Anti-cancer Endocrine Therapies Flashcards
In what way are corticosteroids used in cancer treatment?
- Used as pallative care to reduce inflammation and manage pain during the chemo
What are the three hormonal therapies that are disease specific?
- Breast, Prostate, Endometrail Cancers
What is the molecular action for the steroid hormones?
- Hormone passes into the cytoplasm where it binds to the receptor then it moves into nucleus
- DNA will then transcript and tranlate
What are the two major classes of inhibiting steroid signaling?
- STOP steroid receptor function
- DECREASE production of steroids
Briefly explain the Hypothalamus-Pituitary-Reproductive Axis?
- Hypothalamus makes GnRH that goes to the Pituitary
- Pituitary makes LH/FSH that goes to the Reproductive Tract
- Reproductive Tract makes estrogen/tesosterone
What receptors can be measured in tumors?
- Estrogen and Progesterone
What hormone is produced in the pituitary gland?
- LH/FSH
Where does the estrogen receptor primarily bind estrogen in the cell?
- In the cytoplasm
What enzyme converts andostenedione to estrone making estrodial?
- CYP19 or aromatase
What SERM is used within the treatment of Breast Cancer?
- Tamoxifen & Raloxifene
What is Tamoxifen?
- Its a prodrug that get metabolized by CYP2D6
- FIRST drug approved for prevention of breast cancer
- PRE and POSTmenopausal women
What is the mechanism of action for Tamoxifen?
- MOA: both AGONIST & ANTAGONIST so it can block or active estrogen receptors
How does Tamoxifen act as an antagonist?
- Inhibits both translocaiton and DNA binding
- Stops breast cancer cell proliferation
How does Tamoxifen act as an agonist?
- Increases the endometrail cancer risk by 3x
- Increase bone density in postmenopausal women
In what population is Tamoxifen effective in?
- BOTH pre and postmenopausal women
When should Tamoxifen be used?
- Resected ER+/PR+ breast cancer [3-5 years] OR…
- Metastatic ER+/PR+ breast cancer
What does Raloxifene [SERM] do differently than Tamoxifen?
- NO endometrial hyperplasia
In what way does a SERD affect cancer?
- Binds to the estrogen receptor then causes it to degraded
What SERD is used in breast cancer?
- Fulvestrant
What is important to know about Fulvestrant?
- “pure” Er antagonist = binds to ER and inhibits DNA binding causing the rapid degradation
- Treatment for ER+ metastatic breast cancer in POSTmenopausal women
What is the function of Aromatase [CYP19]?
- Helps convert androstenedione to estrone = estrogen
What is the mechanism of action for the Aromatase inhibitors?
- Block the synthesis of estrogens but NOT androgens or progesterone
What is one way that POSTmenopasual women make estrogen?
- Adiposytes are a source of estrogen
- CANNOT target oravies as they make too much
Are the the two classes of Aromatases?
- Imidazole-Based non-steroidal & Steriodal inhibitors
What are the non-steroidal aromatase inhibitors?
- Anastrozole & Letrozole
What is the mechanism of action for Anastrozole & Letrozole?
- Competitve inhibitors for aromatase inhibition
What is important to know about Anastrozole & Letrozole?
- ER+ treatment of breast cancer in POSTmenopausal women
- 1st line OR 3-5y after tamoxifen
What is the steroidal aromastase inhibitor?
- Exemestane
What is the mechanism of action for Exemestane?
- “suicide inhibitor”: binds to the active site of aromatase and reacts; covalently modifying it to inactive it; only way to make it work would be to destory it
What is important to know about Exemestane?
- ER+ breast cancer in POSTmenopausal women
What are some of the toxicities for Exemestane?
- Hot flashes, weight gain, increase cholesterol
Which compound directly inhibits the activity of ER throughout the body?
- Fulvestrant [pure antagoinst]
What compound is known as a SERM?
- Tamoxifen
Breifly explain the Hypothalamic-Pituitary-Reproductive axis?
- Hypothalamus makes GnRH that goes to pituitary
- Pituitary makes LH/FSH that goes to reporducitve
- Reproductive makes Estrogen or Testosterone
Explain a way that FSH and LH are controlled?
- Feedback inhibition: when there are too high of estrogen or testosterone levels in the body; it will stop the production of GnRH from being produced
What is the mechanism of action for the Gonadotropin Releasing Hormone analogs?
- Induces a surge of LH & FSH that will make A LOT of estrogen or testosterone then shutdown the hypothalamus from making GnRH
- SAME in men
What are the two GnRH analogs?
- Leuprolide & Goserelin
What is important to know about Lueprolide & Goserelin in women?
- Have that surge
- Indicated for PREmenopasual breast cancer = shuting down estrogen IN the ovaries
What breast cancer drugs are good for POSTmenopausal women?
- Tamoxifen [1st]
- Anastrozole & Letrozole
- Exemestane
- Fulvestrant
What breast cancer drugs are good for PREmenopausal women?
- Goserelin & Leuprolide
- Surgery
- Tamoxifen [1st]
What is prostate cancer?
- A slowly progressing disease that is commonly diagnosed in men that is caused by rapidly and irreversibly converted by Type II 5-a reductase to dihydrotestosterone in protstate cells
What is the normal range for Prostate Specific Antigen [PSA]?
- > 6.5 ng/ml = possible cancer
What are the GnRH Analogs that are used in men?
- Same as women; Leuprolide & Goselerin
What is important to know about Leuprolide & Goselerin in men?
- Can cause Gynecomastoa [breast enlargement] and sexual dysfunction
What is another drug that we can use to prevent DHT [dihydrotestosterone] production ?
- Abiraterone
What is the mechanism of action for Abiraterone?
- Inhibits the function of 17 a-hydrolase and C17,20 lyase
- Causes increased cholesterol
What are the androgen receptor antagonists?
- Enzalutamide, Apalutamide, Darolutamide
What is the mechanism of action for the Androgen receptor antagonist?
- Inhibits AR from binding to DNA; preventing translocation to the nucleus
What is important to know about the AR Antagonists?
- Approved for BOTH metastatic and non-metastatic prostate cancer
What is unique about the action of tamoxifen as compared to fluvesterant?
- It can activate ER in the bone
