Biological basis of Cancer Therapy Flashcards
what are the most common cancers worldwide?
lung, breast, bowel, prostate and stomach
what is the most common cancer in men?
lung
what is the most common cancer in women?
breast
what are the “western cancers”?
breast, colorectal, lung and prostate
what are the main anti-cancer modalities?
o Immunotherapy.
o Chemotherapy.
o Radiotherapy.
o Surgery.
what types of genetic mutations can cause cancer?
o Chromosome translocation.
o Gene amplification (from copy number variations).
o Point mutations – in promotor/enhancer regions.
o Deletions/insertions.
o Epigenetic alterations.
o Heritable mutations.
what are the two main types of systemic therapy for cancer?
- cytotoxic chemotherapy
- targetted therapy (non-cytotoxic)
what are the cytotoxic chemotherapy agents?
affect all rapidly dividing cells, cause apoptosis o Alkylating agents. o Antimetabolites. o Anthracyclines. o Vinca alkaloids and Taxanes. o Topoisomerase inhibitors.
what are the targeted therapy, non-cytotoxic agents?
o Small molecule inhibitors.
o Monoclonal antibodies.
what cells do cytotoxic agents target?
select rapidly dividing cells by targeting their structures (e.g. DNA).
They target ALL rapidly dividing cells.
how are cytotoxic agents administered?
IV and function systemically o Post-operatively – adjuvant to clear up residuals o Pre-operatively – neoadjuvant. o Monotherapy/combination. o With curative or palliative intent.
what do alkylating agents do?
o Add alkyl (CnH2n+1) groups to guanine residues.
o Cross-link DNA strands and prevent it uncoiling.
o Trigger apoptosis (via checkpoint pathway).
o Encourage miss-pairing (oncogenic).
examples of alkylating agents
Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide
add alkyl groups to guanine
what are pseudoalkylating agents?
o Add platinum to guanine residues.
o Same other effects as alkylating agents
examples of pseudoalkylating agents?
Carboplatin, Cisplatin, Oxaliplatin.
what are the side effects of alkylating and pseudoalkylating agents?
hair loss (not carboplatin), nephrotoxicity, neurotoxicity, ototoxicity, nausea, vomiting, diarrhoea, immunosuppression, tiredness.
what are anti-metabolites and what do they do?
- inhibiton of dihydrofolate reductase
- i.e. are folate antagonists/ analogues of purine or pyrimidine residues.
- Block DNA replication and transcription.
how do anti-metabolites block DNA replication?
purine (A, G), pyrimidine (T/U, C) or folate antagonists inhibit dihydrofolate reductase needed to make folic acid needed to make nucleic acids.
examples of anti-metabolites
o Folate – Methotrexate.
o Purine – 6-mercaptopurine, decarbazine, fludarabine.
o Pyrimidine – 5-fluorouracil, capecitabine, gemcitabine.
what are the side effects of anti-metabolites?
hair loss (not 5FU, capecitabine),
bone marrow suppression (leads to anaemia, neutropenia, thrombocytopenia)
sepsis
nausea/vomiting, mucositis/diarrhoea
palmar-plantar erythrodysesthesia (PPE), fatigue.
what are anthracylines and what do they do?
1) Inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand.
2) Block DNA repair and create free radicals (DNA/membrane damaging).
examples of anthracyclines
Doxorubicin, Epirubicin.
creation of free radicals to block repair by binding between nucleotides
what are the side effects of anthracyclines?
hair loss cardiac problems (due to free radicals) neutropenia, nausea/vomiting fatigue skin change red urine (doxorubicin).
what are vinca alkaloids and taxanes? what do they do?
Inhibit assembly (Vinca alkaloids) and
disassembly (Taxanes)
of mitotic microtubules
causes mitotic arrest
what are the side effects of vinca alkaloids and taxanes?
nerve damage (neuropathy) hair loss nausea vomiting bone marrow suppression, arthralgia allergy.
what are topoisomerase inhibitors?
Prevent DNA torsional strain during replication and transcription
e.g. Topo 1 and Topo 2
what is the role of topoisomerase inhibitors in cancer therapy?
- inhibition enable DNA torsional strain to exist
- leading to DNA breaks
- Induce temporary single (topo1) or double (topo2) strand breaks in the DNA backbone
this means the cells are induced into cell apoptosis at the checkpoints.
protect free ends from aberrant recombination
examples of topoisomerase inhibitor drugs
Topotecan
Irinotecan (topo1)
Etoposide (topo2)
anthracyclines also have anti-topoisomerase activity in their DNA actions
what are the side effects of topoisomerase inhibitors?
acute cholinergic type syndrome (irinotecan) hair loss nausea/vomiting fatigue Bone marrow suppression
how may a cell survive damage from cytotoxic therapy?
o DNA repair mechanisms upregulated.
o Base excision repair using PARP.
o DNA efflux by ATP-binding cassettes (ABC) transporters.
what is the biological basis of using dual kinase inhibitors?
prevent compensation to the loss of the main signalling pathway:
- cancer cells have networks of internal pathways which can be targeted by treatment.
- Monogenic cancers can be treated easier
- but in other cancers there are parallel pathways that are upregulated or feedback cascades that are activated.
dual kinase inhibitors can prevent feedback loop and target not just monogenic cancers. However, this increases toxicity
what are the 6 hallmarks of cancer cells?
SPINAP Self sufficient Pro-invasive and metastatic Insensitive to anti-growth signals Non-senescent Anti-apoptotic Pro-angiogenic
what is required to shift out of quiescent phase?
growth stimulating signals
how are growth signals transmitted?
by the growth factor receptor pathway
receptor tyrosine kinase contributes to more than 50% of human malignancies
what receptors are often overexpressed?
Her2 (breast cancer)
EGFR (colorectal and breast cancer)
PDGFR (glioma)
what ligands are often over expressed?
VEGF (prostate, kidney and breast cancer)
what receptors can be activated independent of a ligand (ligand-independent receptor activation)?
EGFR (lung)
FGFR (head/neck cancer, myeloma)
what is the result of over expression of receptors, ligands or LIRA?
increase in kinase cascade and signal amplification
-momab
mouse monoclonal
-ximab
chimeric
murine region is maintained integrally
-zumab
humanised
murine regions interspersed with light and heavy chains of the Fab portion.
-mumab
fully human
what do monoclonal antibodies target?
extracellular component of the receptor
what is the action of monoclonal antibodies?
affect the signalling system for proliferation
o The antibody can bind to one of the two receptors and prevent receptor dimerization.
o This causes internalisation of the receptor.
o Neutralise the ligand.
what do monoclonal antibodies activate?
o Fcgamma-receptor-dependant phagocytosis.
o Cytolysis induced complement-dependant cytotoxicity (CDC).
o Antibody-dependant cellular cytotoxicity (ADCC).
examples of monoclonal antibodies
o Bevacizumab – binds and neutralises VEGF (angiogenesis) Improves survival in colorectal cancer.
o Cetuximab – targets EGFR.
what do small molecule inhibitors do?
non-cytotoxic:
binds to the kinase domain and inhibit auto-phosphorylation and thus downstream signalling in ERK pathway
example of small molecule inhibitors
Glivec – first SMI, targets BCR-ABL fusion protein made in CML.
what is the translocation that occurs in CML?
BCR-Abl
how does Glivec help treat CML?
small molecule inhibitor to prevent the signalling patwhay:
targets the ATP-binding region with
(SMIs) act on the receptors TKs but also on the intracellular kinases in the kinase domain so affect the cell signalling pathways
examples of SMIs that target tyrosine kinase receptors
o Erlotibib – EGFR.
o Gefitinib – EGFR.
o Lapatinib – EGFR/HER2.
o Sorafinib – VEGFR.
block autophosphorylation of the tyrosine receptors
(works intracellularly unlike the monoclonal antibodies)
examples of SMIs that target intracellular kinases
- Sorafinib – Raf kinase
- Dasatinib – Src kinase.
- Torcinibs – mTOR inhibitors.
what is the largest disadvantage of targeted therapy?
resistance
how do cancer cells build resistance to targeted therapy?
o Mutation in ATP-binding domain.
o Intrinsic resistance.
o Intragenic mutations.
o Upregulation of downstream parallel pathways.
what are anti-sense oligonucleotides?
Single-stranded, chemically modified DNA-like molecule with 17-22 nucleotides.
The complementary nucleic acid hybridisation to target genes, hinders translation of specific mRNA. It recruits RNase H to cleave target mRNA.
what is an advantage and disadvantage of anti-sense oligonucleotides?
suitable for un-druggable targets
can be very expensive
what is RNAi?
Composed of single-stranded complimentary RNA.
less used now in cancer therapy
why is RNAi used less?
has lagged behind anti-sense technology
Compounds must be packaged to prevent degradation–> expensive
successful treatment of cancer
– b-RAF Targeting: b-RAF inhibitor = Vemurafenib. Extends life span
– Immune Modulation via Programmed Cell Death 1 (PD-1): Nivolumab = anti-PD-1 Antibody. Extends survival
what is PD-1?
T cell activation at tumour antigen:
- present on the surface of cancer cells and is required to maintain T-cell activation.
- After binding it with the ligand PDL-1, the body can no longer recognise the tumour cells as foreign.
If either is blocked, the immune system is stimulated.
in what cancer is the b-RAF mutation often in?
60% of melanomas
glutamine acid to valine
what is nivolumab used in?
treatment-refractory melanoma, non-small-cell lung cancer and renal cell carcinoma
