L3-4: Cancer Endocrine Flashcards
3 common hormone related cancers
prostate, endometrial, and breast
17-α Hydroxylase (CYP17A1) role and location
- converts pregnenolone into 17α-hydroxypregnenolone
- converts progesterone into. 17α-hydroxyprogesterone
located primarily in adrenal glands and gonads
17,20 lyase role and location
- 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
what is CYP19?
aromatase
5α-reductase role in steroid hormone synthesis
convert testosterone to DHT (most active testosterone molecule)
many cancers that belong to what lineage are responsive to glucocorticoids
lymphoid lineage
corticosteroid tx can be used as palliative care in cancer to do what 3 things?
- reduce inflammation
- edema
- manage pain during chemo
corticosteroid tx can also be used to reduce hypersensitivity reactions. what are these?
Nausea
vomiting
immune-related adverse effects
hormonal cancer therapies primarily target which two things?
- estradiol (breast, endometrial
- dihydrotestosterone(DHT) (prostate)
primary hormone for prostate cancer
DHT
primary hormone for breast and endometrial cancer
estradiol
what are the 2 major strategies to endocrine therapies? (from slide 8)
- stop steroid receptor function
- decrease production of steroids
T or F:
Endocrine therapies attempt to increase the production of steroids to regulate cell growth
false, decreases production because these hormones often fuel the growth of cancers
T or F :
Estrogen receptors (ER) and progesterone receptors (PR) are both measurable in tumors
true
Well differentiated tumors are more likely to be ____
ER+
poorly differentiated tumors are generally ___
ER-
T or F:
poorly differentiated tumors have lower growth fractions and are generally more sensitive to cytotoxic agents
false, higher growth fractions
T or F:
PR is estrogen inducible and is a measure of biological response to estrogen
True, don’t know what this means so I didn’t alter it to make it false, just read it twice
T or F:
Hormone therapy in breast cancer is generally limited to ER-/PR- tumors
False, ER+/PR+
what is the difference between ER+ and ER-
ER+ = cancer cells have estrogen on their surface
ER- = cancer cells do not have estrogen on their surface
T or F:
Most breast cancers are ER-
false, most are ER+
T or F:
Hormone therapy is generally limited to ER- cancers
false, use them in ER+
Which hormone is produced in the pituitary gland?
A. GnRH
B. LH
C. estrogen
D. progesterone
B. LH
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
C. Cytoplasm
What enzyme converts androstenedione to estrone?
A. CYP19
B. 5alpha-reductase
C. 17, 20 lyase
D. P450scc
A. CYP19 (aromatase)
T or F:
More differentiation leads to more cancer subtypes
True
Which of the following is a tumor suppressor?
A. HER2
B. BRCA1
C. Luminal progenitor
B. BRCA1
Which of the following is a tyrosine kinase receptor (TKR)?
A. HER2
B. BRCA1
C. Luminal progenitor
A. HER2
what treatment do you consider for basal-like and claudin-low breast tumor subtypes?
Cytotoxic agents, not hormonal
wtf does mesenchymal mean?
cells that develop into connective tissue, blood vessels, and lymphatic tissue
what are the 4 molecular subtypes in breast cancer?
- triple negative (ER-, PR-, HER2-)
- HER2+
- Luminal B
- Luminal A
Are luminal A and B more responsive to endocrine or cytotoxic therapies?
endocrine, they are typically ER+/PR+
what receptor(s) is/are expressed in Luminal B and Luminal A subtypes?
ER+/PR+ combo
what does tamoxifen get metabolized into?
4- hydroxytamoxifen (4-OH-TAM)
what enzyme metabolizes tamoxifen into 4OH-TAM?
CYP2D6
CYP___ converts tamoxifen to ______-_______ hydroxylated and demethylated metabolites
2D6, high-affinity
Binding of tamoxifen to ER will have effects on which 2 things in a tissue-specific manner *
translocation and DNA binding
T or F:
Tamoxifen has antagonist and agonist effects on estrogen
true
What are the estrogen antagonist effects from tamoxifen? (2)
- blocks estrogen-dependent breast cancer cell proliferation
- hot flashes due to anti-estrogen effects
what are the estrogen agonist effects from tamoxifen? (2)
- incidence of endometrial cancer increased 3-fold
- preservation of bone density in post-meno women (less osteoporosis)
what drug class is tamoxifen?
Selective estrogen receptor modulator (SERM)
T or F:
Tamoxifen is effective in both pre and post-meno women
true
Primary use of tamoxifen is treatment for what kind of breast cancer?
resected ER+/PR+
T or F:
tamoxifen can be used in metastatic ER+/PR+ breast cancer
true
what was the first drug approved for breast cancer prevention in high-risk patients?
tamoxifen (easy af)
T or F:
Tamoxifen is more effective in patients with a common CYP2D6 variant
false, less effective. think about what 2d6 does
what does aromatase do?
convert androgens into estrogens
in what tissue do SERMS act as agonists?
bone
in what tissue do SERMS work as antagonists?
Breast
T or F:
SERDS can have antagonist and agonist properties
false, strictly antagonist
what is UPS and what does it do? (from pic in a lot of the slides)
- ubiquitin-proteasome system
- degrades the ER after a SERD binds
what do SERMS recruit after they bind to the ER when they act as antagonists? what does this do?
CoR (corepressors)
inhibit gene transcription -> block estrogen signaling in certain tissues
what do SERMS recruit after they bind to the ER when they act as agonists? what does this do?
CoA
promote gene transcription in breast and uterus tissue
main difference he said to know between tamoxifen and raloxifene
raloxifene has NO endometrial hyperplasia
Tamoxifen is an (agonist/antagonist) in the brain. What does this cause?
antagonist
hot flashes, thermoregulation
what drug class is Fulvestrant?
Selective estrogen receptor down-modulator (SERD)
what drug class is Elacestrant?
Selective estrogen receptor down-modulator (SERD)
T or F:
Fulvestrant is a pure ER agonist with no antagonist effects
False, pure ER antagonist, no agonist effects
Acts as a partial agonist at low doses and full SERD at high doses
A. Fulvestrant
B. Elacestrant
B. Elacestrant
IM dosing
A. Fulvestrant
B. Elacestrant
A. Fulvestrant
PO dosing:
A. Fulvestrant
B. Elacestrant
B. Elacestrant
SERDs bind to ER and inhibit what?
DNA binding
SERDs inhibiting DNA binding leads to what?
rapid receptor degradation
what is the approved tx for ER+ metastatic breast cancer in post-meno women who have progressed on other antiestrogen therapy
SERDs
fulvestrant and elacestrant
what is the main thing that aromatase does at a molecular level that he said he wants us to know (slide 29)
demethylation is end result
aromatase converts:
androstenedione -> _____
testosterone -> _______
estrone
estradiol
aromatase inhibitors block synthesis of estrogens but not ________ or _______
androgens, progesterone
T or F:
Adipocytes are a source of estrogen in post-meno women
True
try your best to explain how adipocytes are a source of estrogen in post-meno women
aromatase in adipocytes converts androstenedione to estrone
estrone then gets converted to estradiol
what is the primary target for aromatase inhibitors?
peripheral tissue (adipose tissue)- not ovaries*
primary application of aromatase inhibitors *
estradiol suppression in post-meno women *
what are the 2 non-steroidal aromatase inhibitors
anastrozole and letrozole
T or F:
Both letrozole and anastrozole are potent and selective competitive inhibitors of aromatase activity
true, read it again to stick
primary indication of non-steroidal aromatase inhibitors
tx of breast cancer in post-meno women. No. Way.
while non-steroidal aromatase inhibitors have minimal toxicity, what is the one concern to look out for?
osteoporosis
what is the steroidal aromatase inhibitor?
exemestane
which of the following is referred to as the “suicide inhibitor”?
A. Tamoxifen
B. Letrozole
C. Exemestane
D. Anastrozole
C. Exemestane
T or F:
Exemestane binds reversibly at the active site and inactivates enzyme
False, irreversible
primary indication for exemestane
tx of ER+ breast cancer in post-meno women who have progressed on antiestrogen therapy. Not used in pre-menopausal women
3 things listed under minimal toxicity on Exemestane slide (side effects i guess?
- hot flashes
- occasional peripheral edema and weight gain
- increased cholesterol levels *
Which compound directly inhibits the activity of the estrogen receptor throughout the body?
A. Letrozole
B. Exemestane
C. Tamoxifen
D. Fulvestrant
D. Fulvestrant
“full antagonist”
“directly” is key word for this
What is the role of FSH in steroid hormone biosynthesis?
directly activates and increases expression of aromatase
FSH and LH are controlled by ________ _________?
feedback inhibition
decreased FSH leads to decreased ________ and ______?
aromatase and estrogen
GnRH analogs have modified amino acids to increase ______ and reduce ________
potency
degradation
What is the formulation of the GnRH analogs?
depot
what are the 3 GnRH analogs we learned
leuprolide
goserelin
triptorelin
long term side effects of GnRH analogs (2)
hot flashes
sexual dysfunction
primary indication of GnRH analogs
women with PRE-meno breast cancer
what are the tx options in breast cancer for pre-meno women
GnRH agonists (goserelin and leuprolide)
Tamoxifen
what enzyme converts testosterone into DHT in prostate cells?
5a-reductase
T or F:
Androgen receptor (AR) is a cytoplasmic receptor
true
binding of AR to DHT leads to what?
translocation to the nucleus and action of genes that drive cell growth
what PSA level is suggestive of prostate cancer?
> 6.5 ng/ml
prolonged tx with GnRH analogs leads to a decrease in ______ production
LH
GnRH primary indication in men
palliative tx of advanced prostate cancer
Long term side effects for GnRH analogs in men
“test-deficient feminization” -> gynecomastia + sexual dysfunction
what is meant by “flare” regarding the initial agonist effects of GnRH analogs in men for prostate cancer?
temporary surge in testosterone levels that occurs shortly after starting treatment
2 GnRH analogs in men indicated for advanced prostate cancer with need for androgen deprivation therapy
degarelix
relugolix
(gotta be something we can remember this with because it sounds like licks)
T or F:
All GnRH analogs used for prostate cancer in men result in the “flare” of test production
False, the -lix ones dont
Abiraterone (Zytiga) MOA
inhibits function of 17 a-hydroxylase and C17,20 lyase
also a steroid analog
common/weird side effect of Abiraterone (zytiga)
increased cholesterol
what are the 3 Androgen receptor (AR) antagonists?
Enzalutamide
Apalutamide
Darolutamide
(all -lutamide)
T or F:
The AR antagonists utilize partial antagonism of AR
false, they are full
T or F:
the “-lutamides” are approved for both metastatic and non-metastatic prostate cancer
true
the 3 -lutamides that we have in these slides are different than previous -lutamides how
higher affinity binding to AR than the old ones
-lutamides prevent AR translocation to what
the nucleus, meaning it inhibits AR binding to DNA
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
D
Which of the following is only used in the postmenopausal setting?
A. Letrozole
B.Tamoxifen
C. Leuprolide
D.Raloxifene
A
