Exam 1 Lecture 2 Flashcards
most commonly mutated gene in cancer
P53
can you get to estrogens without going through androgens? What is the order?
No, you must go through androgens to get to estrogens
Progestin–>androgen–>estrogen
What enzyme forms pregninolone
P 450 SCC
What happens to pregninolone? What is it hydroxylated by? What does it turn to?
17-alkyl hydroxylase hydroxylates pregninolone to 17-a- hydroxy pregninolone
What happens to 17- a- hydroxy pregninolone? in body
17, 20 lyase converts 17-a- hydroxy pregninolone to dehydroepiandosterone
What happens to dehydroepiandosterone in body
Dehydroapiandosterone is converted to androstenediol , which is converted into testosterone
What happens to testosterone in body
Testosterone is converted to dihydrotestpsterone (DHT) by 5-a reductase
What happens to androstenedione and testosterone in body?
androstenedione is converted to estrone and testosterone is converted to estradiol
What is the most active estrogen in body
Estradiol
Collective steps from Pregninolone to estradiol/estrone
- P 450 SCC forms pregninolone
- 17-alkyl hydroxylase hydroxylates pregninolone to 17-a hydroxy pregninolone
- 17, 20 Lyase converts 17-a- hydroxy pregninolone to dehydroepiandosterone
- dehydroepiandosterone is converted to androstenediol, which is converted into testosterone
- Testosterone is converted to DHT by 5-1 reductase
- ANdrostenedione and testosterone are converted by aromatase to either estrone or estradiol
Understand the use of corticosteroids in lymphoid cancers
- pediatric acute lymphoblastic leukemia
- multiple myeloma
-lymphomas
When are glucocorticoids used in chemo
Used as palliative care to reduce inflammation, edema e.t.c
Can be used to reduce hypersensitivity, nausea and vomiting and immune related adverse effects
What are the most common glucocorticoids
Methylprednisolone, Prednisolone, Dexamethasone
When are hormonal therapies used in cancer
Disease specific… only for hormone dependent cancers
Breast cancer, Prostate cancer, Endometrial cancer
What do hormone therapies target
Estradiol (breast and endometrial)
Dihydrotestosterone(DHT) (prostate)
molecular activity of steroidal hormones?
Only unbound hormones can diffuse into target cell (if bound to plasma protein, carrier wont cross)
Steroid hormone receptors are in cytoplasm or nucleus.
receptor-hormone complex forms and binds to DNA. This either activates or represses one or more genes.
activated genes create new mRNA that moves to cytoplasm and translation produces new protein.
What are the two major strategies to inhibition of steroid signaling?
- stop steroid receptor function
- Decrease production of steroids
Which tumors are likely to be well differentiated and which ones are more likely to be poorly differentiated
ER (+) are well differentiated and ER (-) are poorly differentiated. ER= estrogen receptors
Which tumors have a higher growth factor? Well differentiated tumors or poorly differentiated tumors
Poorly differentiated tumors have higher growth fractions. (thus are more reactive to cytotoxic agents as opposed to hormonal agents)
Which tumors have a better prognosis(ER+ or ER-)
WHat about when PR (progesterone receptor is involved)
ER+
Even better prognosis with ER+/PR+ tumors
what type of breast cancer is hormone therapy used in?
ER+/PR+
Where do estrogen receptors bind Estrogen in cell
In cytoplasm
Where is LH (leutenizing hormone ) produced? Andosterone is converted to estrone by?
Pituitary gland
Andristenedione is converted to estrone by CYP 19 (aromatase)
ER+ tumors will be treated with
Endocrine therapy
The range of ER positivity to be treated with endocrine therapy?
about 10%
What are the 4 different types of breast cancer?
- Luminal A, Luminal B
- HER-2
- Basal like
- claudin low
Describe Luminal A and B breast tumor subtypes
Luminal A and B are more differentiated and are the most estrogen and progesterone receptor positive. They are also the most responsive to endocrine therapy.
What is HER 2
Type of cancer cell that is a receptor tyrosine kinase (oncogene)
What breast tumor subtype is BRCA 1
basal like
Describe basal like and claudin low cancers
They are triple negative breast cancers (no estrogen, progesterone receptor or HER-2), will all be treated by cytotoxics.
What is the most used drug in (ER+) breast cancer
tamoxifen
Is tamoxifen a prodrug? If yes what is it hydrolyzed into?
yes it is a prodrug. It is metabolized into 4- hydroxy tamoxifen
What is a SERM? Name a SERM drug?
SERM is a selective estrogen receptor modulator. Tamoxifen is a SERM. It has both agonist and antagonist effects depending on what tissue it is in.
What does tamoxifen bind? Where is it an agonist? Where is it an antagonist?
Tamoxifen binds estrogen receptors. It has antagonist effects in brain and breast. Agonist in bone.
What enzyme metabolizes tamoxifen to 4-hydroxy tamoxifen?
CYP2D6.
Estrogen antagonist effects of tamoxifen
Blocks estrogen dependent breast cancer cell proliferation
Hot flashes due to anti estrogen effects
Is tamoxifen effective for both pre and post menopausal women?
Yes
What type of cell warants tamoxifen usage
ER/PR + breast cancer
What is the 1st drug approved for breast cancer prevention
Tamoxifen
Tamoxifen is much less effective in which type of cell
CYP2D6
Adverse effects of tamoxifen in different parts of the body
Brain- ER antagonist (hot flashes, thermoregulation)
blood- ER agonist (increased coagulability, clot and VTE risk)
Uterus- ER agonist (endometrial hyperplasia)
Beneficial effects of tamoxifen in different body parts
Breast- antagonist (antiproliferative)
bone- partial agonist (blocks bone resorption)
Raloxifene adverse effects
Only differs from raloxifene in that there is no endometrial hyperplasia in uterus
Raloxifene beneficial effects
Same as tamoxifene only differs in uterus as raloxifene has no endometrial hyperplasia. It also increases bone mass is osteoporosis.
What is a SERD? What are some SERD drugs?
SERD= selective estrogen receptor down- modulator.
Fluvestrant and elacestrant are SERD drugs.
SERD is a pure ER antagonist that has no agonist effects (elacestrant acts as a partial agonist at low doses and full SERD at high doses)
What reactions does aromatase control
Androstenedione—> estrone
Testosterone—-> estradiol
Do inhibitors of aromatase block the synthesis of estrogens? androgens? progesterone?
Only blocks synthesis of estrogens, but not androgens or progesterone.
What is another source of estrogen in post menopausal women?
adipocytes
primary target of aromatase inhibitors? (is it ovary or adipose tissue)
Peripheral tissue (adispose tissue)
what is the primary application of aromatase inhibitors
Estradiol suppression in post menopausal women
What are some imidazole based non-steroidal aromatase inhibitors? How do they work? Primary indication?
Anastrazole and letrozole.
Are competitive inhibitors of aromatase activity.
Tx of breast cancer in post menopausal women
Name the steroidal aromatase inhibitor
Exemestane
How does exemestane work?
Is a suicide inhibitor. Aromatase thinks that exemestane is androstenedione due to structural similarity. Intermediate binds irreversibly to aromatase at active site and inactivates enzyme.
Primary indication of exemestane
Primary indication is tx of estrogen responsive breast cancer in POST MENOPAUSAL women
Is exemestane in pre or post menopause? Both?
Post menopause
How does fluvestrant work?
Fluvestrant inhibits the activity of the estrogen receptor throughout the body
The HPA axis is regulated by
feedback inhibition
What are the roles of FSH and LH in steroid hormone biosynthesis
LH activates chol-scc enzyme (side chain cleaving enzyme)
FSH increases expression of aromatase
What are LH and FSH regulated by
Feedback mechanism
What is the effect of chronic administration of GnRH analogues
Chronic administration of GnRH analogues downregulate pituitary GnRH receptors. And leads to pituitary desensitization.
leads to severe loss of estrogen within 3-4 weeks
inhibition of estrogen dependent breast cancer in women.
What is the effect of acute administration of GnRH analogues
Acute administration induces surge of LH and FSH
Acute increase in all steroidal hormone levels.
Corresponding transient increase in tumor growth
What are some GnRH analogues
Leuprolide
Goserelin
Triptorelin
Long term side effects of GnRH analogues
Hot flashes and sexual dysfunction
primary indication of GnRH analogues
in women
PREMENOPAUSAL breast cancer
Summary of hormonal therapy in breast cancer
For postmenopausal women with ER+
-Tamoxifen
-Nonsteroidal aromatase inhibitors (anastrazole, letrozole)
-Steroidal aromatase inhibitor (exemestane)
- Pure anti-estrogens (fluvestrant)
For premenopausal women
- GnRH agonist (goserelin and leuprolide)
-surgical oophorectomy
-tamoxifen
What is the prostate cancer staging? What is it called? What are the grades? Which ones are differentiated? Undifferentiated?
Called the gleason score
- Small uniform glands
- more space between glands
- infiltration of cells from glands at margin
- irregular masses of cells with few glands
- lack of glands
Well differentiated is 1
poorly differentiated is 5. There is a gradient
What happens to testosterone in prostate
Testosterone is rapidly and irreversibly converted by type II 5-a reductse to DHT (dihydrotestosterone) in prostate cells.
What happens to dihydrotestosterone in prostate
DHT binds to androgen receptor (AR) in prostate cells
DHT-AR complex is activated and translocated to nucleus
DNA binding stimulates transcription of AR responsive genes.
describe AR signaling
AR is a cytoplasmic receptor
AR can be amplified in prostate cancer
Binding of AR to DHT leads to translocation to nucleus and action of genes that drive cell proliferation
describe the role of PSA is diagnosis of prostate cancer. What can it also be raised by
High level of PSA can be a sign of prostate cancer.
It can also be a sign of UTI, vigorous exercise, Medication, recent ejaculation or anal sex
Effect of GnRH analogues in men
Just as in women, prolonged tx with these analogues lead to decrease in LH production.
Transient increase in testosterone, but results in “chemical castration” in men within 3-4 weeks
GnRH analogues
Leuprolide acetate
Goserelin
Triptorelin
primary indication of GnRH
Palliative tx of advanced prostate cancer.
What is the transient worsening of symptoms related to in GnRH
initial agonist effects “flare”
Long term side effects of GnRH analogues in men
Long term side effects related to testosterone- deficient feminization
Gynecomastia
sexual dysfunction
GnRH antagonists in men drugs
Degarelix, relugolix
primary indication of GnRH antagonist
advanced prostate cancer with need for androgen deprivation therapy
difference between GnRH analogues and antagonist
GnRH antagonist does not lead to flare of testosterone production
What are the long term side effects of GnRH antagonist
Same as GnRH analogues (gynecomastia and sexual dysfunction.
What is another way we prevent DHT production
Abiraterone (zytiga)
How does abiraterone (zytiga) prevent DHT production
Inhibits function of 17-a-hydroxylase and C 17,20 lyase
it is a steroidal analogue
What is a common side effect of abiraterone
Increase in cholesterol
What is another way to block AR signaling
Androgen receptor (AR) antagonists
Name AR antagonists
Enzalutamide
Apalutamide
Darolutamide
How do AR antagonists block AR signaling
All inhibit AR binding to DNA
Prevent AR translocation to nucleus
What are AR antagonists approved in?
in men
Metastatic and non metastatic prostate cancer
MOA of resistance to endocrine therapy in prostate cancer
Mutations in AR can arise that result in androgen independent activation and prevent binding of AR antagonists.
This is referred to as castration resistant prostate cancer (CRPC)
What is CRPC
castration resistant prostate cancer (CRPC)
mutations in AR that result in androgen independent activation and prevent binding of AR antagonists
