Cancer 3 Flashcards
what are the most common cancers worldwide?
• Lung • Breast • Bowel • Prostate • Stomach
why is the incidence of cancer set to increase?
- 22 million cases in 2030
- greater westernization in developing countries will reduce infection based cancers and increase western cancers
what are the main anti-cancer modalities?
- Surgery
- Radiotherapy
- Chemotherapy
- Immunotherapy
what are types of genetic mutation that cause cancer?
- Chromosome translocation
- Gene amplification (copy number variation)
- Point mutations within promoter or enhancer regions of the genes
- Deletions or insertions
- Epigenetic alterations to gene expression
- Can be inherited
it might be a multitude of these factors
what are the types of systemic chemotherapy drugs :
- Cytotoxic Chemotherapy
- Targeted Therapies
what are cytotoxic chemotherapy options?
- Alkylating agents
- Antimetabolites
- Anthracyclines
- Vinca alkaloids and taxanes
- Topoisomerase inhibitors
what are targeted therapy options?
- Small molecule inhibitors
- Monoclonal antibodies
how do cytotoxic drugs work?
Cytotoxic drugs ‘select’ rapidly dividing cells by targeting their structures (mainly their DNA)
how is cytotoxic chemotherapy given?
- given IV or orally
- works systemically
- it is not targetted
at what times is cytotoxic chemotherapy used?
Post-operatively = adjuvant
Pre-operatively = neoadjuvant
As a monotherapy or in combination with curative or palliative intent
adjuvant = given after initial treatment to prevent secondary cancer formation
what do alkylating agents do?
- adds alkyl groups to guanine residues in DNA
- It then cross-links DNA strands and prevents DNA from uncoiling at replication
- this triggers apoptosis
- It encourages mispairing
Chlorambucil Cyclophosphamide Dacarbazine Temozolomide
what do psuedo- alkylating agents do?
- these add platinum to guanine residues in DNA
- it triggers the same mechanism of death as alkylating agents
Carboplatin Cisplatin Oxaliplatin
what are the side effects of pseudo - alkylating agents and alkylating agents?
- cause hair loss
- vomiting
- nausea
- tiredness
- Nephrotoxicity
- Neurotoxicity
- Ototoxicity (ear)
- Immunosuppression
how do Anti-metabolites work?
- Masquerade as purine or pyrimidine residues leading to
- inhibition of DNA synthesis
- DNA double-strand breaks
- apoptosis
they work by blocking DNA replication and DNA transcription
they can also be folate antagonists which inhibit dihydrofolate reductase preventing folic acid being made ( an important building block for nucleic acids)
Methotrexate
what are the side effects of antimetabolites?
- Hair loss
- Bone marrow suppression causing anaemia
- neutropenia and thrombocytopenia
- Increased risk of neutropenic sepsis
- Nausea and vomiting
- Mucositis and diarrhoea
- Palmar-plantar erythrodysesthesia PPE (Hand-foot syndrome, swelling of hands and feet)
- Fatigue
how do Anthracyclines work?
- Inhibit transcription and replication by intercalating (inserting between) nucleotides within the DNA/RNA strand
- Also block DNA repair
- They create DNA-damaging and cell membrane damaging oxygen free radicals
eg
Doxorubicin
Epirubicin
what are side effects of Anthracyclines?
- Cardiac toxicity (arrythmias, heart failure) – probably due to damage induced by free radicals
- Alopecia
- Neutropenia
- Nausea
- Vomiting
- Fatigue
- Skin changes
- Red urine (doxorubicin “the red devil”)
how do Vinca Alkaloids and taxanes work?
Work by inhibiting assembly or disassembly of mitotic microtubules causing dividing cells to undergo mitotic arrest
side effects of Vinca Alkaloids and taxanes?
- Nerve damage: peripheral neuropathy, autonomic neuropathy
- Hair loss
- Nausea
- Vomiting
- Bone marrow suppression (neutropenia, anaemia etc)
- Arthralgia
- Allergy
how do Topoisomerase inhibitors work?
- Topoisomerases are responsible for the uncoiling of DNA- they prevent DNA torsional strain during DNA replication and transcription
- Topoisomerase Inhibitors induce temporary single strand or double-strand breaks in the phosphodiester backbone of DNA
- drugs such as anthracyclines have anti-topoisomerase effects
- examples: Topotecan, Irinotecan , Etoposide
what are side effects of Topoisomerase inhibitors?
- (irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps and diaphoresis (sweating).
Therefore given with atropine
- Hair loss
- Nausea
- vomiting
- Fatigue
- Bone marrow suppression
what is the greatest recent development in cancer treatment?
immunotherapy
what are resistant mechanisms of the DNA against treatment?
- DNA repair mechanisms upregulated
- Drug effluxed from the cell by ATP-binding cassette
- DNA adducts replaced by Base Excision repair
what are the modern non cytotoxic methods we use to manipulate cancer cells?
- these mainly revolve around the use of monoclonal antibodies and small-molecule inhibitors
- There is a lot of signaling within cancer cells and these signals can be cut in monogenic cancers
- however, for some cancers, the feedback cascades are activated
- we are in an era of dual kinase inhibitors which prevent feedback loops but increase toxicities
what are the defining hallmarks of a cancer cell?
used to be 6 main hallmarks : SPINAP
Self-sufficient
Pro-invasive and metastatic
Insensitive to anti-growth signals
Non-senescent
Anti-apoptotic
Pro-angiogenic
has now become 10 hallmarks: DIE U
Dysregulated metabolism
Evades the immune system
Unstable DNA
Inflammation
what do normal cells need to grow?
- Normal cells need growth signals to move from resting state to proliferating state
- these signals are transmitted into the cell via growth factors binding transmembrane receptors and activating downstream signaling pathways
how might overexpression of receptors cause cancer?
- HER 2 - over expressed in 25% of breast cancer
- EGFR - over-expressed in breast and colorectal cancer
- PDGFR - glioma (brain cancer)
- these are all growth receptors so over expression can cause tumours via upregulation of the kinase cascade and signal amplification
how might over expression of ligands cause cancer?
VEGF - prostate, kidney and breast cancer
this also leads to upregulation of kinase cascade and signal amplification
examples of Constitutive (ligand-independent) receptor activation causing cancer?
- EGFR - lung cancer
- FGFR - head and neck cancers, myeloma
what monoclonal antibodies are used to treat cancer?
how do monoclonal antibodies target the receptors?
The monoclonal antibodies:
- Neutralise the ligand
- Prevent receptor dimerization
- Cause internalisation of the receptor
- they also activate the Fcγ-receptor-dependent phagocytosis
what are examples of monoclonal antibodies used in oncology?
- Bevacizumab binds and neutralises VEGF (helps colorectal cancer)
- Cetuximab targets EGFR
how do small molecule inhibitors work?
- These bind to the kinase domain within the cytoplasm and block autophosphorylation and downstream signalling
what was the first targeted therapy and how does it work?
- in 1973 chromosome translocation in patients with CML was discovered
- This translocation was found to create its own unique fusion protein called Bcr-abl - an enzyme that drove over-production of white cells
- Glivec was the first targetted therapy for Bcr-abl specifically
where does glivec target?
- Glivec is a small molecule inhibitor and targets the ATP binding region within the kinase domain
- It inhibits the kinase activity of ABL1
where do small molecule inhibitors act upon?
what do they affect?
- Small molecule inhibitors act upon receptor protein tyrosine kinases but also intracellular kinases
- they affect cell signaling pathways (kinase cascades)
examples of small molecule inhibitors inhibiting receptors?
Erlotinib (EGFR)
Gefitinib (EGFR)
Lapatinib (EGFR/HER2)
Sorafenib (VEGFR)
what are small molecule inhibitors that inhibit intracellular kinases?
Sorafenib (Raf kinase)
Dasatinib (Src kinase)
Torcinibs (mTOR inhibitors)
what is a big advantage of targeted therapy?
- by working on receptors targetted therapies block cancer hallmarks without the toxicity observed with cytotoxics
what is a major problem with targetted therapy?
- resistance
what are resistance mechanisms to targetted therapies?
- Mutations in the ATP-binding domain
(e. g. BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively) - Intrinsic resistance
(herceptin is effective in 85% of HER2+ breast cancers, suggesting other driving pathways)
- Intragenic mutations
- Upregulation of downstream of parallel pathways
how do anti sense Oligonucleotides work?
- single-stranded, chemically modified, DNA like molecules 17-22 nucleotides in length
- This complementary nucleic acid hybridization to the target gene prevents the translation of specific mRNA
- It recruits RNase H to cleave target mRNA
- this works well on undruggable targets
how does RNA interference work?
- Single-stranded complementary RNA
- this has lagged behind anti sense technology
- Compounds have to be packaged to prevent degradation
-
what is another major obstacle for the targetted approach?
- tumor heterogeneity
example of successful B - Raf inhibitor
side effects?
vemurafenib
- Arthralgia (pain in a joint)
- Skin rash
- Photosensitivity
how does nivolumab an anti PD1 antibody work?
- Binding of the ligand PDL1 to the PD-1 receptor will mean that the body’s T cells can no longer recognise tumour cells as foreign
- So if either the PDL1 ligand or the PD-1 receptor are blocked, the immune system will be stimulated
