Targeted Cancer Therapy Flashcards
What are targeted cancer therapies
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression.
What are the ways in which targeted chemotherapies can be given
oral therapies
- can be used in combination which surgery/conventional chemotherapy and radiation
In what settings is targeted therapy used
- Increasingly at earlier stages – slow down growth and prevent disease
- Adjuvant setting (combination with other drugs)
- Metastatic setting – relieve symptoms
- Can be used in palliative setting
What are the two major growth pathway
- PI3K
- MAPkinase
what happens if you are able to block the major growth pathways
- if we can block the Map Kinase pathway or the PI3 kinase pathway then this can block the growth that is seen in cancer cells where these pathways go into overdrive due to a mutation
What is the best target and the next best target that can be sued in cancer treamtent
• Best therapeutic targets are found in cancer cells but not in normal cells
• Next best targets – more targets in cancer cells than normal cells (e.g. gene amplification - overexpression of HER2 or EGFR) – this is where a oncogene is overexpressed
- then a drug that targets both cancer and normal cells and allowing the normal cell regenerates
What are the benefits of being able to find a specific target in order to treat the cancer
- Reducing serious side effects – if you are specifically targeting a kinase then you are going to reduce targeted effects and side effects of cancer, the more specific the drug the fewer side effects that there is
- Reducing use ineffective drugs
- Improving patient survival
- Improving quality of life
- Reduce costs – drugs for a specific mutation that can be treated with a specific set of drugs
How can you find targets for cancer treatment
- Targets need to be sequenced by:
- molecular biology,
- genomics
- bioformatics (is it an oncogenic change or an SNP change)
- then this information is incorporated into the individualised patient treatment plan
Where can the targets for cancer treatment mean
- Can be at the growth factor
- Extracellular side and intracellular side of the receptor
- Within the nuclei
- Growth factor receptor
- Cytoplasm
Describe the anatomy fo the tyrosine kinase receptor
- transmembrane
- has an extracellular domain and an intracellular domain
- dimerises
- intracellular domain is activated by phosphorylation
Describe how tyrosine kinase receptor carries out signalling
- Binding of the ligand to the extracellular domain
- this allows dimerisation of tyrosine kinases
- dimerisation causes a conformational change in the intracellular domain meaning that the intracellular domain undergoes phosphorylation
- once the tyrosine is phosphorylated they can then recruit adaptor proteins
- this triggers a cascade of signalling proteins such as activation of MAPK and PI3K
- this leads to increased growth and survival and motility of these cells
Wha tis the MAPK pathway important for
Cell proliferation
What is the PI3K pathway important for
- cell growth
- proliferation
- agniogensis
- metabolism
What are the common targets for the extracellular domain
- EGFR
- HER2/3/4
- VEGFR
- PDGFR
- cKIT
What are the common targets for the tyrosine kinase domain
- EGFR
- HER2/3/4
- VEGFR
- PDGFR
- cKIT
What are the common targets for the PI3K pathway
mTOR
name some common targets in the tyrosine kinase receptor activation
- extracellular domain of the tyrosine kinase receptor
- tyrosine kinase domain
- PI3K pathway
How can you block the tyrosine kinase receptor
block ATP from binding
- therefore phosphate is not able to phosphorylate the tyrosine
What is perhaps one of the most important oncogenic driver of human cancers
MAP Kinase
What does Cetuximab do
– binds to the Epidermal growth factor receptor and inhibit binding so we don’t get activation of the growth pathways
- inhibit dimerisation and therefore inhibit activation
What is cetuximab used to treat
2017 NICE recommended (EGFR)-expressing, RAS wild-type metastatic colorectal cancer/ recurrent or metastatic squamous cell cancer of the head and neck
what are the two things that antibodies can do in antibody therapy (biological therapy)
• Antibody inhibitors of growth receptors.
o Bind to growth factor receptor and prevent growth signal.
• Antibody drug conjugates
o Antibody targets drug to tumour cells.
what drug targets VEGF
- Bevacizumab (Avastin) VEGF
What drug targets HER2
- Trastuzumab- (Herceptin) HER2
Describe how to name monoclonal antibodies
- -u- human (100% human antibody): Panitumumab
- -zu- humanized (95% human and 5% mouse): Trastuzumab (Herceptin ®)
- -xi- chimeric (65% human and 35% mouse): Rituximab (MabThera ®)
- -o- mouse, -a- rat, -e- hamster, -i- primate: Tositumomab
• Previous syllable
– -tu(m )- for tumour in general
– -ma(r)- breast, -pr(o)- prostate, - co(l)- colon, etc.
– -ci(r)- for circulatory: Bevacizumab (Avastin ®)
What drug targets HER2/HER3
Pertuzumab
name the 5 drugs that antagonize ligand receptor signalling and inhibit dimerisation and ligand binding
EGFR
- cetuximab
- Panitumumab
HER2
- Trastuzumab
HER2/3
- Pertuzumab
VEGFR
- Bevacizumab
Why is HER2 so oncogenci
HER2 does not bind to a ligand or to a growth factor so when the growth factor binds these receptors but you a dimerization arm so that two receptors can interact and bind to each other but HER2 is different, it has no ligand and doenst bind to a growth factor and the normal conformation of HER2 is the dimerization with the dimersiation arm, therefore all you need is an amplification of HER2 in the breast epithelial cells is a amplication for cancer
Therefore this is why HER2 is so oncogenic
What are the 3 ways in which monoclonal antibodies works
- Kill tumour cell directly
- Killing tumour cells via an immune mediated mechanism
- Vascular or stromal ablation
Describe the ways in which the monoclonal antibodies work
Killing tumour cell directly
• Inhibit ligand binding
• Signalling blocked
• Apoptosis induced
• Possible delivery of
toxic payload
Killing tumour cells via an immune mediated mechanism
• Induction of phagocytosis
• Complement dependent cytotoxicity (CDC)
• Antibody dependent cell
cytotoxicity (ADCC)
Vascular or stromal ablation
- VEGF antagonism
Describe HER2 cancers
- Approximately 15% breast cancers overexpress HER2.
- Approximately 20% of these women respond to Herceptin (Trastuzumab)
- Most women have disease progression within one year.
What is recommended for HER2 breast cancer that is metastatic and recurrent
- Pertuzumab, in combination with trastuzumab and docetaxel ( anti mitotic drug – stabilises microtubules and prevents them from breaking down - can’t carry out there normal function in mitosis therefore mitosis cannot occur), is recommended HER2 positive metastatic or locally recurrent unresectable (cannot have surgery) breast cancer
How does Trastuzumab (Herceptin) work
Binds to domain IV on HER2
Supresses ligand-independent HER2 signalling – HER2 does not bind to the ligand, prevents two HER2 molecules interacting with each other therefore prevents homodimerization
Prevents HER2 ECD shedding
Identifies cells for antibody-dependent cell mediated cytotoxicity
Activate Endocytosis of the HER2 Receptors.
Inhibits Dimerization
Oncogenic because it has a dimerization arm.
Prevents Cleavage
o Prevents cleavage of HER2 receptor.
o If HER2 overexpressed: mutations.
o Allows extracellular part to be cleaved off.
o This causes for it to be continuously activated
What is another word for Trastuzumab
Herceptin
How does bevacizumab work
o Block the receptor.
o Inhibits tumour growth and metastasis.
How does pertuzumab work
Binds to domain II on HER2 and Her1, 3 and 4 – therefore it inhibits ligand dependent HER2 signalling as it binds to HER1, HER3 and HER4 combination with HER2 therefore inhibits hertrodimiersation
Inhibits homo- and heterodimerisation
Supresses ligand dependent HER2 signalling Identifies cells for antibody-dependent cell mediated cytotoxicity
What is the difference between Pertuzumab and Trastuzumab
Trastuzumab
- prevents homodimerisation
Pertuzumab
- inhibits homodimerisation and herterodimerization
what does an monoclonal antibody that targets VEGFR do
prevents angiogenesis
What is VEGF required for
o Required for the formation of new blood vessels.
How does VEGF protect the endothelial cells from death
Protects endothelial cells from death via activation of PKC pathways and up-regulation of anti-apoptotic proteins such as Bcl-2
what is the activity of VEGF mediated by
- – Activity mediated by tyrosine kinase receptors, VEGFR 1 and VEGFR 2
What does VEGF function indirectly as
a survival factor for tumour cells
What inhibits VEGF function
Bevacizumab (Avastin)
o Block the receptor.
o Inhibits tumour growth and metastasis.
- deprives tumours of nutrient providing blood vessels
What is bevacizumab approved for
- Recurrent or metastatic cervical cancer,
- Third line treatment of low grade gliomas (children)
- First line treatment of advanced epithelial ovarian,
- funded by the cancer drugs fund
How do antibodies access tumour cells
Normal Tissue
• Blood vessels have intact endothelial layer.
Tumour Tissue
• Blood vessels leaky, so small and large molecules have access to malignant tissue.
• Tumour tissue: does not have a lymphatic drainage system.
o Macromolecules are retained.
There is an enhanced vascular permeability of circulating antibodies for tumour tissue and subsequent accumulation in solid tumours.
What is a conjugated antibody
- Cytotoxic drug can be attached via stable linked to Fc part.
- When antibody binds to cancer cell: cytotoxic load will be adjacent
Name an example of a conjugated antibody
Trastuzumab Emtansine (Kadcycla)
Who is Trastuzumab Emtansine (Kadcycla) for
- For women who are HER2+ but have inoperable breast cancer or metastatic breast cancer
- Effective but expensive
How much does Trastuzumab Emtansine (Kadcycla) improve lifespan by
5.8 months on average
How do naked antibodies work
- activating the immune system such as Alemtuzumab - CLL
- targeting immune system checkpoints e.g. - PD-1 Keytruda - unresectabel advanced melanoma
- inhibiting the activity of the antigen and preventing growth such as herceptin - breast cancer
How do antibody drug conjugates (ADC) work
- radiolabelled such as ibritumomab
2. chemolabelled such as traastuzumab emtansine - anti HER2 antibody conjugated to a chemotherapy drug called DM1
What do tyrosine kinase inhibitors do
- these work by blocking the kinase activity
What are the types of tyrosine kinase inhibitors
Tyrosine Kinase Inhibitors of Growth Factors
• Bind to growth factor receptor and prevent growth signal.
Inhibition of other kinases - such as B-Raf and inhibitors in the MTOR and PI3K pathway
what part of the tyrosine kinase receptor part can drugs be designed to inhibit
- can be designed to sterically inhibit ATP binding
- kinase domain has a binding pocket for ATP which causes phosphorylation so if this pocket is blocked then phosphorylation does not occur
What is an example of a tyrosine kinase inhibitor that can inhibit the ATP binding domain preventing phosphorylation and what cancer is it used for
- Tarceva (erlotinib) prevents ATP from binding = NICE -Used for locally advanced or metastatic NSCLC - EGFR
What do small molecular tyrosine kinase inhibitors do and what is the advantage and disadvantage of them
- these target the oncogene product
- they inhibit signalling at key stages
Advantage
- safer than chemotherapy
- specific side effects and specificity is often relative
What is the nomenclature of tyrosine kinase inhibitors
ib – inhibitory
tinib – tyrosine kinase inhibitors
e.g. gefitinib (Iressa) and erlotinib (Tarceva) (NSCLC)
imatinib (Glivec) (CML)
What two types of cancer make up non small cell lung cancer
adenocarcinoma
squamous cell carcinoma
What is the largest cause of non small cell lung cancer
adenocarcinoma
What are the mutations that cause squamous cell non small cell lung cancer
- Squamous cell cancer – mutations found – amplification of PI3CA and mutations in PI3CA
What are the mutations found in adenocarcinoma non small cell lung cancer
mutations are in K-Ras, EGFR mutation,
What is another name for HER2
ERBB2
What are the activating mutations in tyrosine kinase domain of EGFR in lung cancer
- there are mutations in exon 18, 19, 21 which occur in 50% of non small cell . lung cancer
- Exon 19 and 21 are particularly important in causing activating mutations (change in ATP sites)
What does a mutation at Exon 19 cause in non small cell lung cancer
- increase in autophopsphorylation
- cell survival via AKT increases
- dimerisation increases
What does a mutation at Exon 21 cause in non small cell lung cancer
dimerisation increases
In non small cell lung cancer what are the activating mutations associated with
- they are associated with drug sensitivity to gefitinib or erlotinib
can drug resistance develop to targeted therapy
yes
How does drug resistance develop to targeted therapy and give examples
- cancerous cells carry on mutating
- Mutations in tyrosine kinase domain of EGFR associated with drug resistance (TKI)- lung cancer
- Up to 70 % these women do not respond or develop resistance to trastuzumab e.g. truncated HER2= breast cancer = one of the things that happen to HER2 is that there is a mutation with the extracellular domain that allows the site for protease to come along and cut of the top of the receptor, so if the receptor is truncated Trastuzumab ca no longer bind as the binding site is gone
What is the most developed acquired resistance to
- TKI - EGFR over-expression leading to a melanoma
What are the mutations associated with drug resistance in tyrosine kinase domain of EGFR in lung cancer
- Mainly on Exon 20
- this mtuation is associated with resistance to gefitinib and erlotinib and prevents it from binding in the ATP binding site
name the
- first generation EGFR tyrosine kinase inhibitors
- second generation EGFR tyrosine kinase inhibitors
- third generation EGFR tyrosine kinase inhibitors
first (reversible)
- Erlotinib
- Gefitinib
Second (irreversible)
- Afatinib
Third (mutant selective - selective to the second mutation that occurs in lung cancer)
- Osimertinib (on the cancer drug fund)
What are the side effects of targeted therapies
Skin changes Skin rashes (acneiform) – EGFR Dry skin Itchy skin Hand foot syndrome - VEGF (peripheral neuropathy-small blood vessels)
Changes in hair (alopecia, brittle, may grow faster)
Dry or red eyes and red and tender eyelids
What cancer drug can lead to high blood pressure
High blood pressure – VEGF
What cancer drug can lead to slow wound healing and blood clotting
Slow wound healing and blood clotting – EGFR
What cancer drug can lead to congestive heart failure
Congestive heart failure - HER2 - trastuzamab causes cardiotoxicity
How does trastuzamab cause cardiotoxicity
- HER2 is important in the survival pathway of cardiomyocytes
- they also increase nitric oxide production which causes vasodilation which increases blood flow through the pulmonary arteries
- if this is inhibited this can lead to a decrease in NO and endothelial cell dysfunction
How often do you have to assess cardiac function with someone who is on trastuzumab
- have to assess cardiac function before starting treatment
- then test every 3 months
- 7-28% of patients have side effects
- and patients who have a left ventricular ejection fraction of less than 55% they are not prescribed trastuzumab and if this is reduced to less than 50% in treatment then it is stopped
What are the effects of trasutzamab on the heart
- Inhibition of HER2 survival pathway - this contributes to myocardial dysfunction
Congestive heart failure
- reduces contracitle efficiency
- leads to apoptosis of cardiomyocytes this indirectly increases myocardial workload
- decline in left ventricular cardiac function
Endothelial dysfunction
- injures epithelial cells by increasing the amount of reactive oxygen species
- impaired vasodilation
- decreases NO
- reduces myocardial blood flow
What combination of drugs is associated with HER2 life length increase
The combination of docetaxel, pertuzumab and trastuzumab is associated with a survival of more than 4.5 years, compared with a life expectancy of 1.5 years achieved 19 years ago in patients with metastatic HER2-positive breast cancer.
