Targeted Therapy Flashcards
Why is there a need for targeted therapy?
To provide effective therapy – cure or induce and maintain remission.
To provide a selective therapy because many conventional systemic therapies are associated with a variety of serious adverse effects.
What are small molecule inhibitors?
Low molecular weight chemical compounds that bind to proteins, and inhibit either enzyme activity or protein-protein interactions.
What are biologics?
Active substances made by or derived from a biological source, rather than a chemical source or synthesized chemically.
Typically proteins or protein containing agents produced using biotechnology (e.g. recombinant DNA techniques) and manufactured in cell culture or living organisms.
These are either relatively small molecules such as human insulin or erythropoietin, or large and complex molecules such as monoclonal antibodies.
What is a companion diagnostic?
A companion diagnostic is an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic.
What is gefitinib?
A type of epidermal growth factor receptor which is a receptor tyrosine kinase.
Epidermal growth factor binding to its receptor leads to activation of a signalling cascade resulting in cell cycle progression and proliferation.
Gefitinib binds to the ATP binding site of the tyrosine kinase domain of EGFR (Her1) and downregulates receptor autophosphorylation and phosphorylation of downstream molecules.
What is JAK?
Janus Kinase (JAK) are members of the family of tyrosine kinases that constitutively bind to the intracellular domains of tyrosine kinase-linked receptors e.g. cytokine and growth factor receptors.
When activated JAK phosphorylates STAT transcription factors leading to changes in gene expression.
JAK1 and JAK2 are predominantly expressed in the immune system.
What is baricitinib?
Baricitinib is a selective and reversible inhibitor for JAK1 and JAK2 > JAK3.
Baricitinib action leads to reduced production of cytokines as a consequence of reduced STAT mediated gene expression – used as an immunosuppressant.
What is vemurafenib?
B-Raf is one of three members of the Raf serine / threonine protein kinase family and has a role in regulating the MAK kinase signalling pathway along with A-Raf and C-Raf.
Vemurafenib binds to the ATP binding site of the constitutively active mutant V600E B-Raf when the enzyme is in its active conformation.
It selectively inhibits the proliferation of cells with unregulated B-Raf.
Used as targeted cancer chemotherapy.
What are the mechanisms of action of immunosuppressants?
Directs activated immune cells for destruction by the immune system.
Prevent the positive feedback of activation that plays a key role in chronic inflammatory disease.
Blockage of cell to cell interactions.
Blockade of cytokine action.
What are the mechanisms of action of anticancer drugs?
Triggering an immune response to kill the cancer cell.
Antibody dependent cellular cytotoxicity (ADCC).
Complement- dependant cytotoxicity (CDC).
Blocking inhibition of the immune response to the cancer cell.
Linking cancer and cytotoxic cells.
Blocking of extracellular signalling molecules or their receptors to inhibit proliferation / induce apoptosis.
Preventing angiogenesis.
Delivering targeted radiotherapy (radioimmunotherapy) or chemotherapy.
Why are biologics based on antibodies?
Small proteins and peptides have a fast renal clearance therefore biologics are based on immunoglobulins to improve their half-life.
What is pegylation?
Improve the pharmacokinetics by increasing the molecular mass and hydrodynamic radius by covalent coupling to Polyethylene Glycol (macrogol) which decreases the rate of glomerular filtration by the kidney.
Small proteins and peptides are cleared rapidly by the kidneys.
What are the benefits of pegylation?
Slower clearance.
Improves stability.
Reduced immunogenicity and proteolysis.
What are some adverse effects associated with biologics?
Infusion related reactions.
Associated with suppression of the immune response.
Can lead to:
An increased risk of serious infections & respiratory infection.
Active TB:
Lower resistance to opportunistic infections.
Upper respiratory tract.
Urinary tract.
Latent TB:
Potential increase in risk of non-melanoma skin cancer.
Immunogenicity of the biologic itself is also a potential issue.
