L4.2 Molecular basis of cancer

Question 1

What is cancer caused by?

Answer 1

Caused by genetic instability
Main risk factor = age (median age 76)

Question 2

10 cancer cell hallmarks involved in pathogenesis of cancer

Answer 2

1. Deregulate cellular energetics
2. Sustain abnormal proliferation
3. Evading growth suppressors
4. Avoid immune destruction
5. Invade & metastase
6. Tumour-promoting inflammation
7. Divides indefinitely (immortal)
8. Induce angiogenesis
9. Genome instability & mutation
10. Resistant to cell death

Question 3

Features of cancer signals

Answer 3

• Cancer signals (release GF/pro-inflam agents) → invasive → metastase
• Microenv initially hostile to cancer, but tumour adapts to env
• When cancer metastase, require lifelong treatment

Question 4

Growth stage of cancer

Answer 4

• Normal cell → initiated → pre-cancer → invasive → metastasis

Question 5

Changes of medicine usage with times

Answer 5

• Old: Use broad cytokines based on tumour classification
• New: Using genomic screening → allows targeting of specific lesions

Question 6

Correlations of cigarettes and cancer

Answer 6

• Cigarette smoking → ↑lung cancer risk → causes inflammation at site → metastase
  
  • Development of cancer could be latent (b/w 1st exposure & development of cancer)
• Genetic lesions from smoking is irreversible
  
  • ↓risk after smoking → but risk doesn’t reset to baseline
• Mech:
  
  • Error in repair mech of DNA → causes genetic instability
  • Mutation in p53 → cannot apoptose → evades cell death

Question 7

Correlations of fat diet and cancer

Answer 7

• ↑fat diet → causes dysplastic mucosa → insave cancer → metastase in gut
• Risk higher for fat diet than smoking, also has different timeframe

Question 8

Viruses that causes cancer

Answer 8

• Integrate to myc gene → ↑proliferation (amplification of regulatory genes)

Question 9

Oncogene mutations

Answer 9

• Mutants of oncogenes causes cancer
• HER & Neu (oncogenes) mutations → amplifies HER
  
  • Promotes cell proliferation & oppose apoptosis (common in breast cancers)

Question 10

Example of Translocation of genes causing cancer

Answer 10

• Bcr-abl protein translocation → associated with leukemia

Question 11

Growth factors causing cancer

Answer 11

• Most GF are tyrosine kinases
• Mutation causes excessive drive from ↑prod. of GF → activates GF genes → cancer
  
  • GF.R mutation → becomes constantly active
• Anti-ligand + receptor strategies → limit tumours

Question 12

Differentiation of cancer cells

Answer 12

• Cancers don’t differentiate properly
• There are mutations in differentiation genes
• e.g:
  
  • Hedgehog pathway → causes cancer
  • Patched → normally inhibits smoothened (smoothened causes cancer)
    
    • Mutation → loss of function of patched
  • WNT & fizzled system (similar to smoothened)

Question 13

Mutations in GCPRs

Answer 13

• GF works through GCPRs
• Mutations in GCPRs → is cancerous (through the transduction pathway)

Question 14

RAS protein mutations

Answer 14

• Commonly mutated, alters downstream functions of:
  
  • PI3K → leads to ↑ cell proliferation
    
    • pTEN (downstream from PI3K) commonly mutated → damages DNA → immunity to apoptosis
  • Raf → ↑pro-inflammation
  • Ral-GEF → ↑cell migration (↑filopodia lamellipodia)

Question 15

Overview of things driving the cancerous cell cycle (proliferation)

Answer 15

Question 16

11 ways of treating cancer

*A^3 Tom Met Carly ToDay. He’s Already In*

Answer 16

1. Alkylating agents
2. Antimetabolites
3. Anti-tumour “antibiotics”
4. Topoisomerase inhibitors
5. Mitotic inhibitors
6. Corticosteroids
7. Targeted momlecular therapies
8. Differentiating agents
9. Hormone therapy
10. Anti CTLA-4
11. Immunotherapy

Question 17

Alkylating agents

Answer 17

• Directly damages DNA and work in all phases of cell cycle leads to cell apoptosis
• Cytoxan

Question 18

Antimetabolites

Answer 18

• Interfere with DNA and RNA growth by substituting building blocks (Damage synthesis)
• Treat leukemia, breast, ovary, intestinal
• 6-mercaptopurine, Methotrexate, 5-flurouracil

Question 19

Anti-tumour antibiotics

Answer 19

• Anthracyclines
  
  • Anti-proliferation by interfering with enzymes involved in DNA replication
  • Adriamycin, Daunorubicin
  • S.E: can permanently damage the heart if give in high dose

Question 20

Topoisomerase inhibitors

Answer 20

• • Inhibit topoisomerase (which is used to separate DNA in synthesis)
• Topoisomerase I inhibitors: CPT-11
• Topoisomerase II inhibitors: VP-16

Question 21

Mitotic inibitors

Answer 21

• Stopping mitosis by affecting spindle formation.
• Taxol, Oncovin
• S.E: May affect cells in all phases, may cause nerve damage

Question 22

Corticosteroids

Answer 22

• Used as adjuncts
• Also used to prevent nausea & vomiting caused by chemotherapy
• Prednisone, Dexamethasone

Question 23

Targeted molecular therapies

Answer 23

• Target specific tyrosine kinase R. and their mutations
• Gleevac, Iressa

Question 24

Differentiating agents

Answer 24

• Acts on cancer cells to make them mature into normal cells
• Retinoids, ATRA

Question 25

Hormone therapy

Answer 25

• Many cancers (e.g. breast & cancer) driven by hormones
• Anti-oestrogens: Faslodex, Arimidex
• Anti-androgens: Casodex, Eulexin
• GnRH agonists: Lupron

Question 26

Anti CTLA-4

Answer 26

• CTLA-4 → strong inhibitory signals to immune cells
• Inhibition stops immune suppression

Question 27

Immunotherapy

Answer 27

• Active: own immune system to fight
• Passive: AB created outside body and given to fight
• Rituxan, Campath