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PED3006 Carcinogenesis > Genetic Alterations & Targeted Therapies > Flashcards

Genetic Alterations & Targeted Therapies Flashcards

1
Q

What is the intrinsic mechanism for p53 mediated apoptosis

A

BAX, NOXA and PUMA
= activation of cytochrome C

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2
Q

What is the extrinsic pathway of p53 mediated apoptosis

A

DR5/TRAILR2 and FAS
= activates caspases

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3
Q

What are the different manifestations of apoptosis

A

Nuclear fragmentation
Cell surface markers
Caspase catalytic activity
Cleavage of target proteins

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4
Q

What is one of the earliest indications of apoptosis

A

Translocation of the membrane phosphatidylserine from the inner to the outer plasma membrane

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5
Q

How can flow cytometry be used to investigate apoptosis

A

See the relative proportion int the different cell phases and the amount undergoing apoptosis

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6
Q

What stain binds to the phosphotidyl residues

A

Annexin 5

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7
Q

What is BAX

A

BCL2 associated protein
Ratio of BAX:BCL2 determines survival or death
Leads to cytochrome C release

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8
Q

What is PUMA

A

A BCL2 binding component 3

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9
Q

What is PIG3

A

Implicated in regeneration of ROS

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10
Q

What is TRAILR2

A

Cell surface transmembrane protein that mediates apoptosis

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11
Q

What is cytochrome C

A

Small heme protein component
Initiates apoptosis by activating caspases

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12
Q

What are the clinical consequences of p53 inactivation

A

Loss of cell cycle arrest in response to DNA damage
Prevention of p53-dependent apoptosis

= acceleration of tumour progression + cells resistant to treatment

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13
Q

What is autophagy

A

Another way of cell death
Cell degrades its own enzymes

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14
Q

Describe senescence

A

Cell remains alive but does not undergo division

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15
Q

Describe the steps of the Vogelstein Model for colorectal cancer

A
  1. Mutation or loss of FAP in 5q = hyperprolif. epthelium
  2. DNA hypomethylation = early adenoma
  3. Mutation in K-RAS in 12p = intermediate adenoma
  4. Loss of DCC? In 18q = late adenoma
  5. Loss of p53 in 17p = carcinoma
  6. Other alteration = metastasis
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16
Q

What does the Vogelstein Model depict

A

A series of mutation that occur n the progression from normal cells to colorectal cancer
And how the mutation are associated with histological features

17
Q

What is Cetuximab

A

EGFR targeted antibody used in advanced colorectal cancer

18
Q

In what tumours would cetuximab be ineffective

A

In RAS mutant tumours

19
Q

How can prognostic and predictive bio markers be used to treat cancers

A

Allow stratified treatment
Better tailoring of therapies to the individual
Disease monitoring during treatment

20
Q

What bio markers can be used in treatments

A

MYCN in neuroblastoma
HER2 in breast cancer

21
Q

How can tumour informed liquid biopsies (TILBs) be useful

A

DNA sequences analysis of a patients tumour tissue sample using genome-wide sequencing
= minimally invasive monitoring of disease

22
Q

Name a few novel therapeutic targets

A

Antibody targeting
Gene therapy
Small molecule inhibitors of oncogenes and associated growth signal transduction

23
Q

What are the properties of an ideal target

A

Casual link with the transformed phenotype
Tumour specificity
Bio markers available for monitoring
Functional assays can be designed

24
Q

Describe the Philadelphia (Ph) translocation in CML and ALL

A

Juxtaposition of BCR and ABL gene sequence
= chimeric fusion protein Bcr-Abl

25
Q

What is Bcr-Abl

A

Constitutively activated tyrosine kinase
Oncogenic activity

26
Q

What is Imatinib (GLEEVEC)

A

A small molecule ATP-competitive inhibitor of the Bcr-Abl tyrosine kinase

27
Q

What is the mechanism of action of Imatinib

A

Suppresses the growth of leukaemia cells and leaves normal cells unaffected
Dephosphorylation of Bcr-Abl protein isn seen followed by apoptosis

28
Q

What is Crizontinib

A

Oral small molecule inhibitor of ALK
Treatment of non-small cell lung cancers

29
Q

Describe Vemurafenib

A

Oral multi-kinase inhibitor
Found active against mutant BRAF

30
Q

Describe the BRAF mutant

A

Serine/threonine kinase
V600E mutation = keeps protein in active state

31
Q

Describe Palbociclib and Ribociclib

A

CDK4/6 inhibitors
Licensed in ER+ HER- advanced breast cancer
(+ aromatase)
Approx doubling of progression-free survival

32
Q

What are Roche, Novartis and Amgen all examples off

A

MDM2 inhibitors in current clinical trials

33
Q

How does the MDM2 inhibitor Nutlin work

A

Binds to p53 pocket in MDM2
Inhibits p53/MDM2 interaction
= induction of p53-dependent cell cycle arrests or apoptosis

PED3006 Carcinogenesis (9 decks)

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