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therapeutics 864 - exam 1 > endocrine therapies > Flashcards

endocrine therapies Flashcards

1
Q

Study steroid hormone biosynthesis Be able to draw out

A

Endocrine Therapies, slide 3

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2
Q

what is the most active estrogen in the body?

A

estradiol

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3
Q

what is the most active testosterone in body

A

DHT

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4
Q

glucocorticoids have anti-_____ effect in tx of _____ cancers including __________, ___________, _________

The most common glucocorticoids are: _________, __________, _________

Used as palliative care to reduce inflammation, edema & manage pain. can be used ro reduce hypersensitivity rxns, n/v & immune-related AEs

A

cancer; blood; ALL, multiple myeloma, lymphomas

methylprednisolone, prednisone & dexamethasone

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5
Q

Hormonal therapies are ________ specific – only for hormone-dependent cancers,
i.e. Hormones regulate the proliferation in these cancers
>______
>______
>_________

Primarily targeting _______ (breast, endometrial) and ________(prostate)

Produced in _____, _____, _____ & ______

A

_________Disease
>Breast cancer
>Prostate cancer
>Endometrial cancer

estradiol; dihydrotestosterone
adrenal glands, ovary, testis, and adipocytes

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6
Q

leading cancer for men? women?

A

prostate; breast

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7
Q

steroid hormones: molecular action steps
1. most hydro—— steroids are bound to plasma protein carriers. only unbound hormones can diffuse into the target ——
2. steroid hormone receptors are in the _______ or _______
3. the receptor-hormone complex binds to ______ & activates or represses 1 or more genes
4.activated genes create new ____ that moves back to the cytoplasm
5. _———produces new proteins for cell processes
6. some steroid hormones also bind to membrane receptors that use _______ messenger systems to create rapid cellular responses

A
  1. phobic; cell
  2. cytoplasm or nucleus
  3. DNA
  4. mRNA
  5. translation
  6. second
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8
Q

what are the two major strategies to endocrine therapy? (inhibition of steroid signaling)

A
  1. stop steroid receptor function
  2. decrease production of steroids
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9
Q

GnRH –> LH/FSH –> ovaries/testes is a _________ feedback loop

A

negative

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10
Q

Estrogen receptors (ER) and progesterone receptors (PR) are measurable in tumors

Well differentiated tumors are more likely to be __ER+ or ER-__ poorly differentiated tumors are generally __ER+; ER-__

> Remember that poorly differentiated tumors have _______growth fractions and are generally ___less/more___ sensitive to cytotoxic agents

Highly significant correlation between presence of _______receptor and the likelihood of response to hormone therapy

Correlation is even stronger for _______ tumors

PR is ______inducible and is a measure of biological response to estrogen

Hormone therapy in breast cancer generally limited to ______tumors

A

ER+; ER-

higher; more

estrogen

ER+/PR+

estrogen

ER+/PR+

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11
Q

Which hormone is produced in the pituitary gland?

a. GnRH
b. LH
c. estrogen
d. progesterone

A

b. LH

FSH is also produced in pituitary gland; they are activated by GnRH

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12
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. In the cytoplasm
once bound then it moves to nucleus

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13
Q

What enzyme converts androstenedione to estrone?

a. CYP19
b. 5alpha-reductase
c. 17, 20 lyase
d. P450scc

A

a. CYP19

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14
Q

____ tumors will be treated with endocrine therapy. ER status can be _____geneous. ~____% positivity are considered for endocrine therapy

A

ER+; hetero; 10%

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15
Q

breast cancer is made up at least _#___ distinct disease. List the 4.

what diagnostics are used to determine subtypes?

A

4
claudin-low
basal-like
HER2-enriched
Luminal B/A

molecular diagnostics

see endocrine therapies, slide 17

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16
Q

triple negative breast cancers (ER-, no HER2, no BRCA mutation) are treated with ______

A

cytotoxics

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17
Q

luminal B/A are the ___most/least___ differentiated breast cancer subtype

A

most (ER+)

least differentiated –> most differentiated
claudin > basal > HER2 > luminal

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18
Q

what subtype of breast cancer is the least common? mostcommon?

A

HER2+ (more high grade, poor prognosis, chemo therapy, trastuzumab tx)

luminal A (ER+/PR+, low grade, endocrine therapy used)

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19
Q

endocrine drugs ending with -fen are modulators or degraders?
-strant?

A

-fen –> SERMs (modulators)
tamoxifen, toremifene, clomiphene

-strant –> SERDs (degraders)
fulvestrant, raloxifene

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20
Q

what is the most commonly used endocrine therapy for ER+ breast cancers?

A

tamoxifen (prodrug)

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21
Q

tamoxifen is a _____drug that must be metabolized to _____. pts with variant CYP____ should not use tamoxifen due to ___more/less___ active drug

A

prodrug; 4-OH-TAM
2D6; less active drug

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22
Q

CYP2D6 converts tamoxifen to __low/high___ affinity hydroxylated and demethylated metabolites

Binding to ______ receptor will have affects on both translocation and DNA binding in a tissue-specific manner.

Estrogen antagonist effects
>Blocks estrogen-dependent breast cancer cell proliferation
>Hot flashes due to anti-estrogen effects

Estrogen agonist effects
>Incidence of _______cancer increased 3-fold
>Preservation of bone density in postmenopausal women

A

high

estrogen

endometrial

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22
Q

t/f tamoxifen has both agonists & antagonist activities

A

true

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23
Q

t/f tamoxifen is effective in both pre- and postmenopausal women

A

true

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24
Q

t/f Primary use is treatment for resected ER+/PR+ breast cancer, but not for tx of metastatic ER+/PR+ breast cancer

A

false; also used for tx of metastatic ER+/PR+ breast cancer

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25
Q

what is the first drug approved for breast cancer PREVENTION in high risk pts?

A

tamoxifen (decrease risk by 50%, use up to 5 years)

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26
Q

t/f SERMS can act as either agonists or antagonists

A

true; will bind to co-activator or co-repressor depending on tissue (tissue-specific)

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27
Q

list the notable differences b/t tamoxifen & raloxifene (SERMs)

A

tamoxifen: endometrial hyperplasia
raloxifene: no endometrial hyperplasia, less osteoporosis risk (blocks bone resorption & ^ bone mass)

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28
Q

what is the main drug in the SERD class? does it have ER antagonist or agonist effects? how is it administered

A

fulvestrant; pure ER antagonist, NO agonist effects; IV

elacestrant is also in class (PO dosing)

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29
Q

what is the MOA of fulvestrant?

A

binds to ER & inhibits DNA binding –> rapid receptor degradation

no activation of receptor

30
Q

Fulvestrant (SERD) is approved for treatment of ____ _______ breast cancer in ______ menopausal women who have progressed on other antiestrogen therapy

A

ER+, metastatic, postmenopausal

31
Q

aromatase inhibitors prevent the conversion of ______ to _____. (prevent the demethylation of enone ring)

A

androgens to estrogens

32
Q

what is another name for aromatase?

A

CYP19

33
Q

aromatase catalyzes the __________ of the _____ ring of _________ to the aromatic ring in _______

aromatases convert _______ > ______ + __________ > _________

A

demethylation; enone; androgens; estrogens

androstenedione > estrone & testosterone > estradiol

34
Q

t/f aromatase inhibitors block synthesis of estrogens, androgens and progesterone

A

false; only blocks synthesis of estrogens

35
Q

_______ are a source of estrogen in postmenopausal women

A

Adipocytes

> Androstenedione produced in adrenal gland and released to circulation
Aromatase in adipocytes converts androstenedione > estrone
Estrone then converted to estradiol

36
Q

what is the primary target of aromatase inhibitors?

A

peripheral tissue (adipose tissue) – NOT OVARY

37
Q

aromatase inhibitors are used primarily as estradiol suppression in ________menopausal women

A

post

38
Q

what are the 2 non-steroidal aromatase inhibitors

A

anastrozole & letrozole
(imidazole-based)

39
Q

t/f anastrazole & letrozole are non-steroidal

A

true

40
Q

Letrozole (Femara) and Anastrozole (Arimidex)

> Potent and selective ______inhibitor of aromatase activity

> Primary indication is treatment of ____cancer in ____menopausal women

> Drug is highly effective as ____ line therapy OR when started after _____years of tamoxifen Rx

> Taken orally everyday

> Minimal toxicity
____increases/decreases____ extent of bone density loss

A

competitive

breast; post

first, 3-5 years

increases - increased fractures vs. tamoxifen

41
Q

what are the 2 steroidal aromatase inhibitors

A

exemestane & androstenedione

42
Q

what steroidal aromatase inhibitors is referred to as the suicide inhibitor?

A

exemestane (aromasin)

43
Q

Exemestane (Aromasin)

Acts as false substrate that aromatase converts to reactive intermediate

Intermediate binds -__reversibly/irreversibly___ at _____ site and inactivates enzyme

Taken _____ everyday

Primary indication is the treatment of _________-responsive breast cancer in ______-menopausal women who have progressed on antiestrogen therapy

Not used in _____menopausal women

Minimal toxicity
>Hot flashes
>Occasional peripheral edema and weight gain
>___decreased/increased___ cholesterol levels

A

irreversibly; active

orally

estrogen

post

pre

increased

44
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

letrozole & exemestabe are AIs, indirectly inhibits
tamoxifen is a modulator so it only works in some tissues

45
Q

Which compound is referred to as a SERM?

a. Letrozole
b. Exemestane
c. Tamoxifen
d. Fulvestrant

A

c. Tamoxifen

letrozole is non steroidal AI
exemestane is steroidal AI
fulvestrant is SERD

46
Q

what hormone can direclty activate/increase expression of estrone & estradiol

A

FSH (acts on aromatase)

47
Q

-Chronic administration of GnRH analogues ___up/down___ regulates pituitary GnRH receptors and causes pituitary _________.

-Decreased FSH, leads to ____i or d_____aromatase, and ___i or d__estrogen.

A

down; desensitization

decreased; decreased

48
Q

Gonadotropin Releasing Hormone analogs:

> Peptide analogs of the neurohormone GnRH with modified amino acids to __increase/decrease__ potency and reduce degradation.

> Depot formulation suitable for slow-release following ___SUBQ or IM_____injection

> Acute administration induces surge of _____and ____ (agonist effect)
-Acute __increase/decrease___ in all steroid hormone levels
-Corresponding transient _increase/decrease___in tumor growth

-Severe loss of estrogen within ____–weeks
-Inhibition of estrogen-dependent breast cancers in women

A

increase

SUBQ

LH & FSH

increase

increase

3-4 weeks

49
Q

what are the 3 LHRH/GnRH analogs? The analogs __increase/decrease___ the half life of the peptide

A

triptorelin (Trelstar), Leuprolide (Lupron), Goserelin (Zoladex)

increase

50
Q

GnRH Analogs [leuprolide, goserelin, triptorelin]

Transient worsening of symptoms related to initial _____ effects

long term side effects
> _______
>_________

primary indication for women with ____menopausal breast cancer

side effects in women typical of antiestrogenic effects

A

agonist

hot flashes, sexual dysfunction

premenopausal

51
Q

SEE SUMMARY OF HORMONAL THERAPY IN BREAST CANCER

tx for postmenopausal w ER+ vs. premenopausal

A

post:
Tamoxifen
Nonsteroidal aromatase inhibitors (anastrozole, letrozole)
Steroidal aromatase inhibitor (exemestane)
Pure anti-estrogens (fulvestrant)

Pre:
GnRH agonists (goserelin and leuprolide)
Surgical oophorectomy
Tamoxifen

52
Q

t/f most prostate cancer is localized

A

true

53
Q

prostate cancer is ___slow or fast___ progressing disease

what is the median age of diagnosis & death

A

slow
diagnosis: 66
death: 80

54
Q

how is prostate cancer staged?

How many stages? is 1 well or poor differentiated?

A

gleason score/scale

5
1 is well differentiated, 5 is poor

55
Q

what is the most important risk factor in prostate cancer?

A

age, extremely rare <40, rate incease after 40 & is the steepest of any cancer

56
Q

Testosterone is rapidly and __reversibly/irreversibly_____ converted by ____________ to ________in prostate cells

A

irreversibly; Type II 5-a reductase to DHT

57
Q

DHT binds to which receptor in prostate cells

A

androgen receptor (AR)

58
Q

when activated the DHT-AR complex is translocated where?

A

nucleus

DNA binding stimulates transcription of AR responsive genes which drive cell growth

59
Q

AR is a ________ receptor and can be ___increased or decreased____ in prostate cancer

A

cytoplasmic; increased (amplified)

60
Q

A ___high or low___ level of PSA is indicative of prostate cancer

A

high

UTI, vigorous exercise, prostate stimulation & some meds can also increase PSA

61
Q

what level of PSA (prostate specific antigen) is suggestive of prostate cancer?

A

> 6.5 ng/mL

62
Q

A 65 y.o. male, with prostate cancer has a radical prostatectomy, and his PSA levels drop from 10 ng/ml to undetectable. On his three year follow up appointment his PSA level is at 5 ng/ml. What does this mean?

A

cancer is likely back, need PET scan

63
Q

like in women, prolonged tx with GnRH analogues leads to a ___increase/decrease___ in LH production.

There is a transient ___increase/decrease___ of testosterone, but overall resuts in “chemical castration” in ____ weeks

A

decrease

increase; 3-4 weeks

64
Q

GnRH analogs in MEN

leuprolide, goselerin triptorelin

primary indication is for palliative tx of advanced __________ cancer.

transient wosening of sxs related to inital ______ effects {“flare”}

long term sxs related to testosterone-deficient “feminization”
-_______
-_______

ONLY USED IN ADVANCED CANCERS

A

prostate; agonist

-gynecomastia
-sexual dysfunction

65
Q

GnRH Antagonists in MEN (2)
-___________
-__________

What hormones are blocked? (2)

primary indication is for advanced prostate cancer with need for __________

sxs are gynecomastia & sex dysfunction

A

degarelix, relugolix

FH & LSH

androgen deprivation therapy

66
Q

Will degarelix or relugolix result in flare of testosterone production

A

no

67
Q

MOA for abiraterone (zytiga)

A

inhibits funciton of 17a-hydrolase & C17,20 lyase (cyp17)

> CYP17 catalyzes the conversion of pregnenolone and progesterone to >DHEA and androstenedione.
Steroid analogue
Much higher step in hormone synthesis

68
Q

what is a common side effect of abiraterone (zytiga)

A

Common side effect is increased levels of cholesterol

69
Q

what are the 3 androgen receptor (AR) antagonists?

A

enzalutamide, apalutamide, darolutamide

70
Q

Enzalutamide (Xtandi), Apalutamide (Erleada), Darolutimide (Nubeqa)

> Higher affinity binding to AR than previous “-lutamides”
Prevents __________ to the nucleus
Inhibits AR binding to DNA

Approved for both _____ + ______ prostate cancer.

A

> AR translocation
metastatic and non-metastatic

71
Q

t/f apalutamide is approved for non metastatic prostate cancer

A

true

72
Q

why is 5-alpha reductase controversial for use in prostate cancer?

A

Controversial! The opinion right now is that it should not be used in prostate cancer as it might increase the chance for high-grade prostate cancers

73
Q

what are the mechanisms of resistance to endocrine therapy; prostate cancer

A

> Mutations in AR can arise that result in androgen independent activation and prevent binding of AR antagonists.
Overall, this is referred to castration resistant prostate cancer (CRPC).

therapeutics 864 - exam 1 (10 decks)

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