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Flashcards in 20. hormone therpay for cancer Deck (75):
1

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

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

2

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

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

3

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

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

4

after hormone therapy, what may occur?

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

5

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

the epithelial cells population
>ER/AR

6

what receptors do breast epithelial cells express?

ER and AR

7

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

AR
>amplified - exploiting androgen signalling for growth

8

what do not all breast cancer express?

ER - they are more heterogeneous than prostate

9

what is seen in over 50% of breast cancers?

ER amplification

10

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

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

11

how is ER status determined?

biopsy

12

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

70%
5-10% - might not detect ER in this case/there is a second ER that is not screened for

13

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

oestrogen withdrawal or anti-oestrogen therapies
>chemotherapy and radiotherapy

14

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

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

15

how is ovarian/testicular ablation do?

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

16

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

LHRH
>released in pulses

17

what does the pituitary gland release?

LH

18

what happens between pulses of LHRH normally?

receptors on the pituitary gland are degraded and remade

19

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

>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)

20

why do some people still require castration?

due to this two week time lag

21

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

90%
40%
often combined with other therapies

22

how do 5α-reductase inhibitor work?

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

23

what is Guevedoces?

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

24

how do aromatase inhibitors work?

>catalyses the conversion of testosterone to oestradoil
>reaction occurs in fat cells and accounts for 30% of oestrogen in circulation

25

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

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

26

what do hormone antagonists do?

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

27

what affect can hormone antagonists also have?

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

28

name an ER antagonist

tamoxifen

29

what affect does tamoxifen have?

inhibits the growth of the oestrogen receptor positive breast cancer cells

30

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

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

31

give 5 ways that antiandrogens inhibit AR activity

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

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

tamoxifen binds ER and recruits co-repressors
>due to helix 12 taking up different position

33

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

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

what are some of the tissues that oestrogen target?

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

35

what are some of the tissues that androgens target?

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

36

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

antioestrogens and antiandrogens will have off target effects

37

give 5 side affect of antiandrogens

osteoporosis
loss of muscle
impotence
loss of libido
hot flushes

38

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

selective oestrogen receptor modulators
>tamoxifen

39

what activity does tamoxifen have in tissues?

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

40

how is tamoxifen a SERM?

it opposes AF2 activity but promotes AF1 activity

41

how is the breast ER mainly activated?

via AF2 activity mainly

42

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

via AF1 activity more significantly

43

what do pure antagonists inhibit about ER receptors?

both AF1 and AF2 activity

44

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

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

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

chemotherapy, effective in 50% of patients
>by this stage men are very ill and so side affects of chemo may be debilitating

46

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

while men are still more healthy

47

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

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

what % of prostate cancer are effectively treated with antiandrogens ?

80%

49

what % of breast cancer are effectively treated with tamoxifen?

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

50

why does hormone independence coma about?

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

51

what is expressed in most prostate tumours and metastatic tumours?

AR

52

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

bcl2

53

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

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

54

what does P of ER affect?

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

55

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

receptors can respond to low levels of hormones more efficiently

56

what may mutations in ER receptor lead to?

increased sensitivity to conjugate hormones or inappropriate activation by alternative hormones

57

how often is AR mutated? and what causes this?

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

58

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

over expression of SRC1 - increasing oestrogenic effect of tamoxifen

59

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

co-activators

60

what can decrease the oestrogenic effect of tamoxifen ?

co-repressors
>these are reduced in some breast cancers

61

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

hey1

62

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

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

63

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

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

64

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

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

what AF has a strong function in AR?

AF1

66

what is the AR variant?

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

how does the AR variant come about?

gene rearrangement/splicing

68

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

inhibit oestrogen synthesis from adrenal androgens

69

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

peptide inhibitors of receptor-co-activator interaction

70

what is Herceptin ?

monoclonal antibody that interferes with HER2/neu receptor

71

what is Iressa?

EGFR inhibitor

72

what do Herceptin and Iressa do?

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

73

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

targeting AF1

74

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

>this targets drugs resistant prostate cancer
>counter acts affects of malfunctions in AR which cause hormone therapy resistance

75

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

>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