Biological Basis of Cancer Therapy Flashcards
What are the 5 most common cancers worldwide
Lung Breast Bowel Prostate Stomach
What are the main anti-cancer treatment modalities
Surgery
Radiotherapy
Chemotherapy
Immunotherapy
What are the types of genetic mutations causing cancer
Chromosome translocation
Gene amplification
Point mutations within promoter/enhancer regions of genes
Deletions or insertions
Epigenetic alterations to gene expression - Inheritance
What cytotoxic can be used in cytotoxic chemotherapy
Alkylating agents Antimetabolites Anthracyclines Vinca alkaloids and taxanes Topoisomerase inhibitors
What can be used in targeted therapies for cancer
Small molecule inhibitors
Monoclonal antibodies
How does cytotoxic chemotherapy work
Cytotoxics select rapidly dividing cells by targeting their structures (mostly of DNA)
Work systemically
Non-targeted (all rapidly dividing cells)
What are the uses of cytotoxic chemotherapy
Given post-operatively: adjuvant
Pre-operatively: neoadjuvant
As monotherapy or in combination
with curative or palliative intent
Describe alkylating agents
Add alkyl (CNH2N+1) groups to guanine in DNA Cross-link DNA strands and prevents DNA from uncoiling at replication, triggering apoptosis (via checkpoint pathway) BUT encourages miss-pairing - oncogenic
Describe pseudo-alkylating agents and give examples
Add platinum to guanine residues in DNA
Same mechanism of cell death as akylating agents
Examples: carboplatin, cisplatin, oxaliplatin
Give examples of alkylating agents
Chlorambucil, cyclophosphamide, dacarbazine, temozolomide
What are the side effects of pseudo-alkylating
Cause hair loss (not carboplatin) Nephrotoxicity Neurotoxicity Ototoxicity (platinums) Nausea Vomiting Diarrhoea Immunosuppression Tiredness
Describe anti-metabolites
Purine or pyrimidine analogues leading to inhibition of DNA synthesis
DNA double strand breaks and apoptosis
Blocks DNA replication and transcription
Give examples of anti-metabolites
methotrexate (folate)
6-mercaptopurine
Decarbazine and fludarabine (purine)
5-fluorouracil, capecitabine, gemcitabine (pyrimidine)
What do folate antagonists do in cancer therapy
Inhibits dihydrofolate reductase required to make folic acid, an important building block for all nucleic acids – especially thymine
What are the side effects
Hair loss (alopecia) – not 5FU or capecitabine
Bone marrow suppression
Increased risk of neutropenic sepsis or bleeding
Nausea and vomiting
Mucositis and diarrhoea
Palmar-plantar erythrodysesthesia (PPE)
Fatigue
What do anthracyclines do
Inserts between nucleotides within the DNA/RNA strand
Blocks DNA repair - mutagenic
Creates free oxygen radicals which can damage DNA and the cell membrane
Give examples of anthracyclines
Doxorubicin, epirubicin
What do vinca alkaloids and taxanes do
Inhibits assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest
What are the side effects of vinca alkaloids and taxanes
Peripheral or autonomic neuropathy Hair loss Nausea Vomiting Bone marrow suppression Arthralgia Allergy
What does bone marrow suppression cause
Anaemia
Neutropenia
Thrombocytopenia
What are topoisomerases required for
Prevents DNA torsional strain during replication and transcription
Induces temporary single (TOPO1) or double strand (TOPO2) breaks in the phosphodiester backbone of DNA
They protect the free ends of DNA from aberrant recombination events
Give examples of topoisomerase inhibitors
TOPO1 - Topotecan, Irinotecan
TOPO2 - Etoposide
What are the side effects of topoisomerase inhibitors
Hair loss
Nausea, vomiting
Fatigue
Bone marrow suppression
What are the side effects of irinotecan and what can be given to alleviate these
Acute cholinergic type syndrome: diarrhoea, abdominal cramps and diaphoresis (sweating)
Therefore given with atropine
State the mechanisms of resistance to cytotoxic drugs, and give an example for each
DNA repair mechanism upregulated so DNA damage repaired – no double strand breaks
DNA adducts replaced via base-excision repair (using PARP)
Drug effluxed from cell by ATP-binding cassette (ABC transporters)
Give an example of cytotoxic drugs that may cause resistance due to DNA repair up regulation
e.g. 6-mercaptopurine and irinotecan
Give an example of cytotoxic drugs that may cause resistance due to DNA adducts replacement
e.g. cylophasphamide and veliparib
Give an example of cytotoxic drugs that may cause resistance due to drug efflux
e.g. Cisplatin or oxaliplatin (MRP1 gene)
What is the advantage of dual-kinase inhibitors
Most cancers don’t have one specific target – multiple abnormalities
Can stop one pathway in monogenic cancers but other cancers will just use a parallel pathway/feedback cascades to activate
Dual-kinase inhibitors prevent feedback loops (but high toxicity)
What are the 6 hallmarks of the cancer cell
Self –sufficient Insensitive to anti-growth signals Anti-apoptotic Pro-invasive and metastatic Pro-angiogenic Non-senescent
How are receptor tyrosine kinases associated with malignancy
> 50% associated with human malignancies
Over-expression of receptors (HER2, EGFR)
Which cancers are associated with over-expression of HER2, EGFR and PDGFR
HER2 – amplified and over-expressed in 25% breast cancer
EGFR – over-expressed in breast and colorectal cancer
PDGFR- glioma (brain cancer)
Which cancers are associated with over-expression of ligands
VEGF – prostate cancer, kidney cancer, breast cancer
Which cancers are associated with constitutive (ligand independent) receptor activation
EGFR - lung cancer
FGFR - head and neck cancers, myeloma
What are the different types of monoclonal antibodies used in cancer therapy (base on suffix)
- momab (derived from mouse antibodies)
- ximab (chimeric) e.g cetuximab
- zumab (humanised) e.g. bevacizumab trastuzumab
- mumab (fully human) e.g. panitumumab
How do monoclonal antibodies work as cancer therapy
Target extracellular component of receptor
- Neutralise ligand
- Prevent dimerization
- Cause internalisation of receptor
- Activating complement-dependent and antibody-dependent cytotoxicity
What do small molecule inhibitors do
Bind to the kinase domain of the tyrosine kinase within the cytoplasm
Blocks autophosphorylation and downstream signalling
What are the advantages of monoclonal antibodies use for cancer therapy
Very specific and can be modified to add radiolabels
Metastatic tumours well targeted
Longer half-life
What are the disadvantages of monoclonal antibodies use for cancer therapy
Risk of immunogenicity and allergy due to use of chimeric forms
IV admin (degrades orally)
Expensive to manufacture
Only useful against external targets
Not useful for constitutively activated targets
What are small molecule inhibitors and give an example
ATP-mimetics
Glivec/Imantinib – first ”targeted therapy” which targets Bcr-abl – a fusion protein encoded by the Philadelphia chromosome drives overproduction of WBC in chronic myeloid leukaemia
What are the advantages of small molecule inhibitors
Cheap
Oral administration
Good tissue penetration
What are disadvantages of small molecule inhibitors
Shorter t1/2 so have to be more frequently administered
↑toxicity which are unexpected
Give examples of small molecule inhibitors that inhibit receptors
Erlotinib (EGFR)
Gefitinib (EGFR)
Lapatinib (EGFR/HER2)
Give examples of small molecule inhibitors that inhibit intracellular kinases
Sorafinib (Raf kinase)
Dasatimib (Src kinase)
What are the advantages of targeted therapies
Block hallmarks of cancer WITHOUT cytotoxic effects
Targets structures not pathway
E.g. VEGF inhibitors alter blood flow to tumour
AKT inhibitors block apoptosis resistance mechanisms
What are the resistance mechanisms to targeted therapy
Mutations in ATP-binding domain
Intrinsic resistance
Intragenic mutations
Upregulation of downstream or parallel pathways
Describe anti-sense oligonucleotides
Single stranded, chemically modified DNA- like molecules
Complementary nucleic acid hybridisation to target gene
Hinders translation of specific mRNA
Recruits Ribonuclease H to cleave mRNA
Good for “undruggable” targets
Describe RNA interference
Single stranded complementary RNA
Compounds must be packaged to prevent degradation Nanotherapies
BUT Tumour heterogeneity means different areas may have different molecular profiles
Describe b-RAF and its side effects
Mutation identified in 60% of melanomas – 500x increase in b-RAF pathway
Vemurafenib – b-RAF inhibitor (SMI)
Side effects: arthralgia, skin rash ,photosensitivity
Give examples of new therapies
Nanotherapies – deliver cytotoxics more effectively
Virtual screening – to identify “undruggable” targets
Immunotherapies – use antigen presenting cells to present “artificial antigen”
Target cancer metabolism
What is the advantage of sequencing tumours before therapy
Used to provide treatment as well as prognostic information
Concentrate on particular pathways for certain cancers
Identification of circulating biomarkers, tumour cells or DNA
What is the most common toxicity with chemotherapy
Bone marrow suppression which leads to neutropenic sepsis
How does radiotherapy kill cancer cells and how is it given?
High doses of radiation disrupts DNA sequencing by causing double strand and single strand breaks via photons and free radicals.
Given in short, intense doses to minimise radiation to other parts of the body, as well as giving most to the target area
Give an example of an immediate, delayed, late and psychological side effect of chemotherapy
Immediate - nausea and vomiting,
Delayed – alopecia, lethargy (due to reduced RBC)
Late – Infertility, immunosuppression
Psychological – loss of hair can be difficult to cope with, anticipatory nausea and vomiting due to conditioning, Concerns about effect on friends and family/depression
