathways: The pathway wherein the TK protein is activated by an outside receptor
2) Intracellular signally kinase pathways: The pathway wherein the protein is activated (by the receptor kinase pathway) and creates intracellular signals to the nucleus
3) Angiogenesis pathway: The pathway wherein the activation of the TK protein directly signals the cell nucleus to develop new blood cells
How do anti-angiogenic agents work?
- Disrupt endothelial cell survival (eg. disrupt basement membrane, deprives of nutrients)
- Inhibit development of new blood vessel supply
What is the suffix for monoclonal antibody drugs?
- mab
What are mono-clonal antibodies?
- Lab-produced molecules that act as substitute antibodies to restore, enhance, or mimic the immune system’s attack on cancer cells
- Bind to antigens that are generally more numerous on cancer cells
- Given almost any substance, it’s possible to produce monoclonal antibodies that bind specifically to that substance, and can then serve to detect that substance
- Kill Ca cells by attaching to the cancer cell antigens (followed then by stimulating the immune system to kill the cell, or by antibody-dependent cellular cytotoxicity (ADCC), or causing apoptosis); leaves normal cells alone
What is the difference between cytotoxic drugs and monoclonal antibodies?
Chemo kills both healthy and cancer cells, but monoclonal antibodies work by attacking tumor cells directly and sparing normal cells
What is the major reason for allergic reactions to monoclonal antibodies?
Exposure to mouse protein that is in a number of monoclonal antibodies. Some products are just humanized antibodies, but there are ‘chimeric’ ones that are both human and mouse.
Theoretically the lower the more human protein in MAb’s the lower the incidence of a hypertensivity to mouse protein
On a cellular level, it is d/t the creation of immunoglobulin E (IgE), which creates antibodies against the antigen
What are the cellular effects of MAb’s?
- When the MAb binds to an antigen like a “lock and key” the Y portion binds to immune cells such as NK cells for the Ca cell can be killed
- Can induce complement activation (enhancement of antibodies), coating the antigen to it can be more effectively killed
- Cause apoptosis just by binding to it
What is the difference between a hypersensivity, anaphlylactic, and cytokine release syndrome?
- With hypersensitivity, a patient is sensitized to the antigen with the first exposure and the body creates immunoglobulin E antibodies against the antigen = the second exposure results with antigen binding to IgE and causing immune cell rupture, releasing inflammatory mediators (creates the signs and symptoms similar to true anaphylaxis)
- Anaphylactic occur on first exposure and are not IgE mediated
- Cytokine release syndrome occurs during administration of MAb and is d/t destruction of cells that release cytokines, creating a systemic inflammatory response
