9. Biological basis of cancer therapy Flashcards
What is the leading cause of cancer death in the UK?
Lung cancer (regardless of sex)
How is the incidence of cancer set to change in the future?
- General increase
* Reduction in infection-based cancer - will increase Western cancer prevalence (breast, colorectal, lung, prostate)
What are the main cancer treatment modalities?
- Surgery
- Chemotherapy
- Radiotherapy
- Immunotherapy
- Some with endocrine therapy
What are the 2 types of chemotherapy?
- Cytotoxic - kills the cells e.g. alkylating agents, taxanes, topoisomerase inhibitors
- Targeted therapies e.g. small molecule inhibitors, monoclonal antibodies
What cells do mainly cytotoxics target?
- Rapidly dividing cells by targeting their structure (mostly DNA)
- e.g. affects the gut mucosa - mucositis
When is cytotoxic therapy administered?
- Curative or palliative intent
- Single agent (monotherapy)
- Pre-operatively e.g. to reduce tumour size for ease (neoadjuvant chemotherapy)
- Post-operatively e.g. to reduce recurrence (adjuvant chemotherapy)
How do alkylating agents work?
- Add alkyl groups to guanine residues in DNA
- Causes cross-linking of DNA strands
- Prevents DNA from uncoiling at replication
- Triggers apoptosis (via checkpoint pathway)
- e.g. decarbazine
What is the ironic problem with alkylating agents?
- Can lead to secondary cancers (encourage miss-pairing => oncogenic)
- However, benefits outweigh the risks
How are pseudo-alkylating agents different to alkylating agents?
- Add platinum to guanine residues in DNA, instead of an alkyl group
- Follow same mechanism of cell death
- e.g. carboplatin, cisplatin
What are the side effects of (psuedo-)alkylating agents?
- Hair loss (not carboplatin)
- Nephrotoxicity
- Neurotoxicity
- Ototoxicity (ear)
- Nausea
- Diarrhoea
- Immunosuppression
- Tiredness
How does cisplatin specifically work?
- Enters cell through copper channels
- Hydrolysis occurs in the low Cl- intracellular environment - loses a Cl
- Binds to guanine residues and cross-links DNA
- Nucleotide excision repair occurs
- Results in unsuccessful cycles of DNA repair and cell undergoes apoptosis
How do anti-metabolites work?
- Pretend to be purine/pyramidine residues
- Incorporate into DNA => inhibition of DNA replication and transcription
- Can be folate antagonist - inhibits dihydrofolate reductase required to make folic acid
- Folic acid is important for nucleic acid formation
- DNA double strand breaks
- Error recognised at DNA checkpoint => apoptosis
- e.g. methotrexate, 6-MP, decarbazine
What are the side effects of anti-metabolites?
- Hair loss (alopecia)
- Bone marrow suppression causing anaemia etc.
- Increased risk of neutropenic sepsis or bleeding
- Nausea and vomiting (dehydration)
- Mucositis and diarrhoea
- Palmar-plantar erythrodysesthesia
- Fatigue
How do anthracyclines work?
- Intercalate nucleotides within the DNA/RNA strand, inhibiting transcription and replication
- Block DNA repair (mutagenic)
- Create DNA and cell membrane damaging free oxygen radical
- e.g. doxorubicin
What are the side effects of anthracyclines?
- Cardiac toxicity (probably due to free radicals)
- Alopecia
- Neutropenia
- Nausea and vomiting
- Fatigue
- Skin changes
- Red urine
How do vinca alkaloids and taxanes work?
• Vinca alkaloids inhibit assembly of mitotic microtubules
• Taxanes inhibit depolymerisation of mitotic microtubules
• Causes dividing cells to undergo mitotic arrest
e.g. paclitaxel, vinorelbine
What are the side effects of microtubule-targeting drugs?
- Nerve damage (peripheral and autonomic neuropathy)
- Hair loss
- Nausea
- Vomiting
- Bone marrow suppression
- Arthralgia (joint pain)
- Allergy
What do topoisomerases do and how do topoisomerase inhibitors work?
- Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription
- They induce temporary single strand (topo1) or (topo2) breaks in the phosphodiester backbone
- They protect the free ends of DNA from aberrant recombination events
- Topotecan (topo1) and etoposide (topo2) alter the binding of the complex to DNA
- This allows permanent DNA breaks
- Causes apoptosis at DNA checkpoints
- Anthracyclines also have anti-topoisomerase effects
What are the side-effects of topoisomerase inhibitors?
- Acute cholinergic type syndrome - irinotecan (diarrhoea, cramps, diaphoreses [sweating]), therefore given with atropine
- Hair loss
- Nausea and vomiting
- Fatigue
- Bone marrow suppression
What can cause resistance to chemotherapy?
- Up-regulation of DNA repair mechanisms
- DNA adducts may be replaced by base excision repair (using PARP)
- Drugs may be effluxed by ATP-binding cassette (ABC) transporters
What do we do if a patient of chemotherapy has a fever?
- Give antibiotics ASAP
* Risk of neutropenic sepsis
What type of inhibitors are being developed to interfere with cancer cell wiring, and what are the problems with these?
- Dual kinase inhibitors
- Block 2 pathways
- Prevent feedback loops
- Problem - increased 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
In which cancers are the following receptors over-expressed:
• HER2
• EGFR
• PDGFR
- HER2 - breast cancer
- EGFR - breast and colorectal cancer
- PDGFR - glioma
Why does over-expression of receptors lead to cancer (2 basic steps)?
• Over-expression
=> increased kinase cascade
=> increased signal amplification
Give examples of how the over-expression of ligands can cause cancer?
• VEGF - prostate, kidney and breast cancer
=> increased kinase cascade
=> increased signal amplification
Where can ligand-independent receptor activation be seen?
- EGFR in lung cancer
* FGFR in head + neck cancers and myeloma
What do the following suffixes for monoclonal antibodies mean:
- momab
- ximab
- zumab
- mumab
- momab = derived from mouse antibodies
- ximab = chimeric
- zumab = humanised
- mumab = fully human
What are humanised monoclonal antibodies?
- Antibodies from non-human species - protein sequences modified to increase their similarity to human antibody
- Murine regions interspersed with light and heavy chains of Fab portion
What are chimeric monoclonal antibodies?
Made by fusing the antigen binding region (variable domains) from one species (mouse) with the constant domain from another species
Which part of the receptor does the monoclonal antibody target and what does this cause?
- Extracellular domain
- Neutralises the ligand
- Prevents dimerisation of the receptor
- Causes the receptor to be internalised into the cell
- Also activate Fcγ-receptor-dependent phagocytosis
- Cytolysis induces complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity
What does bevacizumab and cetuximab do?
- Bevacizumab - binds and neutralises VEGF (colorectal)
* Cetuximab - targets EGFR (colorectal)
How do small molecule inhibitors work?
- Bind to the kinase domain of the tyrosine kinase in the cytoplasm
- Affect both receptor TKs and intracellular kinases
- Blocks auto-phosphorylation and downstream signalling
- e.g. Glivec (imatinib)
What does Glivec specifically target?
- Small molecule inhibitor that targets the ATP binding region within the kinase domain
- Could target BCR-ABL - (9,22) chromosomal translocation in CML, without affecting other proteins
- Example of oncogene addiction - uniquely hyperactive oncogene/pathway driving a tumour
How is the toxicity of VEGF and AKT inhibitors different to general cytotoxics?
VEGF alters the blood flow to tumours and AKT inhibitors block apoptosis resistance without toxicity observed with cytotoxics
What are the mechanisms of resistance to targeted therapies?
- Mutations in ATP-binding domain
- Intrinsic resistance
- Intragenic mutations
- Up-regulation of downstream or parallel pathways
How do anti-sense oligonucleotides work in cancer therapy?
- They are single stranded, chemically modified DNA-like molecules
- Cause complementary nucleic acid hybridisation to target gene
- Recruits RNase H to cleave target mRNA
- This hinders translation of specific mRNA
Why do single stranded complementary RNA need to be packaged for anti-sense technology (cancer therapy)?
Prevent degradation
What mutation do 60% of melanomas have and why is this significant in therapy?
- B-Raf mutation - substitution of glutamic acid for valine
* Therefore B-Raf inhibitors (vemurafenib) have been successful in treatment - life span extended by 7 months
What is PD-1 and why is it significant in cancer therapy?
- Ligand that is present on cancer cells
- If PD-1 binds to PD-1 receptor, T cell can no longer recognise tumour cells as foreign
- If either are blocked, the immune system will be stimulated
- Nivolumab is an anti-PD-1 antibody, which can do this
How effective is nivolumab?
- Good results in non-small cell lung cancer, melanoma and renal cell carcinoma
- Median survival of 16 months (very good for phase I trial)
What new ideas are there for future cancer therapy?
- Nano-therapy
- Virtual screening to identify ‘undruggable’ targets
- Immunotherapies using antigen presenting cells
- Targeting cancer metabolism
- Sequencing tumours prior to starting therapy - concentrate on particular pathways
