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PHAR 557 > Targeted Tx's > Flashcards

Targeted Tx's Flashcards

1
Q

What features characterize an ideal target for targeted cancer tx?

A
  • crucial for cancer growth/survival,
  • not sig expressed in vital organs/tissues,
  • minimal/no tox in non-tumor cells,
  • measurable in easily obtained samples,
  • clinical response in majority of pts whose tumors express the target when target is interrupted/inhibited,
  • target doesn’t have mutations/variants
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2
Q

Most common cancers that undergo endocrine tx’s?

A

breast cancers, prostate cancer, endometrial cancers, ovarian cancers

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3
Q

What’s tamoxifen used for?

A

Breast cancer

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4
Q

tamoxifen MOA

A

estrogen antagonist in breast cancer cells;

agonist effects on endometrium, bone, and lipids

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5
Q

T or F: Tamoxifen is appropriate for breast cancer in females only.

A

F

In males too

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6
Q

AEs of tamoxifen

A

flushing, hot flashes, edema (menopause-like sx’s), thromboembolic events, mood changes, arthralgia, weakness

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7
Q

What’s a major risk of taking tamoxifen?

A

Endometrial cancer

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8
Q

What’s second line endocrine tx for breast cancer?

A

Fulvestrant

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9
Q

Fulvestrant MOA

A

Estrogen receptor antagonist

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10
Q

When is fulvestrant used?

A

Advanced, hormone-receptor positive breast cancer

–>i.e. when breast cancer becomes tamoxifen-resistant or when it metastasizes

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11
Q

Aromatase inhibitor MOA

A

blocks estrogen PRODUCTION

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12
Q

Why are aromatase inhibitors only used in post-menopausal women?

A

bc it can’t overcome the amt of estrogen produced by the ovaries of pre-menopausal women

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13
Q

Name the two nonsteroidal, reversible inhibitors of aromatse

A

anastrozole, letrozole

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14
Q

Name the steroidal, irreversible aromatase inhibitor

A

exemestane

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15
Q

AEs of aromatase inhibitors?

A

hot flashes and flushing

HTN

Osteopenia/osteoporosis

weakness, arthralgia

fatigue

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16
Q

List the androgen deprivation tx’s used for prostate cancer

A

Luteinizing-hormone releasing hormone (LHRH) agonists

LHRH antagonist

abiraterone

androgen receptor blockers

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17
Q

What is NOT an effective tx for prostate cancer?

A

5-alpha-reductase inhibitors (e.g. finasteride, dutasteride)

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18
Q

Leuprolide and goserelin are examples of…

A

LHRH agonists

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19
Q

MOA of LHRH agonists (leuprolide and goserelin)

A

down-regulation of hypothalamus-pituitary axis

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20
Q

What’s important to know when starting LHRH agonist tx?

A

There’s an initial “flare” response

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21
Q

What can be Rx’ed to tx the initial flare from LHRH agonists?

A

bicalutamide for 14-30d

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22
Q

What LHRH antagonist is used for prostate cancer?

A

degarelix

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23
Q

MOA of degarelix?

A

blocks pituitary receptors > reduces LH and FSH secretion > rapid decrease in testosterone production

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24
Q

T or F: Degarelix causes an initial flare.

A

F

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25
Q

What’s abiraterone?

A

androgen biosynthesis inhibitor

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26
Q

MOA of abiraterone

A

Inhibits CYP17 > blocks androgen production in testes, adrenal glands, and tumour

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27
Q

What unique AE does abiraterone cause as a result of its MOA?

A

Reduces cortisol production > causes increased ACTH > causes accumulation of mineralocorticoids > HTN, hypokalemia, edema

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28
Q

What’s given in combo with abiraterone? Why?

A

Prednisone > prevents compensatory rise in ACTH

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29
Q

Name 4 androgen receptor blockers

A

Bicalutamide, flutamide, enzalutamide, apalutamide

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30
Q

Androgen deprivation tx’s: AEs

A

Urinary sx’s, gynecomastia, hot flashes, reduced libido and ED, fatigue, wt gain, loss of muscle mass, osteopenia/-porosis, MI/increased QT

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31
Q

Name the 5 classes of small molecule drugs (and the suffixes used in each drug class)

A
  1. tyrosine kinase inhibitors (-tinib)
  2. proteasome inhibitor (-zomib)
  3. cyclin-dependent kinase inhibitor (-ciclib)
  4. poly ADP-ribose polymerase inhibitor (-parib)
  5. mTOR (mammalian target of rapamycin) inhibitor (-irolimus)
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32
Q

Tyrosine kinase inhibitor MOA?

A

Intracellularly block signals from activated trans-membrane proteins by competing w/ ATP for the TK region of the trans-membrane receptor

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33
Q

Epidermal growth factors receptors - list them

A

HER1/2/3/4

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34
Q

Another name for HER1 receptors?

A

EGFR

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35
Q

What do the epidermal growth factors receptors do?

A

They ctrl cell differentiation, proliferation, and survival

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36
Q

Through which pathway do the epidermal growth factors receptors act?

A

Tyrosine kinase pathway (TKP)

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37
Q

4 EGFR inhibitors for non-small cell lung carcinoma:

A
  1. erlotinib
  2. gefitinib
  3. afatinib
  4. osimertinib
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38
Q

These two EGFR inhibitors target the EGFR tyrosine kinase cytosolic domain

A

erlotinib, gefitinib

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39
Q

This EGFR inhibitor targets EGFR, HER2, HER4, and HER3 (transphorylation of it)

A

afatinib

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40
Q

Which EGFR inhibitor isn’t used often?

A

osimertinib

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41
Q

Diarrhea is a huge AE of this EGFR inhibitor

A

afatinib

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42
Q

HER2 is overexpressed in what types of cancers?

A

15% of breast cancer cases, and some gastroesophageal cancers

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43
Q

AEs of HER2 agents?

A

rash, D, cardiotox, hepatotox

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44
Q

Specific HER-2 agents?

A

lapatinib

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45
Q

Name VEGF inhibitors

A

axitinib

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46
Q

What do VEGF inhibitors do?

A

Reduce/prevent angiogenesis of tumors

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47
Q

What kind of cancer is tx’ed w/ VEGF inhibitors?

A

Renal cell carcinoma

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48
Q

AEs of VEGF inhibitors?

A

HTN, bleeding, impaired wound healing

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49
Q

What do multikinase inhibitors target?

A

> 1 tyrosine kinase region in the cytoplasmic side of transmembrane protein receptors

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50
Q

What’re sunitinib and pazopanib?

A

multikinase inhibitors

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51
Q

sunitinib and pazopanib: how do they help tx cancer?

A

inhibit tumor growth, cellular proliferation, and angiogenesis

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52
Q

What’re sunitinib and pazopanib used to tx?

A

renal cell carcinoma

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53
Q

Unique AEs of sunitinib and pazopanib?

A
  1. hand foot skin rxn (HFSR) aka plantar palmar erythrodysethesia (PPE)
  2. discoloration of nails and/or hair (yellow or white)
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54
Q

Why is bleeding an AE of sunitinib and pazopanib?

A

Due to VEGF-inhibition activity

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55
Q

How do sorafenib and regorafenib work?

A

inhibit cellular proliferation and tumor angiogensis

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56
Q

What’s sorafenib used for?

A

hepatocellular carcinoma, renal cell carcinoma

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57
Q

What’s regorafenib used for?

A

Gastrointestinal Stromal Tumor (GIST), hepatocellular carcinoma

58
Q

Unique AEs of sorafenib and regorafenib?

A

HFSR aka PPE

Severe rash, mild skin discoloration

59
Q

What’s a “Philadelphia Chromosome”?

A

An oncogene that’s formed when the BCR portion of chromosome 22 fuses w/ the ABL portion of chromosome 9

60
Q

The “Philadelphia chromosome” is found in this cancer

A

CML (chronic myelogenous leukemia)

61
Q

List the BCR-ABL inhibitors

A

imatinib, dasatinib, nilotinib, bosutinib, ponatinib

62
Q

What is wrong with the protein made by the BCR-ABL protein in CML (chronic myeloid leukemia)?

A

It’s an abnormal tyrosine kinase, hence the need for a tyrosine kinase inhibitor

63
Q

List the tyrosine kinase inhibitors (classes):

A

EGFR inhibitors, HER2 inhibitors, VEGF inhibitors, multikinase inhibitors, BCR-ABL inhibitors

64
Q

List the two cyclin dependent kinase (CDK) inhibitors

A

palbociclib, ribociclib

65
Q

CDK inhibitors: what kind(s) of cancer are they used in?

A

Estrogen-receptor positive breast cancers

66
Q

CDK inhibitors: MOA

A

Inhibit CDK (cyclin dependent kinase) > decrease breast cancer cell proliferation > induce senescence (i.e. it halts proliferation)

67
Q

CDK inhibitors can be used synergistically with what type of chemotx?

A

anti-estrogen tx’s (e.g. estrogen receptor antagonists, aromatase inhibitors)

68
Q

AEs of CDK inhibitors

A

Neutropenia, stomatitis, N, fatigue

69
Q

Name a poly ADP-ribose polymerase (PARP) inhibitor

A

Olaparib

70
Q

What proteins are responsible for repairing daily DNA damage?

A

PARP, BRCA1 and BRCA2

71
Q

MOA of PARP inhibitors?

A

Inhibits PARP > DNA repair is prevented > cancer cell death

72
Q

When would PARP inhibitors be used?

A

In cancers where BRCA1/2 is damaged/not working properly

73
Q

AEs of PARP inhibitors

A

N/V, fatigue, anemia

74
Q

Name the proteasome inhibitors

A

bortezomib, carfilzomib, ixazomib

75
Q

Proteasome inhibitors are used in these types of cancers

A

hematologic cancers

76
Q

What kind of cancers are tx’ed by proteasome inhibitors?

A

multiple myeloma, non-Hodgkin lymphoma

77
Q

MOA of proteasome inhibitors

A

Damaged proteins and other substrates cannot be degraded by 20S proteasome > toxic metabolites buildup in cancer cell > cancer cell ruptures

78
Q

Anaplastic lymphoma kinase gene mutation: most common pt population?

A

young pts who’re NON-smokers

79
Q

ALK inhibitors: list them

A

crizotinib, alectinib, ceritinib

80
Q

One of this ALK inhibitor’s AEs includes vision disorder

A

ceritinib

81
Q

There’re 3 types of non-small cell lung cancer. What’re they?

A

squamous cell carcinoma, large cell carcinoma, adenocarcinoma

82
Q

What kinds of mutations drive NSCLC adenocarcinoma and large cell carcinoma?

A

PD-L1, EGFR, AKL, ROS

83
Q

BRAF kinase inhibitors: list them

A

vemurafenib, dabrafenib

84
Q

BRAF kinase inhibitors: indication

A

melanoma ONLY

85
Q

BRAF kinase inhibitor MOA:

A

Block BRAF kinase > stop cancer cells from growing

86
Q

AEs of BRAF kinase inhibitors

A

alopecia, N, rash, photosensitivity, severe hypersensitivity, cutaneous squamous cell carcinoma

87
Q

How do we reduce the risk of cutaneous squamous cell carcinoma when tx’ing pts w/ BRAF kinase inhibitors?

A

Combine the BRAF kinase inhibitor w/ MEK inhibitors

88
Q

MEK inhibitors: AEs

A

acneiform rash, cardiotox’s, ocular tox

89
Q

mTOR (mamallian target of rapamycin) - what is it?

A

serine/threonine protein kinase that ctrls cell cycle progression, cell proliferation, and angiogenesis

90
Q

Name mTOR inhibitors

A

temsirolimus, everolimus

91
Q

What kinds of cancers are tx’ed using mTOR inhibitors?

A

renal cell carcinoma, pNET (pancreatic neuroendocrine tumor), breast cancer (historical)

92
Q

What’s the hedgehog pathway?

A

Cell differentiation and organ development pathway that’s active in vertebrate embryonic development

93
Q

What role does the hedgehog pathway play in adults?

A

Tissue maintenance and repair only (or differentiation/organ development)

94
Q

Inappropriate reactivation of the hedgehog pathway in adults is assoc w/ what kind of cancer?

A

basal cell skin cancer

95
Q

Name a hedgehog pathway inhibitor

A

vismodegib (only one with “-gib” suffix)

96
Q

AEs of vismodegib:

A

GI effects, loss of taste, alopecia, arthralgia

97
Q

Which two targeted tx’s are assoc w/ alopecia?

A

hedgehog pathway inhibitors and BRAF inhibitors

98
Q

hedgehog pathway inhibitor CI

A

pregnancy (teratogen)

99
Q

Bruton’s tyrosine kinase (BTK) inhibitors: name them

A

ibrutinib, acalabrutinib

100
Q

BTK inhibitors: used to tx which cancers?

A

chronic lymphocytic leukemia (CLL)

relapsed mantel cell lymphoma (MCL)

101
Q

MOA of BTK inhibitors

A

Inhibition of B-cell receptor and cytokine receptor pathways > inhibits proliferation and survival of malignant B-cells

102
Q

AEs of BTK inhibitors

A

arrhytmias, PR prolongation, tumor lysis syndrome, bleeding, Hep B reactivation

103
Q

Phosphoinositide-3-kinase (PI3K) inhibitors: name it

A

idelalisib

104
Q

MOA of idelalisib:

A

inhibits B-cell signaling > reduced B-cell migration to lymph nodes and bone marrow

ALSO induces malignant B-cell apoptosis

105
Q

Idelalisib (a PI3K) is combined with this to tx CLL (chronic lymphocytic leukemia)

A

rituximab

106
Q

idelalisib AE

A

GI, infections, rash, myelosuppression, pneumonia/pneumonitis, hepatotoxicity

107
Q

BCL-2 inhibitors - name it

A

venetoclax

108
Q

What is BCL-2?

A

B-cell lymphoma-2 = anti-apoptotic protein overexpressed in chronic lymphocytic leukemia (CLL) cells

109
Q

Major AE of venetoclax (BCL-2 inhibitor)

A

Tumor lysis syndrome/hyperuricemia

110
Q

Name the monoclonal antibody targets for cancer tx

A

CD20 antigen, EGFR (HER1), HER2, VEGF

111
Q

Name the two anti-CD2- mabs

A

rituximab, obinutuzumab

112
Q

MOA of anti-CD20 mabs (rituximab, obinutuzumab)

A

CD20 antigen found on malignant and nonmalignant B cells > mabs recruit other immune mediators enabling cell destruction and apoptosis

113
Q

AEs of anti-CD20 mab tx?

A

infusion rxns (facial flushing, hypotension, fever, dyspnea, chest pain), tumor lysis syndrome, Hep B reactivation

114
Q

CIs of anti-CD20 mab tx?

A

live vaccines 6mths before and after tx

115
Q

anti-CD20 mab tx can cause tumor lysis syndrome - how to deal w/ this?

A

Premedicate w/ hydration and allopurinol

116
Q

EGFR (HER1) mab drugs:

A

cetuximab, panitumumab

117
Q

What’s cetuximab used for?

A

head and neck cancers

118
Q

What’s panitumumab used for?

A

colorectal cancer

119
Q

MOA of EGFR (HER1) mab drugs?

A

bind to extracellular ligands > stops intracellular tyrosine kinase pathways

120
Q

Major AE assoc w/ EGFR mab drugs

A

Significant Mg2+ level drop

121
Q

This EGFR mab drug is assoc w/ interstitial pneumonitis

A

panitumumab

122
Q

Name the HER2 mab drugs

A

trastuzumab, pertuzumab

123
Q

MOA of trastuzumab

A

blocks HER-2 dimerization > reduces cell replication

124
Q

MOA of pertuzumab

A

blocks HER-2 heterodimerization > reduces cell replication

125
Q

trastuzumab is also used in these cancers

A

GI cancers that overexpress HER2

126
Q

Name the VEGF mab drugs

A

bevacizumab, ramicirumab,

127
Q

bevacizumab MOA:

A

binds all circulating VEGF > prevents activation of VEGF receptors

128
Q

bevacizumab is used for what types of cancers

A

advanced colorectal cancer, NSCLC, glioblastoma, gynecologic cancers

129
Q

bevacizumab: AEs

A

HTN, bleeding, cerebral infarction, MI, proteinuria

130
Q

ramicirumab MOA:

A

binds to VEGF receptor 2 specifically

131
Q

What’s ramicirumab used for?

A

advanced gastric cancer and gastroesophageal adenocarcinomas

132
Q

Name 3 antibody-drug conjugates

A

DM1, trastuzumab emtansine, brentuximab vedotin, and ibritumomab tiuxetan,

133
Q

DM1 MOA

A

microtubule inhibitor

134
Q

Name two other microtubule inhibitors

A

taxanes and vinca alkaloids

135
Q

Why isn’t DM1 used anymore for cancer tx?

A

Too toxic

136
Q

How is DM1 given nowadays?

A

As trastuzumab emtansine

137
Q

T or F: trastuzumab emtansine is given at the same dose as DM1

A

F

It would kill the pt; half the dose is given

138
Q

MOA of trastuzumab emtansine

A

trastuzumab brings emtansine to cancer cell > emtansine (containing DM1) gets taken up > causes tumor cell death

139
Q

What kind of cancer is tx’ed w/ brentuximab vedotin

A

refractory Hodgkin dz and refractory anaplastic lg cell lymphoma

140
Q

What kind of cancer is tx’ed w/ ibritumomab tiuxetan?

A

relapsed refractory follicular lymphoma

PHAR 557 (36 decks)

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