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Therapeutics IV > Anti-cancer Endocrine Therapies - Dr. Wendt > Flashcards

Anti-cancer Endocrine Therapies - Dr. Wendt Flashcards

1
Q

What is used to describe a wart produced by an HPV infection?

A

papilloma

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2
Q

Increasing in cell size is _______ a hallmark of cancer

A

NOT

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3
Q

Molecular pathology is different from traditional pathology because…

A

…it uses some kind of genetic testing to indicate therapy or predict for tumor recurrence

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4
Q

T or F: Gene expression analyses like Oncotype Dx are currently used to indicate specific therapies

A

False

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5
Q

Hemotoxylin is used in pathology to stain the nucleus of cells a __________ color

A

blueish/purple

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6
Q

Which of the following terms is associated with substitution of tissue type for another?

A

Metaplasia

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7
Q

HER2 is an example of a ______________

A

oncogene

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8
Q

BRCA is an example of a _____________

A

tumor suppressor

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9
Q

Hormones regulate the proliferation in these three cancers

A
  • breast
  • prostate
  • endometrial
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10
Q

Where are common hormones produced?

A
  • adrenal glands
  • ovary
  • testis
  • adipocytes
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11
Q

Recall steroid receptor signal transduction

A
  • 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
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12
Q

Most common/lethal hormone cancers

A
  • prostate
  • breast
  • lung
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13
Q

Which CYP enzyme associated with aromatase?

A

CYP19

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14
Q

Molecular action of steroid hormones

A
  1. Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell
  2. Steroid hormone receptors are in the cytoplasm or nucleus
  3. The receptor-hormone complex binds to DNA and activates or represses one or more genes
  4. Activated genes create new mRNA that moves back to the cytoplasm
  5. Translation produces new proteins for cell processes
  6. Some steroid hormones also bind to membrane receptors that use second messenger systems to create rapid cellular responses
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15
Q

Two major classes of endocrine therapy

A
  1. Stop steroid receptor function

2. Decrease production of steroids

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16
Q

Hypothalamus produces _______ that impacts the _______

A

GnRH; pituitary gland

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17
Q

The pituitary gland produces _______ that impacts _______

A

FSH & LH; Estrogen + Progesterone

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18
Q

Estrogen receptors (ER) and progesterone receptors (PR) ____________ in tumors

A

measurable

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19
Q

Well differentiated tumors are more likely to be ____

A

ER+

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20
Q

poorly differentiated tumors are generally ____

A

ER-

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21
Q

Remember that poorly differentiated tumors have ________ growth fractions and are generally more ________ to cytotoxic agents

A

higher; sensitive

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22
Q

Highly significant ___________ between presence of estrogen receptor and the likelihood of response to hormone therapy

A

correlation

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23
Q

Correlation is even _________ for __________ tumors

PR is estrogen inducible and is a measure of biological response to estrogen

A

stronger; ER+/PR+

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24
Q

Hormone therapy in breast cancer generally limited to _________ tumors. Can be a useful addition to other chemotherapy in __________ tumors.

A

ER+/PR+; ER+/PR-

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25
Q

DCIS means…

A

ductal carcinoma in situ

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26
Q

estrogen receptor primarily binds estrogen where in the cell?

A

cytoplasm

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27
Q

what enzyme converts androstenedione to estrone?

A

CYP19

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28
Q

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.

A

endocrine therapy; determinate

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29
Q

A range of ER positivity are considered for endocrine therapy, usually…

A

~10%

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30
Q

breast tumor subtypes (4)

A
  • triple negative (ER-, PR-, HER2-)
  • HER2+
  • Luminal B
  • Luminal A
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31
Q

Triple negative: % of breast cancers

A

15 - 20%

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32
Q

HER2: % of breast cancers

A

10 - 15%

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33
Q

Luminal B: % of breast cancers

A

20%

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34
Q

Luminal A: % of breast cancers

A

40%

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35
Q

Triple negative tumors respond best to…

A

chemotherapy (similar to other aggressive cancers)

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36
Q

Luminal A tumors respond best to…

A

endocrine therapy (e.g. antiestrogen or aromatase inhibitor)

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37
Q

About when was tamoxifen discovered…

A

~1977

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38
Q

Tamoxifen is a __________ that must be metabolized to ____________

A

prodrug; 4-OH-TAM

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39
Q

Tamoxifen characteristics

A
  • 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
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40
Q

Tamoxifen brand

A

Nolvadex

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41
Q

Tamoxifen estrogen antagonist effects

A

hot flashes

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42
Q

Tamoxifen primary use

A
  • 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
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43
Q

Tamoxifen was the first drug approved for…

A

…breast cancer prevention (reduces risk by 50% in women at high risk)

44
Q

Tamoxifen dosage form

A

orally available

45
Q

Tamoxifen is much less effective in patients with a common ________ variant

A

CYP2D6 (~ 10% of postmenopausal women with breast cancer carry this variant. Several known inhibitors of CYP2D6)

46
Q

SERM Tamoxifen brain adverse effect

A

hot flashes, thermoregulation

47
Q

SERM Tamoxifen breast beneficial effect

A

++antiproliferative

48
Q

SERM Tamoxifen blood adverse effect

A

increased coagulability clots, VTE risk

49
Q

SERM Tamoxifen uterus adverse effect

A

endometrial hyperplasia

50
Q

SERM Tamoxifen bone partial agonist beneficial effect

A

blocks bone resorption

51
Q

SERD Definition

A

Selective Estrogen Receptor Down-Modulator

52
Q

Fulvestrant brand

A

Faslodex

53
Q

Fulvestrant facts

A

“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.

54
Q

Fulvestrant dosage form

A

intramuscular injection once per month

55
Q

What does aromatase do?

A

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

56
Q

adipocytes are a source of _________ in postmenopausal women

A

estrogen

  • Androstenedione produced in adrenal gland and released to circulation
  • Aromatase in adipocytes converts androstenedione  estrone
  • Estrone then converted to estradiol
57
Q

What is the primary target of inhibitors?

A

Peripheral tissue (adipose tissue) — not ovary

58
Q

Primary application of aromatase is…

A

…estradiol suppression in post menopausal women

59
Q

What are two imidazole-based NON-STEROIDAL aromatase inhibitors?

A
  • anastrozole

- letrozole

60
Q

letrozole brand

A

femara

61
Q

anastrozole brand

A

arimidex

62
Q

non-steroidal aromatase inhibitors

A

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)

63
Q

examples of steroidal aromatase inhibitors

A
  • exemestane

- androstenedione

64
Q

exemestane brand

A

aromasin

65
Q

exemestane facts

A

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)

66
Q

exemestane has ________ toxicity

A

Minimal toxicity (Hot flashes, Occasional peripheral edema and weight gain, Increased cholesterol levels)

67
Q

What compound directly inhibits the activity of the estrogen receptor throughout the body?

A

fulvestrant

68
Q

FSH and LH are controlled by…

A

…feedback inhibition

69
Q

Chronic administration of GnRH analogues downregulates pituitary GnRH receptors which causes…

A

pituitary desensitization

70
Q

Decreased FSH leads to __________ aromatase and decreased ___________

A

decreased; estrogen

71
Q

What are gonadotropin releasing hormone analogs?

A

Peptide analogs of the neurohormone GnRH with modified amino acids to increase potency and reduce degradation.

72
Q

Gonadotropin releasing hormone facts (hint: acute vs chronic impact)

A

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)

73
Q

Two examples of GnRH analogues

A
  • leuprolide acetate

- goserelin

74
Q

Leuprolide acetate brand

A

lupron

75
Q

goserelin brand

A

zoladex

76
Q

GnRH analog facts

A

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.

77
Q

Tx for postmenopausal women

A
  • Tamoxifen
  • Nonsteroidal aromatase inhibitors (anastrozole, letrozole)
  • Steroidal aromatase inhibitor (exemestane)
  • Pure anti-estrogens (fulvestrant)
78
Q

Tx for premenopausal women

A
  • GnRH agonists (goserelin and leuprolide)
  • Surgical oophorectomy
  • Tamoxifen
79
Q

Essentially all patients that initially respond to endocrine therapies will develop _________.

A

resistance

80
Q

Tumors are not homogenous. Tumor __________ drives resistance

A

heterogeneity

81
Q

Several ___________ are being combined with ___________ inhibitors

A

anti-estrogens; cyclin-dependent kinase (CDK) inhibitors

82
Q

Prostate cancer is a _______ _______ disease

A

slowly progressing

83
Q

Prostate cancer staging: Gleason Score

1
2
3
4
5
A

(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)

84
Q

What is the most frequently diagnosed cancer among men in the US?

A

Prostate cancer

85
Q

Most important risk factor for prostate cancer?

A

Age

  • Extremely rare prior to age 40
  • Rate of increase after 40 is the steepest of any cancer
86
Q

Hormones and prostate cancer facts

A

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
87
Q

Androgen receptor is a ____________ receptor

A

cytoplasmic

88
Q

Androgen receptor can be __________ in prostate cancer

A

amplified

89
Q

Binding of androgen receptor to dihydrotestosterone (DHT) leads to _____________ to the ________ and action of genes that drive cell growth

A

translocation; nucleus

90
Q

What prostate specific antigen (PSA) value is considered suggestive of prostate cancer?

A

> 6.5 ng/ml

91
Q

GnRH analogues in men

A

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.

92
Q

GnRH analogues in men examples + facts

A

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)

93
Q

GnRH receptor antagonists

A

Blockade of the GnRH receptors has the same overall affect of decreasing Testosterone production

Affects are more immediate avoiding “tumor flare.”

94
Q

Two examples of GnRH antagonists

A
  • abarelix (plenaxis)

- degarelix (firmagon)

95
Q

Abarelix facts

A

is also approved for treatment of prostate cancer

96
Q

Degarelix facts

A
  • Indicated for treatment of advanced prostate cancer

- Administered intravenously once a month

97
Q

How else prevent DHT production? Abiraterone (Zytiga)

A

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

98
Q

How else prevent DHT production? 5-alpha-reductase inhibitors examples (2)

A

finasteride and dutasteride

99
Q

finasteride brand

A

propecia

100
Q

dutasteride brand

A

avodart

101
Q

finasteride fact

A

Inhibits type II isoform of 5-a-reductase

102
Q

dutasteride fact

A

Inhibits type I and type II isoform of 5-a-reductase

103
Q

How do 5-alpha-reductase inhibitors work?

A

May delay growth of benign prostate tumors

Prolonged use may actually select for more aggressive
AR-independent tumors

104
Q

How else do you block AR signaling? AR antagonists (3)

A
  • enzalutamide
  • apalutamide
  • darolutamide
105
Q

AR receptor facts

A

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.”

106
Q

Purdue Success Story: 177Lu-PSMA-617

A

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.
107
Q

Mechanisms of resistance to endocrine therapy; prostate cancer

A

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.

Therapeutics IV (19 decks)

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