9: Biological basis of cancer therapy Flashcards
Explain the main chemotherapeutic and targeted approaches to treating cancer
Explain why many cancer treatments cause side effects and recall approaches to minimise this
Explain the rationale for developing new targets and new drugs in cancer therapy
?
Main types of systemic therapy of cancer?
CYTOTOXIC chemotherapy
Targeted therapies
Explain cytotoxic chemotherapy, give examples
Cytotoxics select rapidly dividing cells by targeting their DNA (e.g. alkylating agents, anti-metabolites)
Works systemically
Non-selective - affects ALL rapidly dividing cells in body hence side effects
Admin of cytotoxic chemo?
IV or mouth
Neoadjuvant = pre op
Adjuvant = post op
Monotherapy or combination
What are alkylating agents? Give examples
Add alkyl groups to guanine residues in DNA
Cross-links DNA, prevents it from uncoiling at replication
Triggers apoptosis
e.g. Chlorambucil, temozolomide
What are pseudo-alkylating agents? Give examples
Adds PLATINUM to guanine residues
Same mechanism as alkylating
e.g. Cisplatin, carboplatin
Side effects of alkylating agents?
Hair loss (not carboplatin)
Nausea, vomiting, diarrhoea
Immunosuppression
Nephro/neurotoxicity
How does cisplatin work?
Enters cell via copper channels
Hydrolysis in low Cl- intracelullar environment
Binds to guanine, forms inter/intra-strand cross-links in DNA
p53 triggers apoptosis
What are anti-metabolites? Give examples
Purine/pyrimidine/folate antagonists
Blocks DNA replication and transcription
Double-strand breaks and apoptosis
e.g. Gemcitabine (pyrimidine), 6-mercaptopurine (purine)
How does gemcitabine work?
Enters cell and is dephosphorylated to form the pyrimidine antagonist which goes into the nucleus and inhibits DNA replication
Also gets DEAMINATED to become TOXIC
Both lead to apoptosis
Used in pancreatic cancer
Side effects of anti-metabolites?
Hair loss (alopecia) Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia Nausea, vomiting, diarrhoea Palmar-plantar erythrodysesthesia (PPE) Fatigue
What are anthracyclines?
Intercalates (inserts between) nucleotides in DNA/RNA strand - inhibits transcription/translation
Also blocks DNA repair
Generates oxygen free radicals which damage DNA/cell membrane
e.g. Doxorubicin, epirubicin
Side effects of anthracyclines?
Cardiac toxicity (arrhythmias, HF) Alopecia Neutropenia Nausea, vomiting, fatigue Red urine (doxorubicin)
What are vinca alkaloids and taxanes?
Microtubule targeting drugs
Vinca alkaloids: inhibit ASSEMBLY of mitotic microtubules
Taxanes: inhibit DISASSEMBLY
Causes mitotic arrest
Side effects of microtubule targeting drugs
Nerve damage (neuropathy) Alopecia Nausea, vomiting Bone marrow suppression Arthralgia, allergy
Topoisomerase inhibitors
Topoisomerases: required to prevent torsional strain in DNA during replication/transcription
Induce temporary single/double-strand breaks in DNA
Protect the free ends of DNA from aberrant recombination
Anthracyclines have anti-topoisomerase effects
Specific topoisomerase inhibitors: Topotecan, etoposide
cause PERMANENT DNA breaks
Side effects of topoisomerase inhibitors?
Acute cholinergic type syndrome (sweating, abdominal cramps etc.) so give with atropine
Alopecia, nausea, vomiting, fatigue, bone marrow suppression
How can growth factor receptor pathways cause cancer?
Over-expression of Her2 (25% of breast cancer) and EGFR (overexpressed in breast and colorectal)
Increased activation of kinase cascade -> cell proliferation
Over-expression of which ligand can cause cancer?
VEGF (prostate, kidney, breast)
Increased activation of kinase cascade -> cell proliferation
Constitutive (Ligand-independent) activation of which receptor causes cancer?
EGFR (epidermal GF receptors) -> Lung cancer
FGFR (fibroblast) -> Head/neck cancers, myeloma
Mechanisms of monoclonal antibody therapy?
Neutralises ligand
Prevents receptor dimerisation (tyrosine kinase)
Causes internalisation of receptor
Examples of monoclonal antibodies in cancer?
Avastin (Bevacizumab) - Neutralises VEGF (improves survival in colorectal)
Cetuximab - binds to EGFR
What are small-molecule inhibitors?
Bind to kinase domain (intracellular) of tyrosine kinase receptor
Blocks downstream signalling
Can also act on intracellular kinases, affecting cell signalling pathways
What is Glivec?
Small molecule inhibitor
Targets ATP-binding region in kinase domain
Why is targeted therapy better than cytotoxic?
Block cancer HALLMARKS (e.g. blow flow to tumour, apoptosis resistance) WITHOUT TOXICITY observed with cytotoxics
Monoclonal antibodies vs small molecules?
Monoclonal: Highly specific, long half-life (less frequent admin), good for haematological malignancy
Small molecules: Multiple targets (useful for heterogenic tumours), cheaper, oral admin, can target TKs even without extracellular domains or are constitutively activated
What is the mechanism of resistance in targeted therapies?
Mutations
Upregulation of parallel pathways
Intrinsic resistance
Mechanism of immunotherapy in cancer?
PD-1 expressed on surface of cancer cells
Binding of ligand means cancer cell no longer recognised as foreign
Inhibition of PD receptor/ligand will stimulate immune system
Nivolumab = Anti-PD1 antibody
New therapies and why are they better?
Nanotherapies - more effective delivery
Virtual screening - to identify undruggable targets
Immunotherapies
Targeting cancer metabolism
