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20. hormone therpay for cancer Flashcards

1
Q

what was John hunter the first person to suggest in 1786?

A

that the testes produced something that regulated the size of the prostate - when this was removed testes were small
>linked the size of the prostate with the function of the gonads

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2
Q

what does castration lead to in terms of hormones? how was this done and how is this done now?

A

removal of 95% of androgens - this process is still done now if a quick solution is needed but now we do it chemically

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3
Q

what are breast and prostate cancer initially? and what does this mean can be used?

A

hormone dependent for growth

>hormone antagonists can be used to effectively treat these cancers e.g. tamoxifen

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4
Q

after hormone therapy, what may occur?

A

may recur in an aggressive form that is now hormone resistant and does not response to antagonist therapy

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5
Q

where do >90% of breast and prostate cancer arise? and what do these express?

A

the epithelial cells population

>ER/AR

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6
Q

what receptors do breast epithelial cells express?

A

ER and AR

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7
Q

what do almost all primary metastatic prostate tumours retain? and how is this seen in 50% of cases?

A

AR

>amplified - exploiting androgen signalling for growth

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8
Q

what do not all breast cancer express?

A

ER - they are more heterogeneous than prostate

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9
Q

what is seen in over 50% of breast cancers?

A

ER amplification

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10
Q

what is used as a prognostic and predictive indicator in breast cancer?

A

ER status

>generally ER+ tumours are well-differentiated and prognosis is better, they are more treatable

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11
Q

how is ER status determined?

A

biopsy

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12
Q

what % of ER+ and ER- breast cancers show positive response to oestrogen withdrawal?

A

70%

5-10% - might not detect ER in this case/there is a second ER that is not screened for

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13
Q

what are ER- tumours unlikely to respond to? what therapies can be used in these cases?

A

oestrogen withdrawal or anti-oestrogen therapies

>chemotherapy and radiotherapy

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14
Q

what hormone therapies can be done for breast and prostate cancer? (4)

A
  1. ovarian/testicular ablation
  2. enzyme inhibition to prevent secondary/peripheral steroid conversion
  3. steroid receptors antagonists (antioestrogen/antiandrogens)
  4. inhibition of adrenal androgen synthesis
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15
Q

how is ovarian/testicular ablation do?

A

either through surgery or GnRH agonist (pituitary down regulation) - blocks production of oestrogen/androgens

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16
Q

what does the hypothalamus release? and how it is released?

A

LHRH

>released in pulses

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17
Q

what does the pituitary gland release?

A

LH

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18
Q

what happens between pulses of LHRH normally?

A

receptors on the pituitary gland are degraded and remade

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19
Q

how does pituitary down-regulation (chemical castration) work?

A

> patient given LHRH analogue
this acts on pituitary gland
initial rise in LH, testosterone and oestrogen
LHRH signal remains constant and so receptors are degraded
after 2 weeks no LH or testosterone (similar levels to castration)

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20
Q

why do some people still require castration?

A

due to this two week time lag

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21
Q

what % of androgens are released from testes, how much DHT is left in tissue and what implication does this have?

A

90%
40%
often combined with other therapies

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22
Q

how do 5α-reductase inhibitor work?

A

inhibits the conversion of testosterone to 5α-dihydroxytestosterone.
this binds androgen receptors with 10 times higher affinity
>inhibiting enzyme can block tumour growth

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23
Q

what is Guevedoces?

A

2% of births in a tribe in the Dominican republic are born female with internalised genitalia but develop into man due to surge in testosterone at puberty
>due to alpha reductase deficiency
>have small semi-functional prostate

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24
Q

how do aromatase inhibitors work?

A

> catalyses the conversion of testosterone to oestradoil

>reaction occurs in fat cells and accounts for 30% of oestrogen in circulation

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25
Q

what percentage of breast carcinoma cells contain increased levels of aromatase?

A

60-70% – they make their own oestrogen to feed their growth

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26
Q

what do hormone antagonists do?

A

antioestrogens/antiandrogens bind to receptors and inhibit steroid receptors meditated action (cell division and growth)

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27
Q

what affect can hormone antagonists also have?

A

some have agonist effect i.e. can activate the receptor, under some circumstances

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28
Q

name an ER antagonist

A

tamoxifen

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29
Q

what affect does tamoxifen have?

A

inhibits the growth of the oestrogen receptor positive breast cancer cells

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30
Q

some antagonists are based on steroidal structure, what are other like?

A

they can be more bulky and so do not allow the receptor to form an active conformation

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31
Q

give 5 ways that antiandrogens inhibit AR activity

A
  1. compete with ligand for binding
  2. sequester AR in cytoplasm
  3. prevent dimerization
  4. prevent DNA binding
  5. prevent formation of active transcription complex
32
Q

give an example of how antioestrogens inhibit ER activity by preventing formation of active transcription complex

A

tamoxifen binds ER and recruits co-repressors

>due to helix 12 taking up different position

33
Q

what was normally used in combination with chemical castration and why is it no longer used? but what can this still be used for?

A

inhibiting androgen synthesis early in pathway with Abiraterone to prevent synthesis of androgens and oestrogens completely, knock on affect on other steroids
>lead to hypertension which can be lethal but also can be controlled with medication
>to improve the survival of metastatic prostate cancer

34
Q

what are some of the tissues that oestrogen target?

A

breast, uterine epithelium, brain, CV, bone, Internal/external genitalia

35
Q

what are some of the tissues that androgens target?

A

prostate, hair follicles, brain, bone, Internal/external genitalia

36
Q

what implications do the fact oestrogen and androgens affect other tissues have?

A

antioestrogens and antiandrogens will have off target effects

37
Q

give 5 side affect of antiandrogens

A 
osteoporosis 
loss of muscle 
impotence 
loss of libido 
hot flushes
38
Q

what does SERM stand for? and give an example of one

A

selective oestrogen receptor modulators

>tamoxifen

39
Q

what activity does tamoxifen have in tissues?

A

> oestrogenic activity in bone, cardiovascular system and uterus
antioestrogenic activity in breast

40
Q

how is tamoxifen a SERM?

A

it opposes AF2 activity but promotes AF1 activity

41
Q

how is the breast ER mainly activated?

A

via AF2 activity mainly

42
Q

how is the other tissue such as bone and uterus ER mainly activated?

A

via AF1 activity more significantly

43
Q

what do pure antagonists inhibit about ER receptors?

A

both AF1 and AF2 activity

44
Q

initially LHRH agonist and antiandrogens are used, what may occur after this?

A

after 13 months relapse may occur
>tumour progresses despite therapy
>this is castrate resistant prostate cancer
>can no longer be controlled by removal of androgens

45
Q

what is the next call of action in castrate resistant prostate cancer? and how affective is this? but what is the problem with this?

A

chemotherapy, effective in 50% of patients

>by this stage men are very ill and so side affects of chemo may be debilitating

46
Q

why do clinicians argue chemotherapy should be used earlier on in prostate treatment?

A

while men are still more healthy

47
Q

what are 5 proposed mechanisms that a tumour may become hormone independent?

A
  1. ligand independent activation
  2. receptor over expression
  3. over expression of co-activators
  4. reduced levels/deletion of co-repressors
  5. receptor mutation
48
Q

what % of prostate cancer are effectively treated with antiandrogens ?

A

80%

49
Q

what % of breast cancer are effectively treated with tamoxifen?

A

50% of ER positive and 10% of ER negative breast cancers

50
Q

why does hormone independence coma about?

A

clonal selection of cells with a growth advantage under the hormonal conditions present in the tumour

51
Q

what is expressed in most prostate tumours and metastatic tumours?

A

AR

52
Q

increase of what expression is also seen in hormone independent cancers?

A

bcl2

53
Q

how might ER be modified to allow ER to function in a ligand independent manner?

A

phosphorylation of ER - this can be through a number of different pathways e.g. EGF

54
Q

what does P of ER affect?

A

transactivation, dimerization and ER sensitivity - might make it very sensitive to low oestrogen concentrations, may also lead to constitutive activation

55
Q

what does over expression of ER and co-activators mean?

A

receptors can respond to low levels of hormones more efficiently

56
Q

what may mutations in ER receptor lead to?

A

increased sensitivity to conjugate hormones or inappropriate activation by alternative hormones

57
Q

how often is AR mutated? and what causes this?

A

rarely in benign prostate
>up to 50% of advanced prostate cancers , AR becomes super active
this is selected for by therapy

58
Q

what results in increased ER activation by tamoxifen of cells in culture?

A

over expression of SRC1 - increasing oestrogenic effect of tamoxifen

59
Q

what is co-expressed with androgen receptors in the prostate?

A

co-activators

60
Q

what can decrease the oestrogenic effect of tamoxifen ?

A

co-repressors

>these are reduced in some breast cancers

61
Q

name a co-repressor of prostate cancer that is sometimes restricted to the cytoplasm

A

hey1

62
Q

what might explain hormone resistance seen in initially hormone dependent tumours?

A

variation in levels of cofactors - corepressors may be required for the repressive function of antioestrogens/antiandrogens

63
Q

mutations are seen throughout the length of AR, what can these mutation lead to?

A

increase sensitivity of AR and they can also alter ligand specificity.
>certain mutation super activated by other steroid hormones and even steroidal antagonists

64
Q

what sort of mutations might occur in AR in order to change its ligand binding specificity?

A

histidine to tyrosine mutation make ligand binding pocket larger, this means other steroid hormones can fit in and induce correct folding of helix 12

65
Q

what AF has a strong function in AR?

A

AF1

66
Q

what is the AR variant?

A

this is an AR made up of AF1 and DBD, it lacks the ligand biding domain
>can drive gene expression and growth in absence of ligand as they are constitutively active
>this is found in and associated with castrate resistant prostate cancer

67
Q

how does the AR variant come about?

A

gene rearrangement/splicing

68
Q

new aromatases are being developed for breast cancer, what will these do?

A

inhibit oestrogen synthesis from adrenal androgens

69
Q

new targets for therapy for resistant tumours are being identified from research into steroid receptor cofactors, give an example

A

peptide inhibitors of receptor-co-activator interaction

70
Q

what is Herceptin ?

A

monoclonal antibody that interferes with HER2/neu receptor

71
Q

what is Iressa?

A

EGFR inhibitor

72
Q

what do Herceptin and Iressa do?

A

inhibit growth factors pathways which may active ER in a ligand-independent manner by phosphorylation

73
Q

what is being looked at form a target in castration resistant prostate cancer?

A

targeting AF1

74
Q

trails are in process using heat shock proteins inhibitors, what are these doing?

A

> this targets drugs resistant prostate cancer

>counter acts affects of malfunctions in AR which cause hormone therapy resistance

75
Q

what does hormone replacement therapy do in prostate cancer? and why it this not used anymore? what is being used instead?

A

> oestrogen can inhibit prostate cancer growth and reduce testosterone in men
oestrogen tablets cause blood clots
HRT patches - these don’t have the side affects but reduce tumour growth

cancer (24 decks)

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