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Year 2 Collin > Cancer 10 - Biological basis of Cancer Therapy > Flashcards

Cancer 10 - Biological basis of Cancer Therapy Flashcards

1
Q

What are the most common cancers worldwide

A 
Lung
Breast
Liver
Stomach
Colon
Cervix
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2
Q

What are the 4 means of anti-cancer treatment

A
  1. Surgery
  2. Radiotherapy
  3. Chemotherapy
  4. Immunotherapy
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3
Q

What mutations can cause cancer

A
  1. Chromosome translocations
  2. Gene amplification
  3. Point mutations in promotor/enhancer regions
  4. Deletions/insertions
  5. Epigenetic alterations to gene expression
  6. Inherited mutations
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4
Q

Systematic therapy involves cytotoxic chemotherapy and targeted therapies. What is involved cytotoxic chemotherapy

A
  1. Alkylating agents
  2. Antimetabolites
  3. Anthracyclines
  4. Vinca alkaloids and taxanes
  5. Topoisomerase inhibitors

Everything except vinca alkaloids and taxanes attack DNA.

Vinca alkaloids and taxanes attack microtubules

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5
Q

Cytotoxic chemotherapy is not very specific/targeted. How does it work

A

They target rapidly dividing cells by attacking their DNA

attacks healthy cells too unfortunately

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6
Q

How is cytotoxic chemotherapy given?

A

IV or orally

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7
Q

What are the uses of cytotoxic chemotherapy

A
  1. Given post-op = adjuvant
  2. Given pre-op = me-adjuvant (to downstage a tumour)
  3. Monotherapy or in combination
  4. Given with palliative/curative intent
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8
Q

How do alkylating agents work

A
  1. Add alkyl groups to guanine residues in DNA

2. DNA crosslinks prevent uncoiling of DNA –> triggers apoptosis via checkpoint pathway

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9
Q

How can alkylating agents cause cancer potentially? (<1% chance)§

A

Encourage miss-pairing

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10
Q

Describe pseudo-alkylating agents

A

Adding platinum to guanine residues in DNA

same mechanism as alkylating agents

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11
Q

Give examples of pseudo-alkylating agents

A

Carboplatin, cisplatin, oxaliplatin

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12
Q

Give examples of alkylating agents

A

Chlorambucil, cyclophosphamide, dacarbazine, temozolomide

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13
Q

List side effects of alkylating agents

A

Hair loss, nephrotoxicity, neurotoxicity, ototoxicity, nausea, vomiting, diarrhoea, immunosuppression, fatigue

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14
Q

How do anti-metabolites work

A

Masquerade as purine/pyrimidine residues —> inhibiting DNA synthesis —> DNA double strand breaks and apoptosis occurs

DNA replication and transcription prevented

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15
Q

Which 3 things can anti-metabolites be?

A

Purine / pyrimidine / folate antagonist

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16
Q

What do folate antagonists do

A

Inhibit dihydrofolate reductase –> needed to make folic acid which is used in nucleic acids (esp thymine)

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17
Q

Give examples of anti-metabolites

A

Methotrexate (folate), 6-mercaptopurine, decarbazine & fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)

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18
Q

Gemcitabine (pyrimidine) is used to treat …

A

Lung cancer, pancreatic cancer, ovarian cancer

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19
Q

What are the side effects of anti-metabolites

A

Hair loss, bone marrow suppression (causing anaemia, neutropenia, thrombocytopenia), increased risk of neutropenic sepsis and bleeding, nausea and vomiting, mucositis and diarrhoea, palmar/plantar erythrodysesthesia, fatigue

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20
Q

How do anthracyclines work

A

Intercalate between nucleotides within DNA/RNA strand –> inhibits transcription and replication

They may also block DNA repair (mutagenic)

May create free radicals that can damage DNA and cell membrane

21
Q

Give 2 examples of anthracyclines

A
  1. Doxorubicin

2. Epirubicin

22
Q

What are the side effects of anthracyclines

A
  1. Cardiac toxicity
  2. Alopecia
  3. Neutropenia
  4. Nausea and vomiting
  5. Fatigue
  6. Skin changes
  7. Red urine (doxorubicin = the Red Devil)
23
Q

How do vinca alkaloids and taxanes work

A

Inhibit assembly (vinca alkaloids) or disassembly (taxanes) or mitotic microtubules - causes dividing cells to undergo mitotic arrest

24
Q

What are the side effects of microtubule targeting drugs?

A

Peripheral neuropathy, hair loss, nausea and vomiting, bone marrow suppression, arthralgia, allergy

25
Q

How do topoisomerase inhibitors work?

A

Topoisomerase inhibitors prevent DNA torsional strain during DNA replication and transcription

  • specific topoisomerase inhibitors include Topotecan & Irinotecan (Topo 1 - single strand break) and Etoposide (Topo 2 - double strand breaks) which alters binding of the complex to DNA and allow permanent DNA breaks
26
Q

Why are topoisomerase inhibitors often given with atropine?

A

To prevent acute cholinergic type syndromes from occurring (e.g. diarrhoea, abdominal cramps and sweating)

27
Q

What are the side effects of topoisomerase inhibitors

A

1, Acute cholinergic type syndrome

  1. Hair loss
  2. Nausea / vomiting
  3. Fatigue
  4. Bone marrow suppression
28
Q

What are the 6 hallmarks of a cancer cell

A
  1. Self sufficient
  2. Insensitive to anti-growth signals
  3. Anti-apoptotic
  4. Pro-invasive and metastatic
  5. Non-senescent
  6. Pro-angiogenic
  7. Dysregulated metabolism
  8. Evades immune system
  9. Unstable DNA
  10. Inflammation
29
Q

Describe the monoclonal antibodies and their suffixes

A
  1. -Momab (derived from mouse antibodies)
  2. -ximab (chimeric - e.g. cuteximab)
  3. -zumab (humanised - e.g. bevacizumab, trastuzumab)
  4. -mumab (fully human - e.g. panitumumab)
30
Q

Describe the difference between a humanised monoclonal Ab and chimeric monoclonal Ab

A

Humanised = murine regions are interspersed within light and heavy chains of Fab portion

Chimeric = murine component of variable region of Fab section is maintained integrally

31
Q

Where do monoclonal antibodies target

A

Extracellular component of receptor

32
Q

What 4 things may monoclonal antibodies do/cause

A
  1. Neutralise ligand
  2. Prevent dimerisation of receptors
  3. Internalisation of receptor
  4. Induces Complement Dependent Cytotoxicity (CDC) or Antibody Dependent Cellular Cytotoxicity (ADCC)
33
Q

Give 2 examples of monoclonal antibodies in oncology

A
  1. Bevacizumab (Avastin) neutralises VEGF - used in coloretal cancer
  2. Cetuximab targets EGFR in colorectal cancer
34
Q

How do Small molecule inhibitors (SMIs) work?

A

They bind the kinase domain of tyrosine kinase in cytoplasm –> blocking autophosphorylation and downstream signalling

35
Q

Give an example of a small molecule inhibitor

A

Glivec (imatinib) - for CML targeted BCR-ABL fusion gene protein - specifically targets ATP binding region in kinase domain –> thus inhibiting kinase activity of ABL-1

36
Q

SMIs can also act on intracellular kinases. Give examples of:

  1. Receptor-inhibition
  2. Intracellular kinase inhibition
A
  1. Erlotinib (EGFR), Sorafinib (VEGFR)

2. Sorafinib (Raf kinase), Dasatinib (Src kinase)

37
Q

What are the advantages of using monoclonal antibodies

A
  1. High target specificity
  2. Cause Complement mediated cytotoxicity and apoptosis induction
  3. Can be radiolabelled
  4. Cause target receptor internalisation
  5. Long Half life so lower dosing frequency
  6. Ideal for haematological malignancies
38
Q

What are some advantages of small molecule inhibitors

A
  1. Can target Tyrosine Kinases without an extracellular domain (or TKs that are constitutively activated)
  2. Oral administration
  3. Good tissue penetration
  4. Cheap
  5. Pleiotropic targets
39
Q

What are the disadvantages of monoclonal antibodies

A
  1. Large and complex structure
  2. Less useful against bulky tumours
  3. Only useful against targets with extracellular domains
  4. May cause immunogenicity, allergy
  5. Expensive
  6. Resistance
40
Q

What are the disadvantages of small molecule inhibitors

A
  1. Shorter half life = more frequent administration

2. Pleiotropic targets

41
Q

What mechanisms may cause resistance to targeted therapies

A
  1. Mutation in ATP-binding domain
  2. Intrinsic resistance
  3. Intragenic mutations
  4. Upregulation of downstream or parallel pathways
42
Q

How do anti-sense oligonucleotides work?

(not used often - only good for “undraggable” targets

A
  • Complementary nucleic acid hybridisation to target gene - hinders translation of specific mRNA
  • Recruits RNAse H to cleave target mRNA
  • Anti sense oligonucleotides are single stranded, chemically modified DNA-like molecules (17-22 nucleotides in length)
43
Q

How can RNA interference be used for cancer treatment (still in phase 1 clinical trials)

A

Single stranded complementary RNA

Compounds must be packaged to prevent degradation (nano therapeutics)

44
Q

Which 2 bodies must approve of the expensive cancer treatments?

A

NICE and EMA

45
Q

What is a major difficulty to the targeted cancer therapy approach

A

Tumour heterogeneity - different parts of the tumour may have different genetic profiles

46
Q

How has targeting B-raf been successful in anti-cancer treatment

A

B-raf activating mutations found in 60% of melanomas (glutamate –> valine) - causing 500x increase in activity

B-raf inhibitor (vemurafinib) was very effective in phase 1 activity in melanoma –> increased lifespan by 7 months

47
Q

Describe a success story of cancer treatment by targeting immune modulation involving programmed cell death (PD-1)

A
  1. PD-1 ligand found on surface of cancer cells
  2. PD-1 required to maintain T cell activation
  3. t-cells bind PD-1 –> cell no longer recognised as foreign
  4. Nivolumab is a anti-PD1 antibody which stimulates the immune system
48
Q

What is nivolumab used to treat

median survival of 16 months - overall response rate of 31%

A
  1. Treatment refractory melanoma
  2. Non-small cell lung cancer
  3. Renal cell carcinoma

Year 2 Collin (114 decks)

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