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Year 2 - Cancer > Cancer 3 > Flashcards

Cancer 3 Flashcards

1
Q

what are the most common cancers worldwide?

A

• Lung • Breast • Bowel • Prostate • Stomach

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2
Q

why is the incidence of cancer set to increase?

A
  • 22 million cases in 2030
  • greater westernization in developing countries will reduce infection based cancers and increase western cancers
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3
Q

what are the main anti-cancer modalities?

A
  • Surgery
  • Radiotherapy
  • Chemotherapy
  • Immunotherapy
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4
Q

what are types of genetic mutation that cause cancer?

A
  • 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

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5
Q

what are the types of systemic chemotherapy drugs :

A
  • Cytotoxic Chemotherapy
  • Targeted Therapies
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6
Q

what are cytotoxic chemotherapy options?

A
  • Alkylating agents
  • Antimetabolites
  • Anthracyclines
  • Vinca alkaloids and taxanes
  • Topoisomerase inhibitors
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7
Q

what are targeted therapy options?

A
  • Small molecule inhibitors
  • Monoclonal antibodies
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8
Q

how do cytotoxic drugs work?

A

Cytotoxic drugs ‘select’ rapidly dividing cells by targeting their structures (mainly their DNA)

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9
Q

how is cytotoxic chemotherapy given?

A
  • given IV or orally
  • works systemically
  • it is not targetted
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10
Q

at what times is cytotoxic chemotherapy used?

A

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

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11
Q

what do alkylating agents do?

A
  • 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

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12
Q

what do psuedo- alkylating agents do?

A
  • these add platinum to guanine residues in DNA
  • it triggers the same mechanism of death as alkylating agents

Carboplatin Cisplatin Oxaliplatin

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13
Q

what are the side effects of pseudo - alkylating agents and alkylating agents?

A
  • cause hair loss
  • vomiting
  • nausea
  • tiredness
  • Nephrotoxicity
  • Neurotoxicity
  • Ototoxicity (ear)
  • Immunosuppression
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14
Q

how do Anti-metabolites work?

A
  • 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

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15
Q

what are the side effects of antimetabolites?

A
  • 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
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16
Q

how do Anthracyclines work?

A
  • 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

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17
Q

what are side effects of Anthracyclines?

A
  • 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”)
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18
Q

how do Vinca Alkaloids and taxanes work?

A

Work by inhibiting assembly or disassembly of mitotic microtubules causing dividing cells to undergo mitotic arrest

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19
Q

side effects of Vinca Alkaloids and taxanes?

A
  • Nerve damage: peripheral neuropathy, autonomic neuropathy
  • Hair loss
  • Nausea
  • Vomiting
  • Bone marrow suppression (neutropenia, anaemia etc)
  • Arthralgia
  • Allergy
20
Q

how do Topoisomerase inhibitors work?

A
  • 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
21
Q

what are side effects of Topoisomerase inhibitors?

A
  • (irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps and diaphoresis (sweating).

Therefore given with atropine

  • Hair loss
  • Nausea
  • vomiting
  • Fatigue
  • Bone marrow suppression
22
Q

what is the greatest recent development in cancer treatment?

A

immunotherapy

23
Q

what are resistant mechanisms of the DNA against treatment?

A
  • DNA repair mechanisms upregulated
  • Drug effluxed from the cell by ATP-binding cassette
  • DNA adducts replaced by Base Excision repair
24
Q

what are the modern non cytotoxic methods we use to manipulate cancer cells?

A
  • 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
25
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
26
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
27
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
28
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
29
examples of Constitutive (ligand-independent) receptor activation causing cancer?
* EGFR - lung cancer * FGFR - head and neck cancers, myeloma
30
what monoclonal antibodies are used to treat cancer?
31
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
32
what are examples of monoclonal antibodies used in oncology?
- **Bevacizumab** binds and neutralises VEGF (helps colorectal cancer) - **Cetuximab** targets EGFR
33
how do small molecule inhibitors work?
- These bind to the kinase domain within the cytoplasm and block autophosphorylation and downstream signalling
34
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
35
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
36
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)
37
examples of small molecule inhibitors inhibiting receptors?
Erlotinib (EGFR) Gefitinib (EGFR) Lapatinib (EGFR/HER2) Sorafenib (VEGFR)
38
what are small molecule inhibitors that inhibit intracellular kinases?
Sorafenib (Raf kinase) Dasatinib (Src kinase) Torcinibs (mTOR inhibitors)
39
what is a big advantage of targeted therapy?
- by working on receptors targetted therapies block cancer hallmarks without the toxicity observed with cytotoxics
40
what is a major problem with targetted therapy?
- resistance
41
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
42
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
43
how does RNA interference work?
- Single-stranded complementary RNA - this has lagged behind anti sense technology - Compounds have to be packaged to prevent degradation -
44
what is another major obstacle for the targetted approach?
- tumor heterogeneity
45
example of successful B - Raf inhibitor side effects?
vemurafenib * Arthralgia (pain in a joint) * Skin rash * Photosensitivity
46
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
47

Year 2 - Cancer (15 decks)

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