Biological basis of cancer therapy

Question 1

What are the most common cancers worldwide?

Answer 1

Lung
Breast
Liver
Bowel- colorectal
Prostate
Stomach

Question 2

What is the predicted cancer incidence for 2030?

Answer 2

22 million cases

Question 3

Why is cancer incidence set to increase?

Answer 3

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

Question 4

What are the main anti-cancer modalities?

Answer 4

Surgery
Radiotherapy
Chemotherapy
Immunotherapy

Question 5

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

Answer 5

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

Question 6

What are the types of systemic cancer therapy?

Answer 6

Cytotoxic chemotherapy

Targeted therapies

Question 7

What are the types of cytotoxic chemotherapy?

Answer 7

Alkylating agents
Antimetabolites
Anthracyclines
Vinca alkaloids and taxanes
Topoisomerase inhibitors

Question 8

What are the types of targeted cancer therapies?

Answer 8

Small molecule inhibitors

Monoclonal antibodies

Question 9

How do cytotoxic agents work to treat cancer?

Answer 9

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.

Question 10

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

Answer 10

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.

Question 11

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

Answer 11

Add platinum to guanine residues in DNA.

Same mechanism of cell death as alkylating agents.

Question 12

Give examples of pseudo-alkylating agents.

Answer 12

Carboplatin
Cisplatin
Oxaliplatin

Question 13

Give examples of alkylating agents.

Answer 13

Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide

Question 14

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

Answer 14

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

Question 15

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

Answer 15

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).

Question 16

Give examples of anti-metabolites.

Answer 16

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

Question 17

What are the side effects of anti-metabolites?

Answer 17

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

Question 18

How do anthracyclines work as an anti-cancer therapy?

Answer 18

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.

Question 19

Give examples of anthracyclines.

Answer 19

Doxorubicin

Epirubicin

Question 20

What are the side effects of anthracyclines?

Answer 20

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')

Question 21

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

Answer 21

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

Question 22

What are the side effects of microtubule-targeting drugs?

Answer 22

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

Question 23

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

Answer 23

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.

Question 24

What are the side effects of topoisomerase inhibitors?

Answer 24

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

Question 25

What are some resistance mechanisms to anti-cancer therapies?

Answer 25

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).

Question 26

What are the ten hallmarks of the cancer cell?

Answer 26

``` 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 ```

Question 27

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

Answer 27

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.

Question 28

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

Answer 28

VEGF- prostate, kidney and breast cancers. | Up-regulates kinase cascade and signal amplification.

Question 29

What are the different types of monoclonal antibodies?

Answer 29

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

Question 30

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

Answer 30

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)

Question 31

Give examples of monoclonal antibodies in oncology.

Answer 31

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

Question 32

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

Answer 32

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

Question 33

What was the first 'targeted' therapy used in CML treatment?

Answer 33

Glivec (Gleevec, Imatinib). | Targets BCR-Abl enzyme to prevent over-production of white cells.

Question 34

Give resistance mechanisms to targeted therapies.

Answer 34

``` 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. ```

Question 35

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

Answer 35

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.

Question 36

How could RNA interference be used in future cancer therapy?

Answer 36

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.

Question 37

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

Answer 37

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.

Question 38

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

Answer 38

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).

Question 39

Give three disadvantages of cytotoxic chemotherapy.

Answer 39

Toxic Non-specific Sometimes ineffective