Oncology 3 Flashcards

1
Q

What is the role of epidermal growth factor receptors?

A

regulate cell differentiation, proliferation, and survival

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2
Q

What are the four EGFR receptors?

A

HER1
HER2
HER3
HER4

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3
Q

Through which pathway does EGFR act?

A

tyrosine kinase pathways

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4
Q

What are growth factors?

A

chemicals produced by the body that control cell growth
-some tell cells what type of cells they should become
-some make cells grow and divide into new cells
-some tell cells to stop growing or to die

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5
Q

How do growth factors work?

A

by binding to receptors on the cell surface
-this sends a signal to the inside of the cell, which sets off a chain of complicated chemical reactions

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6
Q

What is the difference between mAbs and TKIs in terms of where they act at the cell?

A

mAbs work extracellularly
TKIs work intracellularly

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7
Q

In which cancer is EGFR gene commonly overexpressed or mutated?

A

non-small cell lung cancer
-EGFR mutation present in 10-15% of patients (30-40% of Asian pts)

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8
Q

What is the role of the following growth factors?
-EGF
-VEGF
-PDGF
-FGF

A

epidermal growth factor (EGF):
-controls cell growth
vascular endothelial growth factor (VEGF):
-controls blood vessel development
platelet derived endothelial growth factor (PDGF):
-controls blood vessel development and cell growth
fibroblast growth factor (FGF):
-controls cell growth

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9
Q

What are cancer growth blockers?

A

a targeted drug that blocks the growth factors that trigger cancer cells to divide and grow

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10
Q

What are the types of cancer growth blockers?

A

tyrosine kinase inhibitors
proteasome inhibitors
mTOR inhibitors
Hedgehog pathway blockers

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11
Q

Provide the correct naming for small molecule drugs.

A

-tinib: TKI
-zomib: proteasome inhibitor
-ciclib: CDK inhibitor
-parib: PARP inhibitor
-irolimus: mTOR inhibitor

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12
Q

Which TKI was the pioneer?

A

imatinib

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13
Q

What is the MOA of TKIs?

A

block chemical messengers (enzymes) called tyrosine kinases
-TKs help to send growth signals in cells, so blocking them stops the cell growing and dividing

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14
Q

What is a multi-TKI?

A

TKIs that block more than one type of TK

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15
Q

Which TKI does not end in “-tinib”?

A

pazopanib

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16
Q

What are examples of multi-TKIs?

A

sorafenib
sunitinib
vandetinib
cabozantinib
lenvantinib
pazopanib
regorafenib

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17
Q

True or false: the therapeutic use and toxicities of multi-TKIs are the same

A

false
some targets may overlap but therapeutic use and toxicities are different

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18
Q

What are the TKI-EGFR inhibitors for NSCLC?

A

erlotinib
gefitinib
afatinib
osimertinib

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19
Q

Differentiate the TKI-EGFR inhibitors based on target.

A

erlotinib:
-EGFR TK cytosolic domain
gefitinib:
-EGFR TK cytosolic domain
afatinib:
-EGFR, HER2, HER4, HER3 transphorylation
osimertinib:
-EGFR, HER2, HER3, ACK1, BLK

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20
Q

Differentiate the TKI-EGFR inhibitors based on drug interactions.

A

erlotinib: CYP 3A4, PPI
gefitinib: CYP 3A4, 2D6
afatinib: P-gp
osimertinib: CYP 3A4, QT

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21
Q

Differentiate the TKI-EGFR inhibitors based on adverse effects.

A

erlotinib and gefitinib:
-rash, sun sensitivity, diarrhea
afatinib:
-rash, diarrhea, paronychia
osimertinib: milder ADR
-cardiomyopathy, vision disturbance

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22
Q

Which TKI-EGFR inhibitor is used for the T790M mutation?

A

osimertinib

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23
Q

Which cancer are ALK fusion genes sometimes present in?

A

~5% of patients with NSCLC
-more common in young pts who are non-smokers

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24
Q

What is the MOA of ALK inhibitors?

A

block an enzyme called anaplastic lymphoma kinase
-only work in cancer cells that have an overactive version of ALK

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25
Q

Which cancer are ALK inhibitors often used in?

A

some people with advanced NSCLC

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26
Q

What are examples of TKI-ALK inhibitors?

A

alectinib
brigatinib
ceritinib
crizotinib
lorlatinib

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27
Q

Which TKI-ALK is often first line for advanced NSLC (ALK+)?

A

alectinib

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28
Q

What is a PK advantage of alectinib?

A

better CNS penetration if brain metastases

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29
Q

What are the side effects of ALK inhibitors?

A

most commonly GI toxicities (NVD)
some lab abnormalities
-elevated AST and ALT
less common: pneumonitis

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30
Q

What are examples of TKIs that target HER2?

A

lapatinib
neratinib
pyrotinib
tucatinib

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31
Q

Which blood vessel related process is unregulated in many tumors?

A

angiogenesis
-tumor growth, invasion, and metastasis

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32
Q

What is the master regulator of angiogenesis?

A

VEGF

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33
Q

What has emerged as potent anti-tumor weapons against multiple solid tumors?

A

VEGFR-associated multi-targeted TKIs

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34
Q

What is the use of axitinib?

A

metastatic renal cell cancer

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35
Q

What are the adverse effects of axitinib?

A

hypertension
bleeding
impaired wound healing

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36
Q

What are the drug interactions of axitinib?

A

substrate of CYP 3A4
acid blockers

37
Q

What are the targets of sunitinib and pazopanib?

A

VEGF
PDGFR
c-KIT

38
Q

What are the uses of sunitinib and pazopanib?

A

both: metastatic renal cell carcinoma
sunitinib:
-GI stromal tumor
-pancreatic neuroendocrine tumor

39
Q

What are the adverse effects of sunitinib and pazopanib?

A

nausea, diarrhea
hand foot skin reaction (palmar erythrodysesthesia)
discoloration of nails or hair
hypothyroidism
HTN, QT prolongation, decreased LVEF
bleeding

40
Q

What are the drug interactions of sunitinib and pazopanib?

A

substrates of CYP 3A4

41
Q

What are the uses of sorafenib and regorafenib?

A

sorafenib:
-metastatic hepatocellular carcinoma
regorafenib:
-GIST
-hepatocellular carcinoma

42
Q

What are the adverse effects of sorafenib and regorafenib?

A

GI (less severe than sunitinib)
HFSR (more common than sunitinib)
severe rash, mild skin discolouration
hypertension
bleeding
metabolic and electrolyte abnormalities
cardiotoxicity & QT

43
Q

What are the drug interactions of sorafenib and regorafenib?

A

substrates of 3A4
sorafenib inhibits 2B6, 2C8

44
Q

What are the indications for lenvatinib?

A

thyroid cancer
hepatocellular carcinoma
renal cell carcinoma
endometrial cancer
-advanced endometrial with pembrolizumab

45
Q

What do most people with CML have?

A

abnormal chromosome called the Philadelphia chromosome

46
Q

What causes the development of the Philadelphia chromosome?

A

ABL1 gene on chromosome 9 breaks off and sticks to a gene called the BCR gene on chromosome 22
-produces a new gene called BCR-ABL1, known as a fusion gene

47
Q

What is an example of a BCR-ABL inhibitor?

48
Q

What are the targets of imatinib?

A

BCR-ABL kinase
PDGF
c-KIT

49
Q

What are the adverse effects of imatinib?

A

edema
hepatotoxicity
bone marrow suppression

50
Q

What are the drug interactions of imatinib?

51
Q

What are around half of melanomas caused by?

A

a mutation in a gene called BRAF

52
Q

What is the issue with BRAF inhibitors?

A

they quickly develop resistance

53
Q

What is the MOA of BRAF inhibitors?

A

they target the fault BRAF gene
-blocking the BRAF protein to slow or stop the growth of the cancer

54
Q

What are examples of BRAF inhibitors?

A

vemurafenib
dabrafenib
encorafenib

55
Q

What are BRAF inhibitors used in combination with for melanomas?

A

MEK inhibitors

56
Q

What are the adverse effects of BRAF inhibitors?

A

cutaneous toxicities
-maculopapular rash (common)
-phototoxic reactions (wear sunscreen)
-squamoproliferative lesions
-alopecia

57
Q

Describe the interplay of BRAF and MEK.

A

the BRAF protein can affect other proteins, such as MEK, which makes cancer cells divide and grow in an uncontrolled way

58
Q

What is the MOA of MEK inhibitors?

A

they block the MEK protein, which slows down the growth of cancer cells

59
Q

What are examples of MEK inhibitors used for melanoma?

A

trametinib
cobimetinib
binimetinib

60
Q

What are the usual BRAF and MEK inhibitor combinations for melanoma?

A

dabrafenib with trametinib
vemurafenib with cobimetinib
encorafenib with binimetinib

61
Q

Why are BRAF inhibitors and MEK inhibitors combined in melanoma?

A

synergistic and delays onset of drug resistance
-tolerability is also improved

62
Q

What are the adverse effects of MEK inhibitors?

A

fewer cutaneous squamous cell carcinomas
acneiform rash
cardiotoxicities
ocular toxicity

63
Q

What are the drug interactions of MEK inhibitors?

A

trametinib: none significant
cobimetinib: substrate of 3A4

64
Q

What are proteasomes?

A

tiny, barrel shaped structures found in all cells
-they help break down proteins the cell doesnt need into smaller parts
-the cell can then use them to make new proteins that it does not need

65
Q

What is bortezomib?

A

a proteasome inhibitor used to treat multiple myeloma

66
Q

What is the MOA of proteasome inhibitors?

A

cause a buildup of unwanted proteins in the cell, which makes the cancer cells die

67
Q

What are examples of proteasome inhibitors?

A

bortezomib (sc)
carfilzomib (IV)
ixazomib (po)

68
Q

What are proteasome inhibitors used for?

A

multiple myeloma

69
Q

What are the adverse effects of proteasome inhibitors?

A

neutropenia
thrombocytopenia
peripheral neuropathy
diarrhea
reactivation of Hep B or Herpes zoster

70
Q

What is recommend to combat the increased risk of herpes zoster or herpes simplex reactivation with proteasome inhibitors?

A

antiviral prophylaxis
-valacyclovir

71
Q

How can bortezomib-induced peripheral neuropathy be curtailed?

A

adjustments in route (SC rather than IV) and scheduling (weekly s more frequent)
-less common and less severe with carfilzoimb and ixazomib

72
Q

What can repair DNA strand breaks?

A

single-stranded breaks: PARP
double-stranded breaks: BRCA1, BRCA2

73
Q

What happens if PARP enzymes are inhibited?

A

cancer cells lose one of the major mechanisms to repair single-stranded DNA breaks, which decreases their viability

74
Q

What are cancer cells with mutated BRCA genes less able to do?

A

repair dsDNA breaks, thus more likely to die
-because ssDNA breaks left unrepaired by the PARP inhibition will turn into dsDNA breaks during DNA replication
-inhibitors of PARP can stop the growth of cancer, particularly cancers that have mutated BRCA genes

75
Q

Which cancers are PARP inhibitors used for?

A

gynecological
breast
prostate
specifically cancers with BRCA mutation

76
Q

What are the ovarian cancer indications for PARP inhibitors?

A

niraparib:
-advanced or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer and who are in response to platinum-based chemo
olaparib:
-recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer with BRCA-mutation and who are in response to platinum-based chemo

77
Q

What are the breast cancer indications for PARP inhibitors?

A

olaparib:
-early stage, high risk BRCA mutated, HER2 negative as adjuvant tx, continues for 1yr

78
Q

What are the prostate cancer indications for PARP inhibitors?

A

olaparib:
-metastatic castration resistant prostate cancer with BRCA or ATM mutations
niraparib/abiraterone:
-combination production for metastatic castration resistant prostate cancer with BRCA mutation with prednisone

79
Q

How is progression through different phases of the cell cycle controlled?

A

by a group of proteins called cyclins

80
Q

What occurs when there is dysregulation in CDK4 and CDK6?

A

allows cancer cells, despite their genetic damage, to progress through the G1 checkpoint to the S phase of the cell cycle

81
Q

What are CDK4/6 inhibitors used for?

A

adjuvant and metastatic breast cancer

82
Q

Which cancer is CDK often overexpressed in?

83
Q

Which therapies are CDK inhibitors synergistic with?

A

anti-estrogen therapies

84
Q

What are examples of CDK4/6 inhibitors?

A

abemaciclib
-continuous
palbociclib
-3 wks on 1 wk off
ribociclib
-3 wks on 1 wk off

85
Q

What are the adverse effects of abemaciclib?

A

neutropenia (23%, less)
diarrhea (85%, the downside)
increased ALT/AST
alopecia
increased creatinine
VTE/PE
pneumonitis

86
Q

What are the adverse effects of palbociclib?

A

neutropenia (55%)
diarrhea (26%)
alopecia
VTE/PE
pneumonitis

87
Q

What are the adverse effects of ribociclib?

A

neutropenia (61%)
diarrhea (35%)
increased ALT/AST
alopecia
VTE/PE
QT prolongation
pneumonitis

88
Q

What are the drug interactions of the PARP inhibitors?

A

abemaciclib:
-3A4 substrate, P-gp substrate
palbociclib:
-3A4 substrate, weak inhibitor
ribociclib:
-3A4 substrate, moderate inhibitor, QT