Anti-cancer endocrine therapies Flashcards
Corticosteroidal Treatments
anti-cancer effect in treatment of blood cancers
- pediatric ALL
- multiple myeloma
- lymphomas
palliative
- help with ___, ___ , and ___ during chemo
reduce hypersensitivity reations, N/V, and immune related AEs
most common: methylprednisolone, prednisolone, or dexamethasone
inflammation, edema, pain
Hormonal Therapies
hormone dependent cancers (regulate proliferations)
- breast, prostate, endometrial
target ___ (breast, endometrial) and ___ (prostate)
- estradiol
- dihydrotestosterone
produced in adrenal, ovary, testism and adipocytes
Steroid Hormones: Molecular Action
1) plasma protein carrier in the blood drops free steroid off to enter the cell
2) steroid receptor hormone are in the ___ or the ___
3) receptor-hormone complex binds to DNA and activates/represses genes
4) activated genes make new mRNA that is translated into new proteins
5) some steroid hormones also bind to ___ receptors that use 2nd messengers to create rapid cell response
- cytoplasm, nucleus
- membrane
inhibtion of steroid signaling
two major strategies to endocrine therapy
1) stop steroid ___ function
2) decrease production of steroids
receptor
hormones and breast cancer
- ER and PR measurable in tumors
- well differentiated tumors more likely to be ___ positive
- poorly differentiated tumors have ___ growth fractions and are generally more sensitive to cytotoxic agents
- higly significant correleation between presence of ER and likelihood of response to hormone therapy
- correlation is even stronger for ER+/PR+ tumors (PR is estrogen inducible and is a measure of biological response to estrogen)
- hormone therapy in breast cancer generally limitied to ___ tumors
- ER
- higher
- ER+/PR+
which hormone is produced in the pituitary gland?
a) GnRH
b) LH
c) estrogen
d) progesterone
LH
estrogen receptor primarily binds estrogen where in the cell
a) on the membrane
b) in the mitochondria
c) in the cytoplasm
d) in the nucleus
in the cytoplasm
moves to nucleus once it is bound
what enzyme converts androstenedione to estrone?
a) CYP19
b) 5 alpha-reductase
c) 17,20 lyase
d) P450scc
CYP19
also called aromatase
diagnistic driven therapy
ER positive tumors will be treated with endocrine therapy
- ER expression/function can be lost by multiple mechanisms
- ER status can be heterogeneous
breast cancer is made up of at least 4 distinct diseases
these subtypes are determined by molecular disagnostics
- ___ low
- ___ like
- ___ enriched
- Luminal A and B
- claudin
- basal
- HER2
SERMs
Tamoxifen (Nolvadex)
- both agonist and antagonist activities
- ___ converts prodrug tamoxifen to high ___ hydroxylated and demethylated metabolites (4-OH-TAM)
- binding ER will have affects on both translocation and DNA binding in a ___ specific manner
estrogen antagonist effects
- blocks estrogen-dependent breast cancer cell ___
- ___due to anti-estrogen effects
estrogen agonist effects
- incidence of ___ cancer increased 3 fold
- preservation of bone density in postmenopausal women
drug is effective in both pre and post menopausal women
- CYP2D6, affinity
- tissue
- proliferation
- hot flashes
- endometrial
Tamoxifen continued
- primary use is treatment for resected ER+/PR+ breast cancer
- also used for the treatment of metastatic ER+/PR+ breast cancer
- first drug approved for breast cancer ___ in high-risk patients (reduces risk by 50%, recommended use for up to 5 years)
- much less effective in patients with a common ___ variant
- several known inhibitors of ___
- prevention
- CYP2D6
- CYP2D6
T or F: SERMs can act as either agonist or antagonist
T
SERMs AE and Beneficial Effects
Tamoxifen
Brain (-): ER antagonist
- ___
- thermoregulation
Breast (+): antagonist
- anti ___
Blood (-): ER agonist
- increased ___
- clots VTE risk
Uterus (-): ER agonist
- ___ hyperplasia
Bone (+): partial agonist
- blocks bone ___
- hot flashes
- proliferative
- coagulability
- endometrial
- resorption
SERMs AE and Beneficial Effects
Raloxifene
Brain (-): ER antagonist
- ___
- thermoregulation
Breast (+): antagonist
- ___to cancer
Blood (-): ER agonist
- increased ___
- clots, VTE risk
Uterus (+): ER antagonist
- NO ___ hyperplasia
- diffes from Tamoxifen
Bone (+): agonist
- blocks bone ___
- increase bone mass in ___
- hot flashes
- preventive
- coagulation
- endometrial
- osteoporosis
SERDs
Fulvestrant (Faslodex) and Elacestrant
- pure ER ___ that has no ___ effects
- acts are partial agonist at low doses and full SERD at high doses (Elacestrant)
- Fulvestrant: ___ dosing vs Elacetrant: ___ dosing
- MOA: binds to ER and inhibits ___ binding leading to rapid receptor ___
- approved treatment of ER+ metastatic breast cancer in ___ menopausal women who have progressed on other antiestrogen therapy
- antagonist, agonist
- IM, PO
- DNA, degradation
- postmenopausal
aromatase (CYP19)
- catalyzes the ___ of the enone ring of androgens to the aromatic ring in estrogens
- convert androstenedione to ___ and testosterone to ___
- inhibitors block synthesis of ___ but not androgens or progesterone
- ___ are a source of estrogen in postmenopausal women
- primary target of inhibitors is ___ tissue - not ovaries
- primary application is estradiol suppression in ___ menopausal women
- demethylation
- estrone, estradiol
- estrogen
- adipocytes, peripheral/adipose
- postmenopausal
non-steroidsal aromatase inhibitors
letrizole (Femara) and anastrozole (Arimidex)
- potent and selective ___ inhibitor of aromatase activity
- primary indiaction is treatment of breast cancer in ___ menopausal women
- drug is highly effective as first line therapy OR when started after 3-5 years of ___
- administered ___
- minimal toxicity but increased bone density loss/ ___ compared to tamoxifen
- competitive
- postmenopausal
- tamoxifen
- PO
- fractures
Steroidal Aromatase inhibitors
exemestane (Aromasin)
- structurally related to ___ - ‘suicide inhibitor’
- acts as false substrate that aromatase converts to reactive intermediate
- intermediate binds ___ at active site and inactivates enzyme
- administered ___
- primary indication is the treatment of estrogen responsive breast cancer in ___ menopausal women who have progressed on antiestrogen therapy
minimal toxicity
- hot flashes, occasional peripheral edema and weight gain
- increased ___ levels
- androstenedione
- irreversibly
- PO
- postmenopausal
- cholesterol
which compound directly inhibits the activity of the estrogen receptor throughout the body?
a) letrozole
b) exemestane
c) tamoxifen
d) fulvestrant
fulvestrant
which compound is referred to as a SERM?
a) letrozole
b) exemestane
c) tamoxifen
d) fulvestrant
tamoxifen
FSH and LH are conrolled by feedback inhibition
FSH and LH activate direct expression of enzymes
- ___ and ___ respectively
- aromatase
- Chol-SCC
FSH and LH are conrolled by feedback inhibition
- chronic administration of GnRH analogues downregulates pituitary GnRH receptors and leads to pituitary ___
- decreased FSH leads to decreased ___ and ___
- desensitization
- aromatase, estrogen
Gonadotropin Releasing Hormone analogs
- peptide analogs of the neurohormone GnRH with modified amino acids to increase ___ and reduce ___
- depot formulation suitable for slow release following SC injection
acute administration induces surge of ___ and ___ (agonist effect)
- acute increase in all steroid hormone levels
- corresponding transient increase in tumor growth
chronic administration ___ pituitary GnRH receptors and leads to pituitary ___
- severe loss of ___ with 3-4 weeks
- inhibition of estrogen-dependent breast cancers in women
- potency, degradation
- LH, FSH
- downregulates, desensitization
- estrogen
GnRH Analogs
leuprolide acetate (Lupron), goserelin (Zoladex), triptorelin (Trelstar)
- transient worsening of symptoms related to initial agonist effects
- long term SE: ___ and sexual dysfunction
- primary indication for women is ___ menopausal breast cancer
- SE in women typical of antiestrogenic effects (menopausal)
- hot flashes
- pre
summary of hormonal therapy in breast cancer
for postmenopausal women with ER+ disease
- tamoxifen
- nonsteroidal aromatase inhibitors ( ___ and ___ )
- steroidal aromatase inhibitor ( ___ )
- pure anti-estrogens ( ___ )
- anastrozole, letrozole
- exemestane
- fulvestrant
summary of hormonal therapy in breast cancer
for premenopausal women
- GnRH agonists ( ___ and ___ )
- surgical oophorectomy
- tamoxifen
- goserelin, leuprolide
prostate cancer
- most frequently disgnosed cancer in men in the US
- ___ progressing disease
- diagnosed later in life (typically after age ___ )
- uses gleason score
- slowly
- 40
hormones and prostate cancer
testosterone is rapidly and irreversibly converted by type II ___ to dihydrotestosterone (DHT) in prostate cells
- dihydrotestosterone binds to the androgen receptor in prostate cells
- the DHT-AR complex is activated and translocated to the nucleus
- DNA binding stimulates transcription of AR responsive genes
- 5-a reductase
Androgen receptor (AR) signaling
- AR is a ___ receptor
- can be ___ in prostate cancer
- binding of AR to ___ leads to translocation to the nucleus and action of genes
- cytoplasmic
- amplified
- DHT
PSA and prostate cancer
normal ranges dependent on age
greater than ___ ng/mL is suggestive of prostate cancer
6.5 ng/mL
GnRH Analogues in men
- just as in women, prolonged treatment with these analogues leads to a decrease in ___ production
- transient increases in testosterone, but overall results in ___ within 3-4 weeks
- LH
- chemical castration
GnRH analogs in men
leuprolide acetate (Lupron), goselerin (Zoladex), triptorelin (Trelstar)
- primary indication is for palliative treatment of advanced prostate cancer
- transient worsening of symptoms related to initial agonist effects - “flare”
- long term SE related to testosterone deficient ___ , sexual dysfunction
- gynecomstia
GnRH Antagonists in men
___ (Firmagon) and ___ (Orgovyx)
- primary indication is for advanced prostate cancer with need for androgen deprivation therapy
- will not result in ___ of testosterone production
- long term SE related to testosterone deficient ___
- degarelix, relugolix
- flare
- feminization
abiraterone (Zytiga)
inhibits the function of ___ and ___
- ___ catalyzes the conversion of pregnenolone and progesterone to ___ and ___
- steroid analogue
- much higher step in hormone synthesis
- common SE is increased levels of ___
- 17 a-hydroylase, C17,20 lyase
- CYP17, DHEA, androstenedione
- cholesterol
Androgen Receptor Antagonists
enzalutamide (Xtandi), apalutamide (Erleada), darlutamide (Nubeqa)
- higher affinity binding to AR than previous “-lutamides”
- prevents AR translocation to ___
- inhibits AR binding to ___
- approved for both metastatic and ___ prostate cancer
- nucleus
- DNA
- non-metastatic
mechanis of resistance to endocrine therapy: prostate cancer
- mutations in AR can arise that result in androgen ___ activation and prevent binding of AR antagonists
- overall, this is referred to as castration ___ prostate cancer (CRPC)
- independent
- resistant
