T6 - IE2 - Oncology - Elsaid - Hormonal Agents

Aromatase inhibitors do NOT work on ______-________ women due to the negative feedback system

- (do NOT work on) pre-menopausal (women)

Aromatase inhibitors do not work on pre-menopausal women due to the __________ ________ system

- (due to the) negative feedback (system)

_________, _____, ______ regulate the hypothalamus-pituitary-gonadal axis via negative feedback inhibition

- GnRH

- LH

- FSH (regulate)

HPG axis

Hypothalamus-pituitary-gonad axis,

the negative feedback loop that regulates sex-hormone production.

Hypothalamus (female) has both ________ and _______ receptors similar to the pituitary gland

- (has both) estrogen

- progestin (receptors)

Hypothalamus (male) has both __________ and _______ receptors similar to the pituitary gland

- (has both) androgen

- estrogen (receptors)

Estrogen signaling - principal estrogenic hormone is _____ __________ (____)

- 17β estradiol (E2)

estrogen (E2)

17β estradiol

Estrogen signaling - E2 is synthesized by _________ of testosterone in the ovaries and other tissues

- (synthesized by) aromatization (of testosterone)

Estrogen signaling - E2 is synthesized by aromatization of testosterone in the __________ and other _________

- ovaries

- (and other) tissues

E2 mediates its effects via two types of receptors ERα and ERβ (both are nuclear receptors; i.e., transcription factors)

Estrogen signaling - E2 mediates its effects via two types of receptors _____ and _____ (both are _________ receptors; i.e., ____________ factors)

- ERα

- ERβ

- nuclear (receptors)

- transcription (factors)

Estrogen signaling - binding of E2 (an ER _________) to ER results in _________ of the receptor and recruitment of ____-________ proteins.

The chromatin network opens up and transcription of target genes is initiated

- (an ER) agonist

- dimerization (of the receptor)

- co-activator (proteins)

Estrogen signaling - binding of E2 (an ER agonist) to ER results in dimerization of the __________ and recruitment of co-activator proteins

The chromatin network ________ up and _________ of target genes is initiated

- (dimerization of the) receptor

- (network) opens (up)

- transcription (of target genes is initiated)

Estrogen signaling - estrogen _______ a wide array of cell ________, and modulates cell __________ in normal and specific type of cells

- modulates (a wide array)

- (cell) functions

- (modulates cell) proliferation

Estrogen signaling - E2 and Estrogen antagonists __________ interact with ER resulting in ____________ of target genes

- differentially (interact)

- transcription (of target genes)

Drug classes that target the function of ER2 in ER+ Tumors

SERMs

- Tamoxifen

- Raloxifene

- Toremifene

SERD

- Fluvestrant

Aromatase inhibitors

- aminoglutethimide

- anastrozole

E2 in ER+ cell results in: _________ cellular proliferation and increase in ___________

- enhanced (cellular proliferation)

- (increase in) angiogenesis

Thus, SERMs, SERD and aromatase inhibitors target E2 function in ER+ tumors

E2 in ER+ cell results in: reduction in __________ and estrogen was also shown to induce growth factor-induced activation of _________ ________ _______ family

- (reduction in) apoptosis

- (induced activation of) Human Epidermal Receptor (family)

Thus, SERMs, SERD and aromatase inhibitors target E2 function in ER+ tumors

SERMs, SERD, and aromatase inhibitors target _____ function in ER+ tumors

- (target) E2 (function)

SERMs also bind to the _________ receptor

- estrogen (receptor)

Does not agonize or antagonize but MODULATES the site

SERDs ________/_______ the estrogen receptor

- downregulate / degrade (the estrogen receptor)

Aromatase inhibitors inhibit _____ ____________

- (inhibit) E2 biosynthesis

SERMs

selective estrogen receptor modulators

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: indicated for the __________ of breast cancer in _____-____ individuals and as __________ treatment in ER+ breast cancer in pre- and post-menopausal females

- prevention (of breast cancer)

- high-risk (individuals)

- adjuvant (treatment)

Adjuvant = in addition to surgery and chemotherapy

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: indication for the prevention of breast cancer in high-risk individuals and as adjuvant treatment in _______ breast cancer in _____ and _______-________ females

- ER+ (breast cancer)

- pre-

- post-menopausal (females)

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: can be used in BOTH _____ and _____-________ females

UNLIKE, aromatase inhibitors, which can only be used in _______-________ women

- (in BOTH) pre-

- post-menopausal (females)

- (can only be used in) post-menopausal (women)

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: acts as an _________ in breast cancer cells, binding to the _____ results in dimerization and recruitment of corepressors that prevent gene __________

- (acts as an) antagonist

- (binding to the) ER

- (prevent gene) transcription

ER

estrogen receptor

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: acts as an antagonist in breast cancer cells. Binding to ER results in _________ and recruitment of ___________ that prevent gene transcription

- (results in) dimerization

- (recruitment of) corepressors

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen resistance: is due to the recruitment of ________ in Tamoxifen-bound ER instead of its former/typical function of recruitment of ___________

- (due to the recruitment of) coactivators

- (instead of its former/typical function of recruitment of) corepressors

Tamoxifen is a MODULATOR, so thus it has the ability to recruit both (but this is the mechanism of resistance)

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: mechanism of tamoxifen resistance: coactivators are ________ instead of corepressors

- (coactivators are) recruited (instead of corepressors)

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen resistance figure

Selective Estrogen Receptor Modulators (SERMs) - other SERM drugs

Raloxifene

Toremifene

Selective Estrogen Receptor Modulators (SERMs) - SERMS are _______ ______ agonists or antagonists. It ______ either as an agonist or antagonist depending on the ___________

- NOT pure (agonists or antagonists)

- acts (either as an agonist or antagonist)

- (depending on the) tissue

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: if there is resistance to tamoxifen, Raloxifene ________ usually overcome the resistance

- (Raloxifene) cannot (usually overcome the resistance)

Selective Estrogen Receptor Modulators (SERMs) - Tamoxifen: modulating effect (i.e., not pure agonist or antagonist) example: in breast tissue, tamoxifen is used to __________ ER+ breast cancer

Whereas in the uterus, tamoxifen may induce __________ _____ _______, associated with endometrial cancer

- (used to) treat (ER+ breast cancer)

- (Whereas in the uterus, tamoxifen may induce) endometrial cell growth

Selective Estrogen Receptor Modulators (SERMs) - Raloxifene: has ____ _______ in tamoxifen resistant breast cancer but effective at preventing breast cancer

Has a 2nd effect: may also prevent __________ ______ in the uterus, unlike tamoxifen

- no effect (in tamoxifen resistant breast cancer)

- (may also prevent) endometrial cancer (in the uterus)

Tamoxifen may instead cause endometrial cancer

Tamoxifen Metabolic Pathway: is metabolized by a combination of _________ and ________ to generate Endoxifen

- CYP3A4

- CYP2D6 (to generate Endoxifen)

Endoxifen has significantly higher binding affinity to ERα and ERβ and results in ER degradation

Tamoxifen Metabolic Pathway: is metabolized by a combiaontion of CYP3A4 and CYP2D6 to generate ___________

___________ has significantly higher binding affinity to ERα and ERβ and results in ER degradation

- (to generate) Endoxifen

- Endoxifen (has significantly higher binding affinity)

Tamoxifen Metabolic Pathway: Endoxifen has significantly higher __________ _____ to ERα and ERβ and results in ER _____________

- (significantly higher) binding affinity

- (results in ER) degradation

____________ is converted to Endoxifen through CYP2D6

- Tamoxifen (is converted to Endoxifen)

Endoxifen is more active than its parent drug

SERD

selective estrogen receptor downregulator / degrader

SERD drugs

Fluvestrant

SERD: Fluvestrant advantages - is effective in situations of Tamoxifen _____________

___________ _____ levels in the cancer cell

- (in situation of Tamoxifen) resistance

- Reduces ER (levels in the cancer cell)

SERD: Fluvestrant advantages - acts as a pure _______________

- (acts as a pure) antagonist

SERD: Fluvestrant adverse effects

vasomotor symptoms

- hot flashes

SERD: Fluvestrant Mechanism - estrogen receptor is _______ ________ and ER ______ and is tagged for degradation

- not dimerized

- (ER) dissociates (and is tagged for degradation)

SERD: Fluvestrant Mechanism - binding of fluvestrant to estrogen receptor __________ receptor dimerization and binding to estrogen response element and gene transcription.

Instead the Fluvestrant-bound ER is __________

- prevents (receptor dimerization)

- (Fluvestrant-bound ER is) degraded

Distribution and function of aromatase - expression: in _______ tissues and ______ including ovaries, urogenital, brain, heart blood, vessels, breasts and adipose tissue

- multiple (tissues)

- organs (including ovaries...)

Distribution and function of aromatase - pre-menopause: ovarian aromatase is responsible for the majority of ____________ ___

- (majority of) circulating E2

Distribution and function of aromatase - pre-menopause: _________ _________ is responsible for the majority of circulating E2

- ovarian aromatase (is responsible for the majority...)

Distribution and function of aromatase - pre-menopause: ovarian aromatase is regulated by ______. Increasing circulating LH leads to increasing __________ _________

- (is regulated by) LH

- (increasing) aromatase expression

Distribution and function of aromatase - pre-menopause: ovarian aromatase is __________ by LH. ____________ circulating LH leads to increasing aromatase expression

- regulated (by LH)

- Increasing (circulating LH leads to increasing aromatase expression)

Distribution and function of aromatase - post-menopause: circulating E2 is produced by aromatase in ________ tissue, _________ gland and in ____________

Aromatase in these tissues is NOT regulated by LH

- (aromatase in) adipose (tissue)

- adrenal (gland)

- muscles

Distribution and function of aromatase - post-menopause: circulating E2 is produced by aromatase in adipose tissue, adrenal gland and in muscles

Aromatase in these tissues is _____ _________ by LH

Whereas, in pre-menopause, majority of circulating ER is produced by the _____________, where it is regulated by LH

- NOT regulated (by LH)

- (produced by the) ovaries

Distribution and function of aromatase - the majority of E2 is produced by the ovaries ______-_____________

The majority of E2 is produced by adipose tissue, adrenal gland, and in muscle _______-__________

- (produced by the ovaries) pre-menopause

- (adipose tissue, adrenal gland, and in muscle) post-menopause

Distribution and function of aromatase - aromatase inhibitors are ________-______ except for _____-________ women

- (are) first-line

- (except for) pre-menopausal (women)

Ovarian aromatase is also known as _________ ________ aromatase

- hormone sensitive (aromatase)

Distribution and function of aromatase figure

Aromatase inhibitors - first generation

Aminoglutethimide

Aromatase inhibitors - first generation (Aminoglutethimide) MOA: a _____-_________ _______ inhibitor of aromatase

- non-steroidal reversible (inhibitior of aromatase)

Types of aromatase inhibitors

Type I: steroidal

Type II: non-steroidal

Types of aromatase inhibitors (steroidal) are usually _______________ and create __________ bonds

- (are usually) irreversible

- (create) covalent (bonds)

Types of aromatase inhibitors: non-steroidal create ____________ bonds

- reversible (bonds)

Aromatase inhibitors - third generation drugs

Exemestane (steroidal)

Anastrozole

(non-steroidal)

Letrozole

(non-steroidal)

Aromatase inhibitors - third generation STEROIDAL (IRREVERSIBLE) drugs

Exemestane

Exemestane is steroidal and thus irreversible

Aromatase inhibitors - third generation non-steroidal (reversible) drugs

Anastrozole

Letrozole

Aromatase inhibitors - net result: ___________ in circulating estrogen levels

- reduction (in circulating estrogen levels)

Indicated in early and advanced ER+ breast cancer in postmenopausal women

Aromatase inhibitors are indicated in early and advanced ______ breast cancer in ___________ females

- ER+ (breast cancer)

- postmenopausal (females)

Aromatase inhibitors can only be given in premenopausal females AFTER _________ _________

- (premenopausal females AFTER) ovarian ablation

i.e., removal of ovaries

AI

aromatase inhibitor

Tamoxifen vs. Anastrozole Figure

AI Class Effects

Hot flashes

Arthralgia, pain

Osteoporosis, fracture risk

Depression

Tamoxifen vs. Anastrozole: estrogen is ___________ on the bone, thus reduction in estrogen causes _________ bones

- anabolic (on the bone)

- (reduction in estrogen causes) weaker (bones)

Estrogens and androgens inhibit _________ _________ (via inhibiting osteoclast function) and stimulate ________ _________

- (inhibit) bone resorption

- (stimulate) bone formation

ADT

androgen deprivation therapy

Androgen deprivation therapy (ADT) classes

GnRH analogs

GnRH antagonists

Androgen deprivation therapy (ADT): GnRH analog drugs

Leuprolide

Triptorelin

Goserelin

Histrelin

Androgen deprivation therapy (ADT): GnRH antagonists

Degarelix

Androgen deprivation therapy (ADT) - GnRH Analogs / GnRH Antagonists Adverse Effects

Hot flashes

Decreased libido

Osteoporosis

Weight gain and loss of muscle mass

Fatigue and anemia

GnRH stimulates ___________ ________ to release FSH and LH

- (stimulates) anterior pituitary

GnRH stimulates anterior pituitary to release _______ and ________

- (to release) FSH

- LH

GnRH antagonists bind to GnRH receptors and prevent GnRH from binding and suppression of FSH and LH release

ADT: GnRH antagonists bind to GnRH receptors and prevent GnRH from __________ and __________ of FSH and LH release

Results in the decrease of prostate size (for prostate cancer)

- (prevent GnRH from) binding

- suppression (of FSH and LH release)

ADT: first-line for prostate cancer is still ________ ________ although other options include _______ ______ and _______ _________

- (is still) surgical removal

- GnRH analogs

- GnRH antagonists

ADT: GnRH analogs are formulated as ________ to allow ________ exposure to the drug

- (formulated as) depots

- (allow) sustained (exposure)

ADT: GnRH regulates the circulating levels of ______________

- (circulating levels of) androgens

ADT: GnRH releases in a ___________ manner

- pulsatile (manner)

ADT: either the GnRH analog or antagonist is able to _________ circulating androgens

- (GnRH analog or antagonist is able to) reduce (circulating androgens)

ADT: Initially, GnRH analogs _________ FSH and LH release.

_________ exposure to GnRH analog results in desensitization of GnRH receptor

- (GnRH analogs) stimulate (FSH and LH release)

- Sustained (exposure to GnRH analog)

ADT: initially, GnRH analogs stimulate FSH and LH release

Sustained exposure to GnRH analog results in ____________ of GnRH receptor

- desensitization (of GnRH receptor)

ADT: Patients with metastatic prostate cancer on GnRH analogs, may experience an enlargement during the __________ ______-____ due to a surge of __________

- (during the) initial flare-up

- (due to a surge of) testosterone

Thus, may be given with a CAB (combined androgen blockade; GnRH analog and anti-androgen)

ADT: Patients with metastatic prostate cancer on GnRH analogs, may experience an enlargement during the initial flare-up due to a surge of testosterone

Thus, may be given with a ______

- (may be given with a) CAB

CAB = combined androgen blockade; GnRH analog and anti-androgen

CAB

combined androgen blockade

Impact of GnRH analogs and GnRh antagonists on serum testosterone levels

Anti-androgens - androgen receptor antagonists: first-generation drugs

"conventional anti-androgens"

Flutamide

Bicalutamide

Nilutamide

Anti-androgens - androgen receptor antagonists: first-generation (Flutamide, Bicalutamide, Nilutamide) MOA

binding to AR (androgen receptor) and prevent androgens from binding to the AR

Downstream effect: reduce androgen-dependent prostate cancer cell proliferation

Anti-androgens - androgen receptor antagonists: first-generation (Flutamide, Bicalutamide, Nilutamide) MOA: binding to ____ (________ ______) and prevent androgens from _________ to the AR

- AR (androgen receptor)

- (prevent androgens from) binding (to the AR)

Anti-androgens - androgen receptor antagonists: first-generation (Flutamide, Bicalutamide, Nilutamide) downstream effects (from binding): reduce __________-________ prostate cancer cell proliferation

- (reduce) androgen-dependent (prostate cancer cell proliferation)

Anti-androgens - androgen receptor antagonists: first-generation (Flutamide, Bicalutamide, Nilutamide) - established mechanism of resistance - the anti-androgens instead behave like an _________ instead of an antagonist

- (behave like an) agonist

Mechanisms of resistance to ADT

1. more androgens are synthesized and released by the adrenal gland

2. AR activation by corticosteroids

3. AR activated growth factors

4. AR amplification

5. AR mutations