Cancer 10 - Biological basis of Cancer Therapy Flashcards
What are the most common cancers worldwide
Lung Breast Liver Stomach Colon Cervix
What are the 4 means of anti-cancer treatment
- Surgery
- Radiotherapy
- Chemotherapy
- Immunotherapy
What mutations can cause cancer
- Chromosome translocations
- Gene amplification
- Point mutations in promotor/enhancer regions
- Deletions/insertions
- Epigenetic alterations to gene expression
- Inherited mutations
Systematic therapy involves cytotoxic chemotherapy and targeted therapies. What is involved cytotoxic chemotherapy
- Alkylating agents
- Antimetabolites
- Anthracyclines
- Vinca alkaloids and taxanes
- Topoisomerase inhibitors
Everything except vinca alkaloids and taxanes attack DNA.
Vinca alkaloids and taxanes attack microtubules
Cytotoxic chemotherapy is not very specific/targeted. How does it work
They target rapidly dividing cells by attacking their DNA
attacks healthy cells too unfortunately
How is cytotoxic chemotherapy given?
IV or orally
What are the uses of cytotoxic chemotherapy
- Given post-op = adjuvant
- Given pre-op = me-adjuvant (to downstage a tumour)
- Monotherapy or in combination
- Given with palliative/curative intent
How do alkylating agents work
- Add alkyl groups to guanine residues in DNA
2. DNA crosslinks prevent uncoiling of DNA –> triggers apoptosis via checkpoint pathway
How can alkylating agents cause cancer potentially? (<1% chance)§
Encourage miss-pairing
Describe pseudo-alkylating agents
Adding platinum to guanine residues in DNA
same mechanism as alkylating agents
Give examples of pseudo-alkylating agents
Carboplatin, cisplatin, oxaliplatin
Give examples of alkylating agents
Chlorambucil, cyclophosphamide, dacarbazine, temozolomide
List side effects of alkylating agents
Hair loss, nephrotoxicity, neurotoxicity, ototoxicity, nausea, vomiting, diarrhoea, immunosuppression, fatigue
How do anti-metabolites work
Masquerade as purine/pyrimidine residues —> inhibiting DNA synthesis —> DNA double strand breaks and apoptosis occurs
DNA replication and transcription prevented
Which 3 things can anti-metabolites be?
Purine / pyrimidine / folate antagonist
What do folate antagonists do
Inhibit dihydrofolate reductase –> needed to make folic acid which is used in nucleic acids (esp thymine)
Give examples of anti-metabolites
Methotrexate (folate), 6-mercaptopurine, decarbazine & fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)
Gemcitabine (pyrimidine) is used to treat …
Lung cancer, pancreatic cancer, ovarian cancer
What are the side effects of anti-metabolites
Hair loss, bone marrow suppression (causing anaemia, neutropenia, thrombocytopenia), increased risk of neutropenic sepsis and bleeding, nausea and vomiting, mucositis and diarrhoea, palmar/plantar erythrodysesthesia, fatigue
How do anthracyclines work
Intercalate between nucleotides within DNA/RNA strand –> inhibits transcription and replication
They may also block DNA repair (mutagenic)
May create free radicals that can damage DNA and cell membrane
Give 2 examples of anthracyclines
- Doxorubicin
2. Epirubicin
What are the side effects of anthracyclines
- Cardiac toxicity
- Alopecia
- Neutropenia
- Nausea and vomiting
- Fatigue
- Skin changes
- Red urine (doxorubicin = the Red Devil)
How do vinca alkaloids and taxanes work
Inhibit assembly (vinca alkaloids) or disassembly (taxanes) or mitotic microtubules - causes dividing cells to undergo mitotic arrest
What are the side effects of microtubule targeting drugs?
Peripheral neuropathy, hair loss, nausea and vomiting, bone marrow suppression, arthralgia, allergy
How do topoisomerase inhibitors work?
Topoisomerase inhibitors prevent DNA torsional strain during DNA replication and transcription
- specific topoisomerase inhibitors include Topotecan & Irinotecan (Topo 1 - single strand break) and Etoposide (Topo 2 - double strand breaks) which alters binding of the complex to DNA and allow permanent DNA breaks
Why are topoisomerase inhibitors often given with atropine?
To prevent acute cholinergic type syndromes from occurring (e.g. diarrhoea, abdominal cramps and sweating)
What are the side effects of topoisomerase inhibitors
1, Acute cholinergic type syndrome
- Hair loss
- Nausea / vomiting
- Fatigue
- Bone marrow suppression
What are the 6 hallmarks of a cancer cell
- Self sufficient
- Insensitive to anti-growth signals
- Anti-apoptotic
- Pro-invasive and metastatic
- Non-senescent
- Pro-angiogenic
- Dysregulated metabolism
- Evades immune system
- Unstable DNA
- Inflammation
Describe the monoclonal antibodies and their suffixes
- -Momab (derived from mouse antibodies)
- -ximab (chimeric - e.g. cuteximab)
- -zumab (humanised - e.g. bevacizumab, trastuzumab)
- -mumab (fully human - e.g. panitumumab)
Describe the difference between a humanised monoclonal Ab and chimeric monoclonal Ab
Humanised = murine regions are interspersed within light and heavy chains of Fab portion
Chimeric = murine component of variable region of Fab section is maintained integrally
Where do monoclonal antibodies target
Extracellular component of receptor
What 4 things may monoclonal antibodies do/cause
- Neutralise ligand
- Prevent dimerisation of receptors
- Internalisation of receptor
- Induces Complement Dependent Cytotoxicity (CDC) or Antibody Dependent Cellular Cytotoxicity (ADCC)
Give 2 examples of monoclonal antibodies in oncology
- Bevacizumab (Avastin) neutralises VEGF - used in coloretal cancer
- Cetuximab targets EGFR in colorectal cancer
How do Small molecule inhibitors (SMIs) work?
They bind the kinase domain of tyrosine kinase in cytoplasm –> blocking autophosphorylation and downstream signalling
Give an example of a small molecule inhibitor
Glivec (imatinib) - for CML targeted BCR-ABL fusion gene protein - specifically targets ATP binding region in kinase domain –> thus inhibiting kinase activity of ABL-1
SMIs can also act on intracellular kinases. Give examples of:
- Receptor-inhibition
- Intracellular kinase inhibition
- Erlotinib (EGFR), Sorafinib (VEGFR)
2. Sorafinib (Raf kinase), Dasatinib (Src kinase)
What are the advantages of using monoclonal antibodies
- High target specificity
- Cause Complement mediated cytotoxicity and apoptosis induction
- Can be radiolabelled
- Cause target receptor internalisation
- Long Half life so lower dosing frequency
- Ideal for haematological malignancies
What are some advantages of small molecule inhibitors
- Can target Tyrosine Kinases without an extracellular domain (or TKs that are constitutively activated)
- Oral administration
- Good tissue penetration
- Cheap
- Pleiotropic targets
What are the disadvantages of monoclonal antibodies
- Large and complex structure
- Less useful against bulky tumours
- Only useful against targets with extracellular domains
- May cause immunogenicity, allergy
- Expensive
- Resistance
What are the disadvantages of small molecule inhibitors
- Shorter half life = more frequent administration
2. Pleiotropic targets
What mechanisms may cause resistance to targeted therapies
- Mutation in ATP-binding domain
- Intrinsic resistance
- Intragenic mutations
- Upregulation of downstream or parallel pathways
How do anti-sense oligonucleotides work?
(not used often - only good for “undraggable” targets
- Complementary nucleic acid hybridisation to target gene - hinders translation of specific mRNA
- Recruits RNAse H to cleave target mRNA
- Anti sense oligonucleotides are single stranded, chemically modified DNA-like molecules (17-22 nucleotides in length)
How can RNA interference be used for cancer treatment (still in phase 1 clinical trials)
Single stranded complementary RNA
Compounds must be packaged to prevent degradation (nano therapeutics)
Which 2 bodies must approve of the expensive cancer treatments?
NICE and EMA
What is a major difficulty to the targeted cancer therapy approach
Tumour heterogeneity - different parts of the tumour may have different genetic profiles
How has targeting B-raf been successful in anti-cancer treatment
B-raf activating mutations found in 60% of melanomas (glutamate –> valine) - causing 500x increase in activity
B-raf inhibitor (vemurafinib) was very effective in phase 1 activity in melanoma –> increased lifespan by 7 months
Describe a success story of cancer treatment by targeting immune modulation involving programmed cell death (PD-1)
- PD-1 ligand found on surface of cancer cells
- PD-1 required to maintain T cell activation
- t-cells bind PD-1 –> cell no longer recognised as foreign
- Nivolumab is a anti-PD1 antibody which stimulates the immune system
What is nivolumab used to treat
median survival of 16 months - overall response rate of 31%
- Treatment refractory melanoma
- Non-small cell lung cancer
- Renal cell carcinoma
