5.2 Cancer therapies: cytotoxics to targeted therapies Flashcards
What are the phases of drug assessment?
In vitro: shows activity in cell lines
Preclinical: animal models
Phase I: clinical assessment - dose finding
Phase II: Safety and efficacy assessment in various tumours
Phase III: comparing against best available treatment
Phase IV: post marketing safety surveillance
How does chemotherapy work?
Effect cellular division which promotes apoptosis. There is no selection for tumour cells but normal cells are thought to be able to recover better.
Works best against dividing cells
Which cancer is chemo used as curative?
Paediatric tumours, germ cell malignancies, leukaemia, lymphomas
What are monoclonal antibodies?
Proteins synthesised to bind onto specific ligands, tumour cel proteins or receptors on the cell surface necessary for tumour growth and neutralize their action
What are small molecule inhibitors?
Block the activity of a signalling pathway inside the cells to prevent tumour growth
What is the target for rutiximab and what is it used for?
CD 20 in lymphoma
What is transtuzumab, what is its trade name and what is it used for?
Her2 receptor - Herceptin in breast cancer and gastric cancer
What is imatinib, what does it target and what is it used for?
Glivec, c-KIT and bcr-abl used in GIST and CML
small molecule transduction inhibitor
What is the role of Her2?
The Her2 receptors play a key role in cell growth and survival. Over expression or mutation leads to increased proliferation of the cancer cells.
Promotes invasion, survival and angiogenesis of cancer cells
How to you determine Her status?
Immunohistochemistry to look for the receptors
What are the strategies for inhibiting Her2?
Transtuzumab (Herceptin): monoclonal antibody to block ligand binding or receptor dimerization
Lapatinib (Tykerb): small molecule kinase inhibitor
What is the main toxicity of transtuzumab?
Reversible cardiotoxicity
What is transtuzumab emtansine and when is it used?
T-DM1
monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent DM1. This enters the cell and causes damage this way. Used in transtuzumab resistant Her2+ breast cancer
What is Lapatinib and when is it used?
Small molecule dual kinase inhibitor (EGFR or Her2) and is used in transtuzumab resistant advanced cancer in combination with Xeloda
What is the theory behind targeting VEGFR?
Causes regression of tumour microvasculature and normalisation of surviving mature vasculature to improve access of chemo drugs and inhibits new vessel growth
What is EGFR
EGFR is a regulator of cell cycle progression, repair and survival and is involved in tumour metastases
What is Bevacizumab and what is it used for?
Monoclonal antibody to VEGF
Works in metastatic colorectal, NSCLC, Breat and renal cell cancer
What is Cetuximab and what is it used for?
IgG monoclonal antibody against EGFR the blocks EGFR and inhibits proliferation, angiogenesis and metastases and stimulates apoptosis
Used for EGFR positive colorectal and head and neck
What is the marker in colorectal patients to indicate cetuximab (anti EGFR) usage?
K-RAS and NRAS wild type will respond to anti EGFR therapy
What is the main side effect of cetuximab?
Acneiform rash - severity of which indicate positive response
What are the tyrosine kinase inhibitors drugs of EGFR and what are the side effects?
Gefitinib
Erlotinib
Afatinib
Side effects: rash and diarrhoea
What is Ipilimumab and what is it used for?
Anti CTLA-4 monoclonal antibody which blocks T cell activation - used for melanoma
What is Dabrafenib and what is it used for?
Inhibitor of BRAF which blocks the MAPK pathway used for melanoma
