Anti-Cancer Endocrine Therapies - Mabe

Function of Aromatase aka CYP19

Catalyzes converstion of androstendione into estrone or testosterone and then into estradoil

Dexamethasone is a corticosteroid that has anti-cancer effects in the treatment of what?

Pediatric ALL, multiple myeloma, lymphomas

Corticosteroid treatment can be used as palliative care to do what?

Reduce inflammation, edema, and manage pain during chemotherapy

Corticosteroid treatment can be used to reduce what (not palliative)

Hypersensitivity reactions, n/v, and immune-related adverse effects

What do hormonal therapies primarily target?

Estradiol and dihydrotestosterone

Where are steroid hormone receptors located

cytoplasm or nucleus

Two major strategies to endocrine therapy

stop steroid receptor function and decrease production of steroids which is done primarily in the pituitary gland

Which hormone is produced in the pituitary gland?

LH

Estrogen receptor primarily binds estrogen where in the cell?

Cytoplasm

What converts androstendione to estrone?

Aromatase or CYP19

How does pregnenolone convert to 17a hydroxy pregnenolone?

17a hydroxylase

What converts 17a-hydroxy pregnenolone into dehydroepiandrosterone

17,20 lyase

Diagnostic determinants for estrogen therapy

They have ER+ tumors, estrogen receptor expression and/or function may be lost by numerous mechanisms, ER+ status are hetergenous but generally around 10%, ER+/PR+ have a strong correlation as PR is estrogen-inducible

Tamoxifen: how it works and it’s MOA. Who can it be used on on? What does it treat?

Metabolized by CYP2D6 into 4-OH-TAM. It is a serm so it is both an agonist and antagonist. Can be used on high risk breast cancer patients. Treats resected ER+/PR+

Explain how SERMs like Tamoxifen are both agonist and antagonist

It is agonist because it increases endometrial cancer by 3x and preserves bone density in postmenopausal women. It is an antagonist because it blocks estrogen dependent breast cancer cell proliferation and causes hot flashes due to its anti-estrogen effects

SERDs

1) Example

2) MOA

3) Who is it approved for

Fulvestrant and Elacestrant. Binds to ER and inhibits DNA which causes rapid receptor degradation. Approved for ER+ postmenopausal women who progressed on other antiestrogen therapy

Fulvestrant and Elacestrant are both SERDs but how do they differ?

Fulvestrant is a pure ER antagonist with no agonist effects. Elacestrant is a partial agonist at low doses and full SERD at high doses

Primary target of Aromatase inhibitors and why

Targets adipocytes in the peripheral tissue as they are a source of estrogen in postmenopausal women and this is where it converts androstenedione into estrone

Non-Steroidal Aromatase Inhibitors:

1) Examples

2) MOA

3) Who it is used for and how it is used in terms of what line of therapy

Letrozole and Anastrozole. Selective competitive inhibitor of aromatase activity. Used in postmenopausal women as a highly effective first line therapy or 3-5 years after tamoxifen

Which compound directly inhibits the activity of the estrogen
receptor throughout the body?
A. Letrozole
B. Exemestane
C. Tamoxifen
D. Fulvestrant

D. Fulvestrant

Steroidal Aromatase Inhibitor

1) Example

2) MOA and structural importance

3) Used for

Exemestane. Intermediates binds irreversibly at the active site and inactivate the enzyme. It is considered a suicide inhibitor as it’s structurally related to androstenedione. Used only for postmenopausal women who progressed on antiestrogen therapy

Which compound is referred to as a SERM?
A. Letrozole
B. Exemestane
C. Tamoxifen
D. Fulvestrant

Tamoxifen

Explain what happens with chronic administration of GnRH analogues

Downregulation of pituitary GnRH receptors which causes pituitary desensitization. This decreases FSH leading to decreased aromatase and estrogen

MOA of GnRH analogues

Acute administration causes surge of LH and FSH which causes transient tumor growth and increase in steroid hormone levels. Chronic administration causes downregulation of pituitary GnRH receptors which leads to pituitary desensitization. This decreases FSH which decreases aromatase and thus decreases estrogen

GnRH Analogs

1) Examples

2) used for

3) SE

Leuprolide, Goserelin, Triptorelin. Used for premenopausal breast cancer. Side effects of hot flashes and sexual dysfunction

If a women needs hormonal therapy in breast cancer and is postmenopausal w/ER+ disease…what can you use?

Tamoxifen, aromatase inhibitors, and pure anti-estrogens like fulvestrant

If a women needs hormonal therapy in breast cancer and is premenopausal…what can you use?

GnRH agonists, surgical oophorectomy, and tamoxifen

Androgen Receptor (AR) signaling

1) Where are they located

2) State in prostate cancer

3) MOA

Cytoplasmic receptor that is amplified in prostate cancer. AR binds to DHT which causes translocation to nucleus and action of genes that increase cell growth

normal range for PSA that is suggestive of prostate cancer

>6.5

Use of GnRH analogs

Palliative treatment of advanced prostate cancer

GnRH antagonists in men

1) example

2) used for

3) SE

Degarelix and relugolix. Used for advanced prostate cancer with need for androgen deprivation therapy with no flare in testosterone. SE of gynecomastia and sexual dysfunction

Abiraterone

1) MOA

2) Side effects

CYP17 inhibitor that blocks the conversion of pregnenolone and progesterone to DHEA nad androstenedione. SE of increased cholestero levels and hypertension

AR antagonists

1) Examples

2) MOA

3) used for

Enzalutamide, Apalutamide, and Darolutimide. They have higher binding affinity to AR. They prevent AR translocation to nucleus and inhibits AR binding to DNA. Used for both metastatic and non-metastatic prostate cancer

What is unique about the action of the Tamoxifen as compared to
Fluvestrant?
a) Tamoxifen induces ER degradation
b) Tamoxifen prevents ER shuttling to the nucleus
c) Tamozifen ejects ER from the cell
d) Tamoxifen activates ER in bone

d) Tamoxifen activates ER in bone

Which of the following is not a hormone responsive cancer type?
a) Breast cancer
b) Ovarian cancer
c) Prostate Cancer
d) Endometrial cancer

b) Ovarian cancer

Which of the following is only used in the postmenopausal setting?
a) Letrozole
b) Tamoxifen
c) Leuprolide
d) Raloxifene

Letrozole

Which compound acts directly on AR?
a) Leuprolide
b) Abiraterone
c) Degarelix
d) Enzalutamid

d) Enzalutamid