Anti-cancer Endocrine Therapies_Edit Flashcards
What regulates the proliferation of breast cancer, prostate cancer and endometrial cancer
HORMONES
Receptors are ___________ hormone-dependent transcription factors
cytosolic
Describe steroid receptor signal transduction
When ligand enters cell and binds to receptor, ligand-receptor complex translocated to nucleus, binds to DNA promoters and induces transcription
Two major classes of endocrine therapy
- Stop steroid receptor function
2. Decrease production of steroids
Well-differentiated tumors are more likely to be ____
ER+
Poorly differentiated tumors are generally ____
ER-
Which hormone(s) are produced in the pituitary gland?
LH and FSH
Where does the estrogen receptor primarily bind estrogen in the cell?
In the cytoplasm
What enzyme converts androstenedione to estrone?
CYP19
Tamoxifen is a __________
pro-drug
What converts tamoxifen to high-affinity hydroxylated and demethylated metabolites?
CYP2D6
Tamoxifen Pharmacology
SERM
both agonist and antagonistic activities
block estrogen-dependent breast cancer cell proliferation
Which women for Tamoxifen
Pre- and postmenopausal women
Tamoxifen primary use for tx
tx for resected ER+/PR+ breast cancer (3 - 5 years Rx)
also used for the tx of metastatic ER+/PR+ breast cancer
Beneficial effects of Tamoxifen
Breast: anti-proliferative
Blocks bone resorption
AE of Tamoxifen
hot flashes; thermoregulation
increased coagulability; clots, VTE risk
Endometrial hyperplasia
Beneficial effects of Raloxifene
Preventative to breast cancer
No endometrial hyperplasia (differs from tamoxifen)
Blocks bone resorption; increases bone mass is osteoporosis
Name a SERD
Fulvestrant
What effect does fulvestrant have
ER antagonist
What types of breast cancer does fulvestrant treat?
Approved for tx of ER+ metastatic breast cancer
What type of women for fulvestrant
postmenopausal women who have progressed on other antiestrogen therapy
Alternate name for CYP19
aromatase
Adipocytes are a source of estrogen in what type of women
postmenopausal
What is the primary target of inhibitors
peripheral tissue (adipose tissue)
Primary application of aromatase inhibitor estradiol suppression for what women
postmenopausal
Name two imidazole-based NON-steroidal aromatase inhibitors
anastrozole and letrozole
anastrozole and letrozole for which women
breast cancer in postmenopausal women
first line therapy OR when started after 3 - 5 years
Name steroidal aromatase inhibitors
exemestane and androstenedione
exemestane for which women
tx of estrogen-responsive breast cancer in postmenopausal women who have progressed on anti-estrogen therapy
NOT used in premenopausal women
Which compound directly inhibits the activity of the ER receptor throughout the entire body
Fulvestrant
What do aromatases convert
androstenedione –> estrone and testosterone –> estradiol
Letrozole and anastrozole are what type of inhibitors
competitive
how does exemestane bind and what does it do
binds irreversibly at active site and inactivates enzyme
decreased FSH leads to
decreased aromatase and decreased estrogen
Describe GnRH analogs
peptide analogs of the neurohormone GnRH with modified amino acids to increase potency and reduce degradation
GnRH inhibits…
…estrogen-dependent breast cancers in women
name GnRH analogs
leuprolide
goserelin
triptorelin
buserelin
leuprolide and goserelin used in what type of women
premenopausal
For post menopausal women, what hormone therapy can be used
Tamoxifen
Nonsteroidal aromatase inhibitors (anastrozole, letrozole)
Steroidal aromatase inhibitor (exemestane)
Pure anti-estrogens (fulvestrant)
For pre menopausal women, what hormone therapy can be used
GnRH agonists (goserelin and leuprolide)
Surgical oophorectomy
Tamoxifen
what drives tumor resistance
heterogeneity
Name 3 CDK4/6 inhibitors
CDK = cyclin dependent kinase
palbociclib
ribociclib
abemaciclib
How is testosterone converted to dihydrotestosterone
Type II 5-alpha reductase
AR is what kind of receptor
cytoplasmic
binding of AR to DHT does what
leads to translocation to the nucleus and action of genes that drive cell growth
What PSA level is suggestive of prostate cancer
> 6.5 ng/ml
GnRH analogs in men
just as in women, prolonged treatment with GnRH analogs leads to a decrease in LH production
transient increases in testosterone, but overall results in “chemical castration
Name GnRH analogs in men
leuprolide acetate and goserelin
use GnRH in men when
primary indication is for the palliative tx of advanced prostate cancer
Name GnRH antagonists for men
abarelix and degarelix
CYP17 is also
17alpha-hydrolase/C17,20 lyase
What does CYP17 do
CYP17 catalyzes the conversion of pregnenolone and progesterone to DHEA and androstenedione
What does abiraterone do
inhibit the function of CYP17
Name 5-alpha-reductase inhibitors
finasteride
dutasteride
what does finasteride do
inhibits type II isoform of 5-alpha-reductase
what does dutasteride do
inhibits type I and type II isoform of 5-alpha reductase
Prolonged use of 5-alpha-reductase inhibitors does what
select for more aggressive AR-independent tumors
Name androgen receptor (AR) antagonists
enzalutamide
darolutamide
apalutamide
AR antagonists approved for what
metastatic and non-metastatic prostate cancer
177Lu-PSMA-617 is
a Purdue success story
describe 177Lu-PSMA-617
- 177Lutetium (Lu) is a radioisotope.
- 177Lu is conjugated to a peptide that binds to Prostate Specific Membrane Antigen (PSMA).
- In this way the radiation is effectively “delivered” to the prostate tumors.
- 177Lu radiation only works over short distances, limiting damage to surrounding tissues.
Mechanisms of resistance to endocrine therapy for prostate cancer
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).
Development of new treatments for CRPC is an active area of research.
