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PHRM 864 > L3-4: Cancer Endocrine > Flashcards

L3-4: Cancer Endocrine Flashcards

1
Q

3 common hormone related cancers

A

prostate, endometrial, and breast

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2
Q

17-α Hydroxylase (CYP17A1) role and location

A
  • converts pregnenolone into 17α-hydroxypregnenolone
  • converts progesterone into. 17α-hydroxyprogesterone

located primarily in adrenal glands and gonads

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3
Q

17,20 lyase role and location

A
  • cleaves the 17-hydroxy intermediates made from 17α-hydroxylase into DHEA and androstenedione (both precursors to androgens and estrogens)
    located in adrenal glands and gonads
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4
Q

what is CYP19?

A

aromatase

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5
Q

5α-reductase role in steroid hormone synthesis

A

convert testosterone to DHT (most active testosterone molecule)

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6
Q

many cancers that belong to what lineage are responsive to glucocorticoids

A

lymphoid lineage

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7
Q

corticosteroid tx can be used as palliative care in cancer to do what 3 things?

A
  • reduce inflammation
  • edema
  • manage pain during chemo
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8
Q

corticosteroid tx can also be used to reduce hypersensitivity reactions. what are these?

A

Nausea
vomiting
immune-related adverse effects

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9
Q

hormonal cancer therapies primarily target which two things?

A
  • estradiol (breast, endometrial
  • dihydrotestosterone(DHT) (prostate)
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10
Q

primary hormone for prostate cancer

A

DHT

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11
Q

primary hormone for breast and endometrial cancer

A

estradiol

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12
Q

what are the 2 major strategies to endocrine therapies? (from slide 8)

A
  • stop steroid receptor function
  • decrease production of steroids
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13
Q

T or F:
Endocrine therapies attempt to increase the production of steroids to regulate cell growth

A

false, decreases production because these hormones often fuel the growth of cancers

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14
Q

T or F :
Estrogen receptors (ER) and progesterone receptors (PR) are both measurable in tumors

A

true

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15
Q

Well differentiated tumors are more likely to be ____

A

ER+

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16
Q

poorly differentiated tumors are generally ___

A

ER-

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17
Q

T or F:
poorly differentiated tumors have lower growth fractions and are generally more sensitive to cytotoxic agents

A

false, higher growth fractions

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18
Q

T or F:
PR is estrogen inducible and is a measure of biological response to estrogen

A

True, don’t know what this means so I didn’t alter it to make it false, just read it twice

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19
Q

T or F:
Hormone therapy in breast cancer is generally limited to ER-/PR- tumors

A

False, ER+/PR+

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20
Q

what is the difference between ER+ and ER-

A

ER+ = cancer cells have estrogen on their surface
ER- = cancer cells do not have estrogen on their surface

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21
Q

T or F:
Most breast cancers are ER-

A

false, most are ER+

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22
Q

T or F:
Hormone therapy is generally limited to ER- cancers

A

false, use them in ER+

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23
Q

Which hormone is produced in the pituitary gland?

A. GnRH
B. LH
C. estrogen
D. progesterone

A

B. LH

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24
Q

Estrogen receptor primarily binds estrogen where in the cell?

A. On the plasma membrane
B. In the mitochondria
C. In the cytoplasm
D. In the nucleus

A

C. Cytoplasm

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25
Q

What enzyme converts androstenedione to estrone?

A. CYP19
B. 5alpha-reductase
C. 17, 20 lyase
D. P450scc

A

A. CYP19 (aromatase)

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26
Q

T or F:
More differentiation leads to more cancer subtypes

A

True

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27
Q

Which of the following is a tumor suppressor?
A. HER2
B. BRCA1
C. Luminal progenitor

A

B. BRCA1

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27
Q

Which of the following is a tyrosine kinase receptor (TKR)?
A. HER2
B. BRCA1
C. Luminal progenitor

A

A. HER2

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28
Q

what treatment do you consider for basal-like and claudin-low breast tumor subtypes?

A

Cytotoxic agents, not hormonal

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29
Q

wtf does mesenchymal mean?

A

cells that develop into connective tissue, blood vessels, and lymphatic tissue

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30
Q

what are the 4 molecular subtypes in breast cancer?

A
  • triple negative (ER-, PR-, HER2-)
  • HER2+
  • Luminal B
  • Luminal A
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30
Q

Are luminal A and B more responsive to endocrine or cytotoxic therapies?

A

endocrine, they are typically ER+/PR+

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31
Q

what receptor(s) is/are expressed in Luminal B and Luminal A subtypes?

A

ER+/PR+ combo

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32
Q

what does tamoxifen get metabolized into?

A

4- hydroxytamoxifen (4-OH-TAM)

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33
Q

what enzyme metabolizes tamoxifen into 4OH-TAM?

A

CYP2D6

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34
Q

CYP___ converts tamoxifen to ______-_______ hydroxylated and demethylated metabolites

A

2D6, high-affinity

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35
Q

Binding of tamoxifen to ER will have effects on which 2 things in a tissue-specific manner *

A

translocation and DNA binding

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36
Q

T or F:
Tamoxifen has antagonist and agonist effects on estrogen

A

true

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37
Q

What are the estrogen antagonist effects from tamoxifen? (2)

A
  • blocks estrogen-dependent breast cancer cell proliferation
  • hot flashes due to anti-estrogen effects
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38
Q

what are the estrogen agonist effects from tamoxifen? (2)

A
  • incidence of endometrial cancer increased 3-fold
  • preservation of bone density in post-meno women (less osteoporosis)
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39
Q

what drug class is tamoxifen?

A

Selective estrogen receptor modulator (SERM)

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40
Q

T or F:
Tamoxifen is effective in both pre and post-meno women

A

true

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41
Q

Primary use of tamoxifen is treatment for what kind of breast cancer?

A

resected ER+/PR+

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42
Q

T or F:
tamoxifen can be used in metastatic ER+/PR+ breast cancer

A

true

43
Q

what was the first drug approved for breast cancer prevention in high-risk patients?

A

tamoxifen (easy af)

44
Q

T or F:
Tamoxifen is more effective in patients with a common CYP2D6 variant

A

false, less effective. think about what 2d6 does

45
Q

what does aromatase do?

A

convert androgens into estrogens

46
Q

in what tissue do SERMS act as agonists?

A

bone

47
Q

in what tissue do SERMS work as antagonists?

A

Breast

48
Q

T or F:
SERDS can have antagonist and agonist properties

A

false, strictly antagonist

49
Q

what is UPS and what does it do? (from pic in a lot of the slides)

A
  • ubiquitin-proteasome system
  • degrades the ER after a SERD binds
50
Q

what do SERMS recruit after they bind to the ER when they act as antagonists? what does this do?

A

CoR (corepressors)
inhibit gene transcription -> block estrogen signaling in certain tissues

51
Q

what do SERMS recruit after they bind to the ER when they act as agonists? what does this do?

A

CoA
promote gene transcription in breast and uterus tissue

52
Q

main difference he said to know between tamoxifen and raloxifene

A

raloxifene has NO endometrial hyperplasia

53
Q

Tamoxifen is an (agonist/antagonist) in the brain. What does this cause?

A

antagonist
hot flashes, thermoregulation

54
Q

what drug class is Fulvestrant?

A

Selective estrogen receptor down-modulator (SERD)

55
Q

what drug class is Elacestrant?

A

Selective estrogen receptor down-modulator (SERD)

56
Q

T or F:
Fulvestrant is a pure ER agonist with no antagonist effects

A

False, pure ER antagonist, no agonist effects

57
Q

Acts as a partial agonist at low doses and full SERD at high doses
A. Fulvestrant
B. Elacestrant

A

B. Elacestrant

58
Q

IM dosing
A. Fulvestrant
B. Elacestrant

A

A. Fulvestrant

59
Q

PO dosing:
A. Fulvestrant
B. Elacestrant

A

B. Elacestrant

60
Q

SERDs bind to ER and inhibit what?

A

DNA binding

61
Q

SERDs inhibiting DNA binding leads to what?

A

rapid receptor degradation

62
Q

what is the approved tx for ER+ metastatic breast cancer in post-meno women who have progressed on other antiestrogen therapy

A

SERDs
fulvestrant and elacestrant

63
Q

what is the main thing that aromatase does at a molecular level that he said he wants us to know (slide 29)

A

demethylation is end result

64
Q

aromatase converts:
androstenedione -> _____
testosterone -> _______

A

estrone
estradiol

65
Q

aromatase inhibitors block synthesis of estrogens but not ________ or _______

A

androgens, progesterone

66
Q

T or F:
Adipocytes are a source of estrogen in post-meno women

A

True

67
Q

try your best to explain how adipocytes are a source of estrogen in post-meno women

A

aromatase in adipocytes converts androstenedione to estrone
estrone then gets converted to estradiol

68
Q

what is the primary target for aromatase inhibitors?

A

peripheral tissue (adipose tissue)- not ovaries*

69
Q

primary application of aromatase inhibitors *

A

estradiol suppression in post-meno women *

70
Q

what are the 2 non-steroidal aromatase inhibitors

A

anastrozole and letrozole

71
Q

T or F:
Both letrozole and anastrozole are potent and selective competitive inhibitors of aromatase activity

A

true, read it again to stick

72
Q

primary indication of non-steroidal aromatase inhibitors

A

tx of breast cancer in post-meno women. No. Way.

73
Q

while non-steroidal aromatase inhibitors have minimal toxicity, what is the one concern to look out for?

A

osteoporosis

74
Q

what is the steroidal aromatase inhibitor?

A

exemestane

75
Q

which of the following is referred to as the “suicide inhibitor”?
A. Tamoxifen
B. Letrozole
C. Exemestane
D. Anastrozole

A

C. Exemestane

76
Q

T or F:
Exemestane binds reversibly at the active site and inactivates enzyme

A

False, irreversible

77
Q

primary indication for exemestane

A

tx of ER+ breast cancer in post-meno women who have progressed on antiestrogen therapy. Not used in pre-menopausal women

78
Q

3 things listed under minimal toxicity on Exemestane slide (side effects i guess?

A
  • hot flashes
  • occasional peripheral edema and weight gain
  • increased cholesterol levels *
79
Q

Which compound directly inhibits the activity of the estrogen receptor throughout the body?

A. Letrozole
B. Exemestane
C. Tamoxifen
D. Fulvestrant

A

D. Fulvestrant
“full antagonist”
“directly” is key word for this

80
Q

What is the role of FSH in steroid hormone biosynthesis?

A

directly activates and increases expression of aromatase

81
Q

FSH and LH are controlled by ________ _________?

A

feedback inhibition

82
Q

decreased FSH leads to decreased ________ and ______?

A

aromatase and estrogen

83
Q

GnRH analogs have modified amino acids to increase ______ and reduce ________

A

potency
degradation

84
Q

What is the formulation of the GnRH analogs?

A

depot

85
Q

what are the 3 GnRH analogs we learned

A

leuprolide
goserelin
triptorelin

86
Q

long term side effects of GnRH analogs (2)

A

hot flashes
sexual dysfunction

87
Q

primary indication of GnRH analogs

A

women with PRE-meno breast cancer

88
Q

what are the tx options in breast cancer for pre-meno women

A

GnRH agonists (goserelin and leuprolide)
Tamoxifen

89
Q

what enzyme converts testosterone into DHT in prostate cells?

A

5a-reductase

90
Q

T or F:
Androgen receptor (AR) is a cytoplasmic receptor

A

true

91
Q

binding of AR to DHT leads to what?

A

translocation to the nucleus and action of genes that drive cell growth

92
Q

what PSA level is suggestive of prostate cancer?

A

> 6.5 ng/ml

93
Q

prolonged tx with GnRH analogs leads to a decrease in ______ production

A

LH

94
Q

GnRH primary indication in men

A

palliative tx of advanced prostate cancer

95
Q

Long term side effects for GnRH analogs in men

A

“test-deficient feminization” -> gynecomastia + sexual dysfunction

96
Q

what is meant by “flare” regarding the initial agonist effects of GnRH analogs in men for prostate cancer?

A

temporary surge in testosterone levels that occurs shortly after starting treatment

97
Q

2 GnRH analogs in men indicated for advanced prostate cancer with need for androgen deprivation therapy

A

degarelix
relugolix
(gotta be something we can remember this with because it sounds like licks)

98
Q

T or F:
All GnRH analogs used for prostate cancer in men result in the “flare” of test production

A

False, the -lix ones dont

99
Q

Abiraterone (Zytiga) MOA

A

inhibits function of 17 a-hydroxylase and C17,20 lyase

also a steroid analog

100
Q

common/weird side effect of Abiraterone (zytiga)

A

increased cholesterol

101
Q

what are the 3 Androgen receptor (AR) antagonists?

A

Enzalutamide
Apalutamide
Darolutamide
(all -lutamide)

102
Q

T or F:
The AR antagonists utilize partial antagonism of AR

A

false, they are full

103
Q

T or F:
the “-lutamides” are approved for both metastatic and non-metastatic prostate cancer

A

true

104
Q

the 3 -lutamides that we have in these slides are different than previous -lutamides how

A

higher affinity binding to AR than the old ones

105
Q

-lutamides prevent AR translocation to what

A

the nucleus, meaning it inhibits AR binding to DNA

106
Q

What is unique about the action of the Tamoxifen as compared to Fluvestrant?

A. It leads to ER degradation
B.It holds ER out of the nucleus
C. It ejects ER from the cell
D. It activates ER in bone

A

D

107
Q

Which of the following is only used in the postmenopausal setting?

A. Letrozole
B.Tamoxifen
C. Leuprolide
D.Raloxifene

A

A

PHRM 864 (11 decks)

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