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MCD: Cancer > Biological basis of cancer therapy > Flashcards

Biological basis of cancer therapy Flashcards

1
Q

What are the most common cancers worldwide?

A 
Lung
Breast
Liver
Bowel- colorectal
Prostate
Stomach
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2
Q

What is the predicted cancer incidence for 2030?

A

22 million cases

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3
Q

Why is cancer incidence set to increase?

A

Greater westernisation of developing countries will reduce infection-based cancers (cervical, stomach, etc.) and increase western cancers such as breast, colorectal, lung and prostate.

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4
Q

What are the main anti-cancer modalities?

A

Surgery
Radiotherapy
Chemotherapy
Immunotherapy

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5
Q

What are the types of genetic mutations that can cause cancer?

A

Chromosome translocation
Gene amplification (copy number variation)
Point mutations within promoter or enhancer regions of genes
Deletions or insertions
Epigenetic alterations to gene expression
Can be inherited

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6
Q

What are the types of systemic cancer therapy?

A

Cytotoxic chemotherapy

Targeted therapies

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7
Q

What are the types of cytotoxic chemotherapy?

A 
Alkylating agents
Antimetabolites
Anthracyclines
Vinca alkaloids and taxanes
Topoisomerase inhibitors
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8
Q

What are the types of targeted cancer therapies?

A

Small molecule inhibitors

Monoclonal antibodies

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9
Q

How do cytotoxic agents work to treat cancer?

A

Select rapidly dividing cells by targeting their structures (mostly DNA).
Administered i.v. or orally (occasionally)
Work systemically
Non-targeted
Given post-operatively as adjuvant, pre-operatively as neoadjuvant, as monotherapy or in combination, with curative or palliative intent.

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10
Q

How do alkylating agents work as an anti-cancer therapy?

A 
Add alkyl (CnH2n+1) groups to guanine residues in DNA.
Cross-link (intra, inter, DNA-protein) DNA strands and prevent DNA from uncoiling at replication.
Trigger apoptosis (via checkpoint pathway).
Encourage mispairing- oncogenic.
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11
Q

How do pseudo-alkylating agents work as an anti-cancer therapy?

A

Add platinum to guanine residues in DNA.

Same mechanism of cell death as alkylating agents.

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12
Q

Give examples of pseudo-alkylating agents.

A

Carboplatin
Cisplatin
Oxaliplatin

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13
Q

Give examples of alkylating agents.

A

Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide

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14
Q

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

A 
Hair loss (not carboplatin)
Nephrotoxicity
Neurotoxicity
Ototoxicity (platinums)
Nausea
Vomiting
Diarrhoea
Immunosuppression
Tiredness
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15
Q

How do anti-metabolites work as an anti-cancer therapy?

A

Masquerade as purine (adenine and guanine) or pyrimidine (thymine/uracil and cytosine) residues, or folate antagonists (which inhibit dihydrofolate reductase required to make folic acid, an important building block for all nucleic acids, especially thymine) leading to inhibition of DNA synthesis, DNA double strand breaks and apoptosis.
Block DNA replication (DNA-DNA) and transcription (DNA-RNA).

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16
Q

Give examples of anti-metabolites.

A 
Methotrexate (folate)
6-mercaptopurine
Dacarbazine
Fludarabine (purine)
5-fluorouracil
Capecitabine
Gemcitabine (pyrimidine)
17
Q

What are the side effects of anti-metabolites?

A

Hair loss (alopecia)- not 5FU or capecitabine
Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
Increased risk of neutropenic sepsis (and death) or bleeding
Nausea and vomiting (dehydration)
Mucositis and diarrhoea
Palmar-plantar erythrodysesthesia (PPE)
Fatigue

18
Q

How do anthracyclines work as an anti-cancer therapy?

A

Inhibit transcription and replication by intercalating nucleotides within DNA/RNA strand.
Also block DNA repair- mutagenic.
Create DNA and cell membrane damaging free oxygen radicals.

19
Q

Give examples of anthracyclines.

A

Doxorubicin

Epirubicin

20
Q

What are the side effects of anthracyclines?

A 
Cardiac toxicity (arrhythmias, heart failure)- probably due to damage induced by free radicals
Alopecia
Neutropenia
Nausea and vomiting
Fatigue
Skin changes
Red urine (doxorubicin- 'the red devil')
21
Q

How do vinca alkaloids and taxanes work as an anti-cancer therapy?

A

Inhibit assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest.

22
Q

What are the side effects of microtubule-targeting drugs?

A

Nerve damage- peripheral neuropathy, autonomic neuropathy
Hair loss
Nausea
Vomiting
Bone marrow suppression (neutropenia, anaemia, etc.)
Arthralgia
Allergy

23
Q

How do topoisomerase inhibitors work as an anti-cancer therapy?

A

Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription.
They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA.
They protect the free ends of DNA from aberrant recombination events.
Drugs such as anthracyclines have anti-topoisomerase effects through their action on DNA.
Specific topoisomerase inhibitors include Topotecan and irinotecan (topo1) and etoposide (topo2)- alter binding of the complex to DNA and allow permanent DNA breaks.

24
Q

What are the side effects of topoisomerase inhibitors?

A 
Hair loss
Nausea and vomiting
Fatigue
Bone marrow suppression
Irinotecan: acute cholinergic type syndrome- diarrhoea, abdominal cramps and diaphoresis (sweating), therefore given with atropine.
25
Q

What are some resistance mechanisms to anti-cancer therapies?

A

Drug effluxed from the cell by ATP-binding cassette (ABC) transporters.
DNA repair mechanisms unregulated and DNA damage is repaired- DNA double strand doesn’t break.
DNA adducts replaced by Base Excision repair (using PARP).

26
Q

What are the ten hallmarks of the cancer cell?

A 
Self-sufficient
Insensitive to anti-growth signals
Anti-apoptotic
Pro-invasive and metastatic
Pro-angiogenic
Non-senescent
Dysregulated metabolism
Evades the immune system
Unstable DNA
Inflammation
27
Q

Give an example of a receptor that is over-expressed in cancer.

A

HER2- amplified and over-expressed in 25% of breast cancer cases
EGFR- over-expressed in breast and colorectal cancer
PGDFR- glioma (brain cancer)
Up-regulates kinase cascade and signal amplification.

28
Q

Give an example of a ligand that is over-expressed in cancer.

A

VEGF- prostate, kidney and breast cancers.

Up-regulates kinase cascade and signal amplification.

29
Q

What are the different types of monoclonal antibodies?

A
  • momab, derived from mouse antibodies
  • ximab, chimeric, e.g. cetuximab
  • zumab, humanised, e.g. bevacizumab, trastuzumab
  • mumab, fully human, e.g. panitumumab
30
Q

How do monoclonal antibodies work as an anti-cancer therapy?

A

Neutralise the ligand
Prevent receptor dimerisation
Cause internalisation of receptor
Target the extracellular component of the receptor.
Also activate Fc-gamma-receptor-dependent phagocytosis or cytolysis- induces complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)

31
Q

Give examples of monoclonal antibodies in oncology.

A

Bevacizumab- binds and neutralises, VEGF, improves survival in colorectal cancer.
Cetuximab- targets EGFR, used in colorectal cancer.

32
Q

How do small molecule inhibitors work as an anti-cancer therapy?

A

Bind to the kinase domain of the tyrosine kinase within the cytoplasm and block auto-phosphorylation and downstream signalling.

33
Q

What was the first ‘targeted’ therapy used in CML treatment?

A

Glivec (Gleevec, Imatinib).

Targets BCR-Abl enzyme to prevent over-production of white cells.

34
Q

Give resistance mechanisms to targeted therapies.

A 
Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively).
Intrinsic resistance (perception effective in 85% HER2+ breast cancers, suggesting the driving pathways).
Intragenic mutations.
Up-regulation of downstream or parallel pathways.
35
Q

How could anti-sense oligonucleotides be used in future cancer therapy?

A

Single-stranded, chemically modified DNA-like molecule 17-22 nucleotides in length.
Complementary nucleic acid hybridisation to target gene hindering translation of specific mRNA.
Recruits RNase H to cleave target mRNA/
Good for ‘undruggable’ targets.

36
Q

How could RNA interference be used in future cancer therapy?

A

Single stranded complementary RNA.
Has lagged behind anti-sense technology- especially in cancer therapy.
Compounds have to be packaged to prevent degradation- nanotherapeutics.
CALAA-01 targeted to M2 subunit of ribonucleotide reductase.
Phase I clinical trials in cancer- results awaited.

37
Q

Why can targeting b-RAF in cancer therapy be successful?

A

Activating mutations of b-RAF identified in 60% of melanomas.
Substitution of glutamic acid for valine (V600E) causes a 500-fold increase in activity.
b-RAF inhibitor (vemurafenib) showed dramatic Phase I activity in melanoma (80% PR or CR).
Extends the lifespan of mutation holders by 7 months.
Side effects: arthralgia, skin rash and photosensitivity.

38
Q

Why can immune modulation via programmed cell death 1 (PD-1) in cancer therapy be successful?

A

Ligand present on the surface of cancer cells.
Required to maintain T cell activation.
After binding the ligand PDL1, the body’s T cells can no longer recognise tumour cells as foreign.
If either is blocked, immune system is stimulated.
Nivolumab (developed by BMS) is anti-PD1 antibody.
In treatment-refractory melanoma, non-small cell lung cancer, and renal cell carcinoma.
Saw overall response rates of 31% in melanoma (usually 5-15%).
Median survival of 16 months (phase I trial).

39
Q

Give three disadvantages of cytotoxic chemotherapy.

A

Toxic
Non-specific
Sometimes ineffective

MCD: Cancer (17 decks)

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