Anti-cancer Endocrine Therapies - Dr. Wendt Flashcards
What is used to describe a wart produced by an HPV infection?
papilloma
Increasing in cell size is _______ a hallmark of cancer
NOT
Molecular pathology is different from traditional pathology because…
…it uses some kind of genetic testing to indicate therapy or predict for tumor recurrence
T or F: Gene expression analyses like Oncotype Dx are currently used to indicate specific therapies
False
Hemotoxylin is used in pathology to stain the nucleus of cells a __________ color
blueish/purple
Which of the following terms is associated with substitution of tissue type for another?
Metaplasia
HER2 is an example of a ______________
oncogene
BRCA is an example of a _____________
tumor suppressor
Hormones regulate the proliferation in these three cancers
- breast
- prostate
- endometrial
Where are common hormones produced?
- adrenal glands
- ovary
- testis
- adipocytes
Recall steroid receptor signal transduction
- Receptors are cytosolic hormone-dependent transcription factors
- When ligand enters cell and binds to receptor, ligand-receptor complex translocated to nucleus, binds to DNA promoters and induces transcription
Most common/lethal hormone cancers
- prostate
- breast
- lung
Which CYP enzyme associated with aromatase?
CYP19
Molecular action of steroid hormones
- Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell
- Steroid hormone receptors are in the cytoplasm or nucleus
- The receptor-hormone complex binds to DNA and activates or represses one or more genes
- Activated 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
Two major classes of endocrine therapy
- Stop steroid receptor function
2. Decrease production of steroids
Hypothalamus produces _______ that impacts the _______
GnRH; pituitary gland
The pituitary gland produces _______ that impacts _______
FSH & LH; Estrogen + Progesterone
Estrogen receptors (ER) and progesterone receptors (PR) ____________ in tumors
measurable
Well differentiated tumors are more likely to be ____
ER+
poorly differentiated tumors are generally ____
ER-
Remember that poorly differentiated tumors have ________ growth fractions and are generally more ________ to cytotoxic agents
higher; sensitive
Highly significant ___________ between presence of estrogen receptor and the likelihood of response to hormone therapy
correlation
Correlation is even _________ for __________ tumors
PR is estrogen inducible and is a measure of biological response to estrogen
stronger; ER+/PR+
Hormone therapy in breast cancer generally limited to _________ tumors. Can be a useful addition to other chemotherapy in __________ tumors.
ER+/PR+; ER+/PR-
DCIS means…
ductal carcinoma in situ
estrogen receptor primarily binds estrogen where in the cell?
cytoplasm
what enzyme converts androstenedione to estrone?
CYP19
Estrogen receptor positive tumors will be treated with _____________. Estrogen receptor expression and or function can be lost by numerous mechanisms. This is an extremely important ___________ in therapy.
endocrine therapy; determinate
A range of ER positivity are considered for endocrine therapy, usually…
~10%
breast tumor subtypes (4)
- triple negative (ER-, PR-, HER2-)
- HER2+
- Luminal B
- Luminal A
Triple negative: % of breast cancers
15 - 20%
HER2: % of breast cancers
10 - 15%
Luminal B: % of breast cancers
20%
Luminal A: % of breast cancers
40%
Triple negative tumors respond best to…
chemotherapy (similar to other aggressive cancers)
Luminal A tumors respond best to…
endocrine therapy (e.g. antiestrogen or aromatase inhibitor)
About when was tamoxifen discovered…
~1977
Tamoxifen is a __________ that must be metabolized to ____________
prodrug; 4-OH-TAM
Tamoxifen characteristics
- SERM
- Complex pharmacologic actions – both agonist and antagonist activities
- CYP2D6 converts tamoxifen to high-affinity hydroxylated and demethylated metabolites
- Binding to estrogen receptor inhibits both translocation and DNA binding
- Blocks estrogen-dependent breast cancer cell proliferation
- Estrogen agonist effects (1. Incidence of endometrial cancer increased 3-fold 2. Preservation of bone density in postmenopausal women)
- Other estrogen antagonist effects (Hot flashes)
- Drug is effective in both pre- and postmenopausal women
Tamoxifen brand
Nolvadex
Tamoxifen estrogen antagonist effects
hot flashes
Tamoxifen primary use
- Primary use is treatment for resected ER+/PR+ breast cancer (3-5 years Rx)
- Also used for the treatment of metastatic ER+/PR+ breast cancer
Tamoxifen was the first drug approved for…
…breast cancer prevention (reduces risk by 50% in women at high risk)
Tamoxifen dosage form
orally available
Tamoxifen is much less effective in patients with a common ________ variant
CYP2D6 (~ 10% of postmenopausal women with breast cancer carry this variant. Several known inhibitors of CYP2D6)
SERM Tamoxifen brain adverse effect
hot flashes, thermoregulation
SERM Tamoxifen breast beneficial effect
++antiproliferative
SERM Tamoxifen blood adverse effect
increased coagulability clots, VTE risk
SERM Tamoxifen uterus adverse effect
endometrial hyperplasia
SERM Tamoxifen bone partial agonist beneficial effect
blocks bone resorption
SERD Definition
Selective Estrogen Receptor Down-Modulator
Fulvestrant brand
Faslodex
Fulvestrant facts
“pure” ER antagonist that has NO agonist effects
Binds to ER and inhibits DNA binding rapid receptor degradation
Approved for treatment of ER+ metastatic breast cancer in postmenopausal women who have progressed on other antiestrogen therapy
Same target (ER) but different mechanism (receptor degradation)
May explain relative lack of cross-resistance with other antiestrogens
Administered as intramuscular injection once per month
Poorly solubility limit its effectiveness.
Fulvestrant dosage form
intramuscular injection once per month
What does aromatase do?
Aromatase catalyzes the demethylation of the enone ring of androgens to the aromatic ring in estrogens
Aromatases convert androstenedione estrone, and testosterone estradiol
Inhibitors block synthesis of estrogens but not androgens or progesterone
adipocytes are a source of _________ in postmenopausal women
estrogen
- Androstenedione produced in adrenal gland and released to circulation
- Aromatase in adipocytes converts androstenedione estrone
- Estrone then converted to estradiol
What is the primary target of inhibitors?
Peripheral tissue (adipose tissue) — not ovary
Primary application of aromatase is…
…estradiol suppression in post menopausal women
What are two imidazole-based NON-STEROIDAL aromatase inhibitors?
- anastrozole
- letrozole
letrozole brand
femara
anastrozole brand
arimidex
non-steroidal aromatase inhibitors
Potent and selective competitive inhibitor of aromatase activity
Primary indication is treatment of breast cancer in postmenopausal women
Drug is highly effective as first line therapy OR when started after 3-5 years of tamoxifen Rx
Taken orally everyday
Minimal toxicity (Increases extent of bone density loss – increased fractures vs. tamoxifen)
examples of steroidal aromatase inhibitors
- exemestane
- androstenedione
exemestane brand
aromasin
exemestane facts
Structurally related to androstenedione – “suicide inhibitor”
Acts as false substrate that aromatase converts to reactive intermediate
Intermediate binds irreversibly at active site and inactivates enzyme
Taken orally everyday
Primary indication is the treatment of estrogen-responsive breast cancer in *postmenopausal women who have progressed on antiestrogen therapy (Not used in premenopausal women)
Minimal toxicity (Hot flashes, occasional peripheral edema and weight gain, Increased cholesterol levels)
exemestane has ________ toxicity
Minimal toxicity (Hot flashes, Occasional peripheral edema and weight gain, Increased cholesterol levels)
What compound directly inhibits the activity of the estrogen receptor throughout the body?
fulvestrant
FSH and LH are controlled by…
…feedback inhibition
Chronic administration of GnRH analogues downregulates pituitary GnRH receptors which causes…
pituitary desensitization
Decreased FSH leads to __________ aromatase and decreased ___________
decreased; estrogen
What are gonadotropin releasing hormone analogs?
Peptide analogs of the neurohormone GnRH with modified amino acids to increase potency and reduce degradation.
Gonadotropin releasing hormone facts (hint: acute vs chronic impact)
Depot formulation suitable for slow-release following subcutaneous injection
Acute administration induces surge of LH and FSH (agonist effect) [Acute increase in all steroid hormone levels, Corresponding transient increase in tumor growth]
Chronic administration downregulates pituitary GnRH receptors and –> pituitary desensitization (Severe loss of estrogen within 3-4 weeks, Inhibition of estrogen-dependent breast cancers in women)
Two examples of GnRH analogues
- leuprolide acetate
- goserelin
Leuprolide acetate brand
lupron
goserelin brand
zoladex
GnRH analog facts
Transient worsening of symptoms related to initial agonist effects
Long term side effects: Hot flashes, Sexual dysfunction
Primary indication for women is for *premenopausal breast cancer
Side effects in women typical of antiestrogenic effects (menopausal)
Other LHRH analogs include Triptorelin, Buserelin.
Tx for postmenopausal women
- Tamoxifen
- Nonsteroidal aromatase inhibitors (anastrozole, letrozole)
- Steroidal aromatase inhibitor (exemestane)
- Pure anti-estrogens (fulvestrant)
Tx for premenopausal women
- GnRH agonists (goserelin and leuprolide)
- Surgical oophorectomy
- Tamoxifen
Essentially all patients that initially respond to endocrine therapies will develop _________.
resistance
Tumors are not homogenous. Tumor __________ drives resistance
heterogeneity
Several ___________ are being combined with ___________ inhibitors
anti-estrogens; cyclin-dependent kinase (CDK) inhibitors
Prostate cancer is a _______ _______ disease
slowly progressing
Prostate cancer staging: Gleason Score
1 2 3 4 5
(well-differentiated)
1: small, uniform glands
2: more space between glands
3: infiltration of cells from glands at margins
4: irregular masses of cells with few glands
5: lack of glands, sheets of cells
(poorly differentiated)
What is the most frequently diagnosed cancer among men in the US?
Prostate cancer
Most important risk factor for prostate cancer?
Age
- Extremely rare prior to age 40
- Rate of increase after 40 is the steepest of any cancer
Hormones and prostate cancer facts
Testosterone is rapidly and irreversibly converted by Type II 5- reductase to dihydrotestosterone (DHT) in prostate cells
- **Dihydrotestosterone binds to the androgen receptor (AR) in prostate cells
- **DHT-AR complex is activated and translocated to the nucleus
- **DNA binding stimulates transcription of AR responsive genes
Androgen receptor is a ____________ receptor
cytoplasmic
Androgen receptor can be __________ in prostate cancer
amplified
Binding of androgen receptor to dihydrotestosterone (DHT) leads to _____________ to the ________ and action of genes that drive cell growth
translocation; nucleus
What prostate specific antigen (PSA) value is considered 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 LH production.
Transient increases in testosterone, but overall results in “chemical castration” within 3-4 weeks.
GnRH analogues in men examples + facts
Primary indication is for the palliative treatment of advanced prostate cancer
Transient worsening of symptoms related to initial agonist effects (“Flare”)
Long term side effects related to testosterone-deficient “feminization” (Gynecomastia -breast enlargement-, Sexual dysfunction)
GnRH receptor antagonists
Blockade of the GnRH receptors has the same overall affect of decreasing Testosterone production
Affects are more immediate avoiding “tumor flare.”
Two examples of GnRH antagonists
- abarelix (plenaxis)
- degarelix (firmagon)
Abarelix facts
is also approved for treatment of prostate cancer
Degarelix facts
- Indicated for treatment of advanced prostate cancer
- Administered intravenously once a month
How else prevent DHT production? Abiraterone (Zytiga)
Inhibits the function of 17 a-hydroylase and C17,20 lyase
CYP17 catalyzes the conversion of pregnenolone and progesterone to DHEA and androstenedione.
Steroid analogue
Much higher step in hormone synthesis
Common side effect is increased levels of cholesterol
How else prevent DHT production? 5-alpha-reductase inhibitors examples (2)
finasteride and dutasteride
finasteride brand
propecia
dutasteride brand
avodart
finasteride fact
Inhibits type II isoform of 5-a-reductase
dutasteride fact
Inhibits type I and type II isoform of 5-a-reductase
How do 5-alpha-reductase inhibitors work?
May delay growth of benign prostate tumors
Prolonged use may actually select for more aggressive
AR-independent tumors
How else do you block AR signaling? AR antagonists (3)
- enzalutamide
- apalutamide
- darolutamide
AR receptor facts
Higher affinity binding to AR than previous “-lutamides”
Prevents AR translocation to the nucleus
Inhibits AR binding to DNA
Approved for both metastatic and non-metastatic prostate cancer. [SPARTAN trial looked at apalutamide, PROSPER trial looked at ezalutamide, ARAMIS trial looked at darolutamide]
These trials are bringing into question the “wait and watch approach.”
Purdue Success Story: 177Lu-PSMA-617
Developed by the Purdue start-up company, Endocyte. Sold to Novartis in 2018.
Breakthrough therapy designation in June 2021
- 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; 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.
