Lecture 2 - Anti-Cancer Endocrine Therapies Flashcards
Understand the use of corticosteroids in lymphoid cancers
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
Steroid hormones: molecular action
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
Inhibition of steroid signaling
two major strategies: stop steroid receptor function or decrease production of steroids
Example glucocorticoids
methylprednisolone, prenisolone, dexamethasone
Understand the underlying principles governing the antineoplastic activity of hormonal therapies
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
What hormone is produced in the hypothalamus
GnRH
What hormone is produced in the pituitary gland
LH/FSH
Hormones and breast cancer
hormone therapy in breast cancer generally limited to ER+/PR+ tumors
Understand diagnostic determinants required for endocrine therapy
ER+ tumors will be treated with endocrine therapy
there are 4 subtypes of breast cancer that are determined by molecular diagnostics
Breast tumor subtypes
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
Selective estrogen receptor modulators (SERMs)
tamoxifen, toremifene, clomiphene
prevent ER signaling by binding to ER and causing an inactive complex
Selective estrogen receptor degraders (SERDs)
fulvestrant and raloxifene
prevent ER signaling by causing degradation of ER
Tamoxifen
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
Understand the mechanisms of action of estrogen receptor inhibitors both agonist and antagonist
SERMs can act as eithter agonist or antagonist
SERMs: coactivator or corepressor is tissue specific
SERDs: not tissue specific
Tamoxifen estrogen antagonist effects
in brain and breast
blocks estrogen-dependent breast cancer cell proliferation
hot flashes due to anti-estrogen effects
Tamoxifen estrogen agonist effects
in bone, blood, and endometrium
increased incidence of endometrial cancer
preservation of bone density in postmenopausal women, blocks bone resorption
in blood, increased coagulability
Tamoxifen used to treat
resected ER+/PR+ breast cancer
1st drug approved for breast cancer prevention in high-risk patients
Raloxifene estrogen antagonist effects
brain: hot flashes, thermoregulation
breast: preventive to breast cancer
uterus: NO endometrial hyperplasia
Raloxifene estrogen agonist effects
blood: increased coagulability
bone: blocks bone resorption
Fulvestrant and Elacestrant
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
Understand the mechanism of action of the aromatase inhibitors
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
Aromatase inhibitors block synthesis of
estrogens, but not androgens or progesterone
Primary target of aromatase inhibitors is
peripheral tissue (adipose tissue) - not ovary
adipocytes are a source of estrogen in postmenopausal women - aromatase in adipocytes converts androstenedione –> estrone –> estradiol
Primary application of aromatase inhibitors is
estradiol suppression in postmenopausal women
Imidazole-based non-steroidal aromatase inhibitors
anastrozole and letrozole
competitive inhibitors against aromatase
Letrozole and anastrozole
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
Steroidal aromatase inhibitor
exemestane inhibitor - structurally similar to androstenedione - actual hormone
Exemestane
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
FSH and LH are controlled by
feedback inhibition
LH directly activates expression of chol-SCC
FSH directly acticates (increase expression) of aromatase
Control of estrogen and progesterone levels by feedback inhibition
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
Chronic administration of GnRH analogues
downregulates pituitary GnRH receptors and –> pituitary desensitization; this then blocks gonadotropin secretion
decreased FSH leads to decreased aromatase and decreased estrogen
Understand the mechanisms of action and side effects of GnRH analogs
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
GnRH analogs
GnRH
leuprolide
goserelin
Leuprolide, goserelin, triptorelin
long term SEs: hot flashes and sexual dysfunction
transient worsening of sx related to initial agonist effects
primary indication for premenopausal breast cancer
For postmenopausal women w/ ER+ disease
tamoxifen
anastrozole and letrozole
exemestane
fulvestrant
For premenopausal women
goserelin and leuprolide
surgical oophorectomy
tamoxifen
Estrogen and steroid receptors are found in
the cytosol
Understand the mechanisms of action of the AR antagonists, compared to 5-alpha-reductase and CYP17 inhibitors
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
Androgen receptor is a
cytoplasmic receptor
AR is amplified in prostate cancer
Blood serum levels of ________ is used as a biomarker
prostate specific antigen
>6.5 ng/mL is suggestive of prostate cancer
Just as in women, prolonged treatment with GnRH analogues leads to
a decrease in LH production
transient increases in testosterone, but overall results in chemical castration
GnRH analogs in men
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
GnRH antagonists in men
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
How else can we prevent DHT production
CYP17
Abiraterone
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
How else do we block AR signaling
androgen receptor antagonists
Androgen receptor antagonists
enzalutamide, apalutamide, darolutamide
full antagonism, full inhibition
Enzalutamide, apalutamide, darolutimide
higher affinity binding to AR
prevents AR translocation to nucleus
inhibits AR binding to DNA
for metastatic and non-metastatic prostate cancer
Mechanism of resistance to endocrine therapy
castration resistant prostate cancer
from mutations in AR that result in androgen independent activation and prevent binding of AR antagonists
