Molecular Targeted Therapy Flashcards
What is the aim of targeted therapy?
To be more precise, targeting specific oncogenic drivers.
These therapies block the growth/spread of cancer by interfering with specific molecules involved in tumour growth and progression. Many are oral therapies often used in combination with surgery/conventional
chemotherapy/radiation.
It is used increasingly at earlier stages. It can be used in an adjuvant setting or a palliative setting.
Give some examples of cancer targets. (5)
Tyrosine kinase (intracellular) Growth factor receptors (extracellular) Epigenetic modifications Angiogenesis Hormone (receptor) (oestrogen/progesterone/androgens)
How do monoclonal antibodies work (using named examples)?
Monoclonal antibodies inhibit signalling by binding to the extracellular domain to inhibit growth-factor signalling mediated by the receptor tyrosine kinase is, resulting in arrest in tumour growth.
An example is trastuzumab. It works by preventing cleavage to prevent unregulated signalling pathways being activated, inhibiting dimerization to inactive signalling pathways, antibody-dependent cell mediated cytotoxicity to destroy the tumour cell, and by endocytosis to degrade HER2.
What are the differences between naked therapeutic antibodies and antibody drug conjugates?
Naked antibodies work by activating the immune system, targeting immune system checkpoints, and inhibiting the activity of the antigen and preventing growth.
Antibody drug conjugates are efficient carriers for delivery of anti-tumour agents. They are either radiolabelled or chemolabelled.
How do tyrosine kinase inhibitors work?
Bind to growth factor receptor and prevent growth signal
What are taxanes and vinca alkaloids?
Plant alkaloids
What two treatments make up targeted therapy?
Monoclonal antibodies
Small tyrosine kinase inhibitors
Best targets are…?
Next best targets…?
What is also possible in terms of targets?
Found in cancer cells but not in normal cells
More targets in cancer cells than normal cells (e.g. gene amplification – overexpression of HER2 or EGFR)
Targets in both cancer and normal cells, but the normal cell regenerates.
Which cancers can be targeted? (4)
Breast
Colorectal
Lung
Melanoma
How is breast cancer targeted?
13-20% of breast cancers overexpress HER2 due to HER2 gene amplification, so all primary, recurrent and metastatic breast cancers are tested for HER2
Treated with trastuzumab
How is colorectal cancer targeted?
35-50% overexpress EGFR
Treated with cetuximab with oxaliplatin-containing chemotherapy
How is lung cancer targeted?
15% EGFR positive
Treated with afatinib, erlotinib, gefitinib, bevacizumab
How is melanoma targeted?
50% with metastatic melanoma have a BRAF mutation and 20% have intrinsic resistance
Treat with vemurafenib, with trametinib
How do receptor tyrosine kinases signal?
The growth factor binds to the extracellular domain and leads to growth, cell death, survival, motility intracellularly
What biological therapies are there? (3)
Antibody inhibitors of growth receptors bind to growth factor receptor and prevent growth signal
Antibody-drug conjugates - the antibody targets drug to tumour cells
Tyrosine kinase inhibitors
How are antibodies modified for cancer treatment? (3)
Stable linker that release the payload only in target cell
Potent cytotoxic payload
Selective monoclonal antibody that preferentially targets tumour specific or tumour associated antigens
How do MaBs work? (3)
Killing tumour cell directly – blocking signalling, inducing apoptosis, delivery of toxic payload
Killing tumour cells via an immune-mediated mechanism – phagocytosis, complement dependent cytotoxicity, antibody dependent cell cytotoxicity
Vascular or stromal ablation – delivery of toxic payload, VEGF antagonism (inhibits angiogenesis)
What is VEGF? Why is it relevant in cancer?
Required for formation of nascent blood vessels
One of most upregulated antigens in cancer and functions indirectly as survival factor for tumour cells.
If you inhibit VEGF signalling, you inhibit angiogenesis, so inhibit cell growth and metastasis
How can antibodies access tumour cells?
Blood vessels are leaky in tumour tissue, so molecules have access to the tissue. Also tumour tissue doesn’t have lymphatic drainage system, so these molecules are retained and acculumate.
A ‘mab’ that ends in ‘mab’ - what does this mean?
What about ending in ‘zumab’?
100% human
Humanized (95%)
What does a chimeric mab end in?
ximab (65%)
o for…?
a for…?
e for…?
i for…?
Mouse
Rat
Hamster
Primate
Small molecule tyrosine kinase inhibitors – what do they do?
What is their major benefit?
Target oncogene product by inhibit signalling at key steps
Safer than chemotherapy
What mutation is associated with drug resistance?
Mutations in tyrosine kinase domain of EGFR
What are the side effects of targeted therapies?
Skin changes (rashes, dry skin, itchy skin, hand foot syndrome, hair, dry or red eyes)
High blood pressure
Slow wound healing and blood clotting
Congestive heart failure
What is the main problem with trastuzamab?
Cardiotoxicity
