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PHRM 864 > Lecture 2 - Anti-Cancer Endocrine Therapies > Flashcards

Lecture 2 - Anti-Cancer Endocrine Therapies Flashcards

1
Q

Understand the use of corticosteroids in lymphoid cancers

A

glucocorticoids have anti-cancer effect in treatment of blood cancers including: pediatric acute lymphoblastic leukemia (ALL), mutiple myeloma, lymphomas
used as palliative care to reduce inflammation, edema, and manage pain during chemotherapy
can be used to reduce hypersensitivity reactions, N/V, and immune-related adverse effects

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2
Q

Steroid hormones: molecular action

A

most hydrophobic steroids are bound to plasma protein carriers, only unbound hormones can diffuse into target cell
steroid hormone receptors are in cytoplasm or nucleus
receptor-hormone complex binds to DNA and activates or represses one or more genes
activates genes create new mRNA that moves back to the cytoplasm
translation produces new proteins for cell processes
some steroid hormones also bind to membrane receptors that use second messenger systems to create rapid cellular responses

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3
Q

Inhibition of steroid signaling

A

two major strategies: stop steroid receptor function or decrease production of steroids

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4
Q

Example glucocorticoids

A

methylprednisolone, prenisolone, dexamethasone

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5
Q

Understand the underlying principles governing the antineoplastic activity of hormonal therapies

A

only for hormone-dependent cancers; hormones regulate the proliferation in breast cancer, prostate cancer, and endometrial cancer
primarily target estradiol (breast, endometrial) and dihydrotestosterone (prostate)
produced in adrenal, ovary, testis, and adipocytes

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6
Q

What hormone is produced in the hypothalamus

A

GnRH

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7
Q

What hormone is produced in the pituitary gland

A

LH/FSH

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8
Q

Hormones and breast cancer

A

hormone therapy in breast cancer generally limited to ER+/PR+ tumors

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9
Q

Understand diagnostic determinants required for endocrine therapy

A

ER+ tumors will be treated with endocrine therapy
there are 4 subtypes of breast cancer that are determined by molecular diagnostics

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10
Q

Breast tumor subtypes

A

claudin-low and basal-like: triple negative, no estrogen, HER2, progesterone - use cytotoxics/chemo
HER2-enriched - use trastuzumab
Luminal A/B: ER positive, most differentiated - use endocrine therapy

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11
Q

Selective estrogen receptor modulators (SERMs)

A

tamoxifen, toremifene, clomiphene
prevent ER signaling by binding to ER and causing an inactive complex

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12
Q

Selective estrogen receptor degraders (SERDs)

A

fulvestrant and raloxifene
prevent ER signaling by causing degradation of ER

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13
Q

Tamoxifen

A

is a prodrug that must be metabolized to 4-OH-TAM, metabolized by CYP2D6; forms high-affinity hydroxylated and demethylated metabolites
not recommended in poor metabolizers of CYP2D6
has both agonist and antagonist activities; binding to ER will have affects on both translocation and DNA binding in a tissue-specific manner
effective in both pre- and postmenopausal women

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14
Q

Understand the mechanisms of action of estrogen receptor inhibitors both agonist and antagonist

A

SERMs can act as eithter agonist or antagonist
SERMs: coactivator or corepressor is tissue specific
SERDs: not tissue specific

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15
Q

Tamoxifen estrogen antagonist effects

A

in brain and breast
blocks estrogen-dependent breast cancer cell proliferation
hot flashes due to anti-estrogen effects

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16
Q

Tamoxifen estrogen agonist effects

A

in bone, blood, and endometrium
increased incidence of endometrial cancer
preservation of bone density in postmenopausal women, blocks bone resorption
in blood, increased coagulability

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17
Q

Tamoxifen used to treat

A

resected ER+/PR+ breast cancer
1st drug approved for breast cancer prevention in high-risk patients

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18
Q

Raloxifene estrogen antagonist effects

A

brain: hot flashes, thermoregulation
breast: preventive to breast cancer
uterus: NO endometrial hyperplasia

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19
Q

Raloxifene estrogen agonist effects

A

blood: increased coagulability
bone: blocks bone resorption

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20
Q

Fulvestrant and Elacestrant

A

pure ER antagonist, NO agonist effects - fulvestrant (IM dosing)
partial agonist at low doses, full SERD at high doses - elacestrant (PO dosing)
bind to ER and inhibits DNA binding –> rapid receptor degradation
for ER+ metastatic breast cancer in postmenopausal women

21
Q

Understand the mechanism of action of the aromatase inhibitors

A

androstenedione (contains methyl group) forms estrone (no methyl group) from aromatase
demethylation of enone ring by aromatase
aromatase catalzyes the demethylation of the enone ring of androgens to the aromatic ring in estrogens
aromatases convert androstenedione –> estrone and testosterone –> estradiol

22
Q

Aromatase inhibitors block synthesis of

A

estrogens, but not androgens or progesterone

23
Q

Primary target of aromatase inhibitors is

A

peripheral tissue (adipose tissue) - not ovary
adipocytes are a source of estrogen in postmenopausal women - aromatase in adipocytes converts androstenedione –> estrone –> estradiol

24
Q

Primary application of aromatase inhibitors is

A

estradiol suppression in postmenopausal women

25
Q

Imidazole-based non-steroidal aromatase inhibitors

A

anastrozole and letrozole
competitive inhibitors against aromatase

26
Q

Letrozole and anastrozole

A

potent and selective competitive inhibitor of aromatase activity
for treatment of breast cancer in postmenopausal women
increases extent of bone density loss - increased fractures vs tamoxifen

27
Q

Steroidal aromatase inhibitor

A

exemestane inhibitor - structurally similar to androstenedione - actual hormone

28
Q

Exemestane

A

irreversible inhibitor; acts as false substrate that aromatase converts to reactive intermediate, intermediate binds irreversibly at active site and inactivates enzyme
used in estrogen-responsive breast cancer in postmenopausal women

29
Q

FSH and LH are controlled by

A

feedback inhibition
LH directly activates expression of chol-SCC
FSH directly acticates (increase expression) of aromatase

30
Q

Control of estrogen and progesterone levels by feedback inhibition

A

hypothalamus releases GnRH –> anterior pituitary releases LH and FSH –> LH forms progesterone, FSH forms estrogen
estrogen and progesterone inhibit LH and FSH production by the anterior pituitary and inhibit GnRH by hypothalamus

31
Q

Chronic administration of GnRH analogues

A

downregulates pituitary GnRH receptors and –> pituitary desensitization; this then blocks gonadotropin secretion
decreased FSH leads to decreased aromatase and decreased estrogen

32
Q

Understand the mechanisms of action and side effects of GnRH analogs

A

peptide analogs of GnRH with modified amino acids to increase potency and reduce degradation
acute administration induces surge of LH and FSH (agonist effect) –> acute increase in all steroid hormone levels –> increase in tumor growth before shutdown phase
chronic administration downregulates pituitary GnRH receptors and leads to pituitary desensitization –> severe loss of estrogen

33
Q

GnRH analogs

A

GnRH
leuprolide
goserelin

34
Q

Leuprolide, goserelin, triptorelin

A

long term SEs: hot flashes and sexual dysfunction
transient worsening of sx related to initial agonist effects
primary indication for premenopausal breast cancer

35
Q

For postmenopausal women w/ ER+ disease

A

tamoxifen
anastrozole and letrozole
exemestane
fulvestrant

36
Q

For premenopausal women

A

goserelin and leuprolide
surgical oophorectomy
tamoxifen

37
Q

Estrogen and steroid receptors are found in

A

the cytosol

38
Q

Understand the mechanisms of action of the AR antagonists, compared to 5-alpha-reductase and CYP17 inhibitors

A

testosterone is rapidly and irreversibly converted by type II 5-alpha reductase to DHT in prostate cells
DHT binds to AR in prostate cells, DHT-AR complex is activated and translocated to the nucleus, DNA binding stimulates transcription of AR responsive genes –> cell growth and survival

39
Q

Androgen receptor is a

A

cytoplasmic receptor
AR is amplified in prostate cancer

40
Q

Blood serum levels of ________ is used as a biomarker

A

prostate specific antigen
>6.5 ng/mL is suggestive of prostate cancer

41
Q

Just as in women, prolonged treatment with GnRH analogues leads to

A

a decrease in LH production
transient increases in testosterone, but overall results in chemical castration

42
Q

GnRH analogs in men

A

leuprolide acetate, goselerin, triptorelin
primary indication for advanced prostate cancer
transient worsening sx related to initial agonist effects “flare”
long term SEs: gynecomastia and sexual dysfunction

43
Q

GnRH antagonists in men

A

degarelix and relugolix
for advanced prostate cancer with need for androgen deprivation therapy
will not result in flare of testosterone production
long term SEs: gynecomastia and sexual dysfunction

44
Q

How else can we prevent DHT production

A

CYP17

45
Q

Abiraterone

A

inhibits function of 17-alpha hydroylase and C17,20 lyase
CYP17 catalyzes the conversion of pregnenolone and progesterone to DHEA and androstenedione
inhibits production of testosterone in all tissues throughout the body
SE: increased cholesterol

46
Q

How else do we block AR signaling

A

androgen receptor antagonists

47
Q

Androgen receptor antagonists

A

enzalutamide, apalutamide, darolutamide
full antagonism, full inhibition

48
Q

Enzalutamide, apalutamide, darolutimide

A

higher affinity binding to AR
prevents AR translocation to nucleus
inhibits AR binding to DNA
for metastatic and non-metastatic prostate cancer

49
Q

Mechanism of resistance to endocrine therapy

A

castration resistant prostate cancer
from mutations in AR that result in androgen independent activation and prevent binding of AR antagonists

PHRM 864 (20 decks)

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