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CPAT > Cancer 2 > Flashcards

Cancer 2 Flashcards

1
Q

What are the four stages of developing a cancer drug?

A

Drug discovery
Drug development
Clinical trials
Drug marketing

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2
Q

Why does a drug usually not work?

A

Disease isn’t well understood

Pick the wrong target

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3
Q

List four reasons for genetic damage

A

Inherited mutations
Somatic/acquired mutations
Environmental
Spontaneous

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4
Q

What is vogelstein’s cascade?

A

Molecular model of the proposed evolution of a colorectal cancer through benign adenoma-carcinoma sequence

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5
Q

T/F:

To get a late benign adenoma (sessile polyp) in Vogelstein’s cascade, there is a mutation in p53

A

False
There is a mutation in DCC and ras gene

(mutation in p53 gives a colonic carcinoma)

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6
Q

T/F:

Cancer is heterogenous

A

True

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7
Q

What is a glioma?

A

Tumour derived from a glial cell

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8
Q

What happens when oncogenes are activated?

A

Self-sufficiency in growth signals

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9
Q

What happens when you activate bcl-2 and inactivate p53?

A

Evasion of apoptosis

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10
Q

What happens when you over express proteases?

A

Have the ability to invade tissues/metastasise

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11
Q

What is the first hallmark of cancer?

A

Sustaining proliferative signaling

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12
Q

What is a proto-oncogene?

A

Normal cellular genes whose products promote cell proliferation

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13
Q

What is an oncogene?

A

Mutated/overexpressed proto-oncogene promoting autonomous cell growth

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14
Q

T/F:

Too much growth factors is enough to cause a neoplasmic transformation

A

False

But does increase the risk of mutation in proliferating cells

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15
Q

What happens when a cell over-expresses a growth factor?

A

Secretes too much of it
Feeds back onto itself= autocrine

(not a major problem)

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16
Q

What is the EGFR family and what type of abnormal activity is it associated with? What type of cancer is associated with it?

A

Growth factor receptor
Mutated/amplified
Often associated with glioblastoma, lung cancer and breast cancer

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17
Q

What is Ras?

A

Signal transducing g protein

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18
Q

How is ras activated?

A

Receptor tyrosine kinase is activated by a growth factor
This leads to the exchange of GDP for GTP
Ras is activated

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19
Q

How do GTPase activating proteins (GAPs) affect Ras?

A

Binds to Ras, augments its GTPase activity, terminates signal transduction, prevents uncontrolled Ras activity

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20
Q

What two things does Ras activate?

A

Braf and PI3K/AKT arms of the RTK pathways

activates kinases

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21
Q

T/F:

15-20% of cancers express a mutated Ras protein

A

True

Really common mutation in cancers

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22
Q

Mutations in Ras often introduce amino acid substitutions at positions 12, 13 and 61. What do these mutations normally target??

A

They make Ras resistant to GTPase activating proteins (GAPs)

Ras accumulates in the active GTP- bound conformation (constantly active)

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23
Q

T/F:

Mutations in BRAF often affect the catalytic domain and result in increased catalytic activity

A

False
This is true for mutations in PI3K

BRAF= glutamic acid is substitued for valine at amino acid 600, mimics phosphrylation of the activation loop and induces constitutive BRAF protein kinase activity

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24
Q

What is the role of transcription factors?

A

Bind specifically to DNA regulatory elements to stimulate or repress transcription within the nucleus

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25
Q

T/F:

MYC transcription factor when mutated in commonly involved in tumour growth

A

True

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26
Q

What happens when MYC is overexpressed?

A

activate the expression of many genes that are involved in cell growth

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27
Q

Explain what the ABLE-BCR chimera is and how it is formed

A

ABL gene is translocated from its normal place at chromosome 9 to chromosome 22
It forms a hybrid with BCR (Breakpoint cluster region) Gene
ABL-BCR complex encodes for a ABL-BCR kinase that is very active
Also known as philadelphia chromosome
Occurs in Chronic Myeloid Leykemia and Acute Lymphoblastic Leukemia

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28
Q

How do they often block chronic myeloid leukemia (CML) cells?

A

They require ABL-BCR tyrosine kinase to survive
Inhibit this and you can stop the CML cells
Resistance is common

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29
Q

What are janus kinases?

A

Located on the cytoplasmic surface of the cell membrane, no cell receptor element

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30
Q

What is JAK2?

A

Tyrosine kinase that engages with cytokine receptors, becomes active, results in proliferation

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31
Q

What type of neoplasm are JAK2 mutations often associated with?

A

Myelo-proliferative neoplasms (MPNs)

Mutations result in cytokine independent proliferation and survival of tumour cells

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32
Q

What regulates the cell cycle?

A

Cyclins and cyclin-dependent kinases (CDKs)

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33
Q

What stage of the cell cycle are most cells arrested in and what is the next stage?

A

Mostly arrested in the G1 phase
Progress to the S phase
Once they get to the S phase they must complete the cycle (therefore proliferate)

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34
Q

What is the second hallmark of cancer?

A

Evading tumour suppression

35
Q

What genes are mutated that lead to the second hallmark of cancer?

A

Tumour suppressor genes

36
Q

What happens if you introduce an oncogene into a cell that lacks a tumour suppressor gene?

A

Uncontrolled proliferation (tumour suppressor genes stop proliferation)

37
Q

List three ways tumour suppressor genes/proteins work

A

Block uncontrolled proliferation
Active growth-inhibitory pathways leading to apoptosis
Induce cell differentiation causing cells to enter a pot-mitotic stage without replicative potential

38
Q

T/F:

Usually one inactive allele is required to cause a mutation in a tumour suppressor gene

A

False
Usually need both alleles
First is inherited and the second is a somatic mutation in susceptible tissue

39
Q

What occurs at the G2/M stage of the cell cycle?

A

Determine the integrity of the DNA and decide whether or not to proliferate or die

40
Q

T/F:

Hyperphosphorylated Rb inhibits transcription of S genes

A

False

Hypophosphorylated Rb does this

41
Q

What do growth inhibitors stimulate?

A

CDK inhibitors e.g. p16

42
Q

What do CDK inhibitors do?

A

Inactivate cyclins

43
Q

What do inactive cyclins do to Rb?

A

Keep it hypophosphorylated

Rb reamins in the EF2 complex and S genes can’t be transcribed

44
Q

In cancer, often ___ is deleted which encodes ____. This results in CDK kinase being ______ and Rb is ________.

A

In cancer, often CDN2A is deleted which encodes p16. This results in CDK kinase being activated and Rb is hyperphosphorylated (inactive)

E2F is then released
Cells move into S phase

45
Q

What two key tumour suppressor genes does Human Papilloma Virus inactivate?

A

Rb (viral E7 inactivates it)

p53 (viral E6 inactivates it)

46
Q

What two things does CDKN2A encode?

A

p16 (cyclin inhibitor) and p14 (activates p53)

47
Q

What happens when CDKN2A gene is mutated?

A

Silences p16 and p14
Cyclins can become active and hyperphosphorylate Rb, S phase begins
no p53= no apoptosis

48
Q

What is neurofibromin-1? (NF-1)

A

GTPase-activating protein (GAP)

Increases the GTPas rate of G proteins

49
Q

T/F:

NF-1 activates Ras

A

False

Inactivates ras, negative regulator

50
Q

If you increase the GTPase activity of Ras, Ras ______ quicker

A

Inactivates

51
Q

What is the role of neurofibromic-2 (NF2)?

A

Codes for neurofibromin-2/merlin

This is a cytoskeletal protein that links actin filaments to the membrane in nervous tissue

52
Q

What happens to cells when you don’t have merlin?

A

Can’t make cell to cell junctions, insensitive to normal growth arrest signals

53
Q

What is APC and what does it down regulate?

A

Tumour suppressor

Down regulates growth promoting Beta catenin

54
Q

What type of cancer is associated with mutations in APC

A

Colon cancer

55
Q

What does beta catenin do??

A

Normally is destructed by APC and is involved in cell-cell adhesion (with E cadherin)

When it is mutated, it cant be destructed by APC and cell-cell contact inhibition is stopped

56
Q

What does Wnt signalling do in terms of APC and Beta catenin??

A

Wnt releases beta catenin from APC complex

Beta can then go to the nucleus and active transcription of the cell-cycle progression genes

57
Q

What does APC stand for?

A

Adenomatous polyposis coli

58
Q

What happens when E-cadherin is lost?

A

Cells aren’t attached to each other and can invade other tissues

59
Q

What is the 3rd hallmark of cancer?

A

Genomic instability

60
Q

What is the physiological function of BRCA1 and BRCA2?

A

DNA repair via homologous recombination or they destroy cells if the DNA damage can’t be repaired

61
Q

T/F:

In healthy cells, p53 is detectable

A

False

normally inhibited by MDM2

62
Q

What two mechanisms stop inhibition of p53 by MDM2?

A
  1. DNA damage/hypoxia activates ATM/ATR, ATM/ATR phosphorylate p53 and MDM2, p53 is activated
  2. Oncogenic stress leads to MAPK and PI3K/AKT signalling, this increases expression of p14/ARF, p14/ARF can bind to MDM2 and displace p53
63
Q

Explain transient p53-induced cell cycle arrest

A

p53 dependent transcription of CDK1A gene= this encodes p21
p21 inhibits cyclin D-CDK4
Rb is maintained in active hypophosphorylated state
Progression from G1 phase to S phase is stopped and cell can repair the dna damage and return to normal

64
Q

Explain p53-induced sensescence

A

Senscent cells are metabolically active but not proliferating therefore the tumor can’t grow

65
Q

What is the 4th hallmark of cancer?

A

Evasion of apoptosis

66
Q

T/F:

BAX and BAK are pro-survival

A

False

They are pro-apoptotic

67
Q

T/F:

BCL-2, BCL-X and MCL-1 are pro survival

A

True

68
Q

What is the role of BH3-only proteins?

A

These inhibit the pro-survival proteins and therefore active the pro-apoptotic proteins

69
Q

What do BAX and BAK do?

A

They disrupt the mitochondrial membrane

Both cytochrome C and SMAC are released from the mitochondria

70
Q

What is XIAP?

A

Caspase inhibitor

71
Q

What does BCL-2 protein do?

A

Prevents apoptosis and programmed cell death

72
Q

What is the 5th hallmark of cancer?

A

Replicative immortality

evasion of sensecence

73
Q

What happens when telomeres reach a certain point?

A

Chromosomes undergo end-to-end fusion and cell death occurs by apoptosis

74
Q

What is the role of telomerase?

A

Repairs telomeres by adding nucleotide repeats to the ends of chromosomal DNAs to compensate for these losses
Cellular immortalizing enzyme

75
Q

What are the 5 ways cancer genes can be activated?

A

Point mutations
Chromosomal translocation
Activation by gene amplification
Epigenetic changes miRNA

76
Q

T/F:

Chemotherapeutic agents are non-specific

A

True

77
Q

What do chemotherapeutic agents target?

A

They damage dna

78
Q

T/F:

There are more side effects when using molecularly targeted therapy in comparison to chemotherapy

A

False

Chemo has more side effects because it is less specific

79
Q

What is target validation?

A

Understanding of the target’s function in disease

80
Q

What is druggability?

A

Describes a biological target that is known to bind with high affinity to a drug

81
Q

T/F:

Enzymes are non-druggable

A

False

Druggable

82
Q

Distinguish between a kinase and a phosphotase

A 
Kinase= catalyzes the transfer of a phosphate group
Phosphotase= catalyzes the removal of a phosphate group
83
Q

What does Vemurabenib inhibit?

A

BRAF

CPAT (9 decks)

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