Lecture 2 - Anti-Cancer Endocrine Therapies Flashcards
(49 cards)
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
