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
2
Q
Most common cancers that undergo endocrine tx’s?
A
breast cancers, prostate cancer, endometrial cancers, ovarian cancers
3
Q
What’s tamoxifen used for?
A
Breast cancer
4
Q
tamoxifen MOA
A
estrogen antagonist in breast cancer cells;
agonist effects on endometrium, bone, and lipids
5
Q
T or F: Tamoxifen is appropriate for breast cancer in females only.
A
F
In males too
6
Q
AEs of tamoxifen
A
flushing, hot flashes, edema (menopause-like sx’s), thromboembolic events, mood changes, arthralgia, weakness
7
Q
What’s a major risk of taking tamoxifen?
A
Endometrial cancer
8
Q
What’s second line endocrine tx for breast cancer?
A
Fulvestrant
9
Q
Fulvestrant MOA
A
Estrogen receptor antagonist
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
11
Q
Aromatase inhibitor MOA
A
blocks estrogen PRODUCTION
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
13
Q
Name the two nonsteroidal, reversible inhibitors of aromatse
A
anastrozole, letrozole
14
Q
Name the steroidal, irreversible aromatase inhibitor
A
exemestane
15
Q
AEs of aromatase inhibitors?
A
hot flashes and flushing
HTN
Osteopenia/osteoporosis
weakness, arthralgia
fatigue
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
17
Q
What is NOT an effective tx for prostate cancer?
A
5-alpha-reductase inhibitors (e.g. finasteride, dutasteride)
18
Q
Leuprolide and goserelin are examples of…
A
LHRH agonists
19
Q
MOA of LHRH agonists (leuprolide and goserelin)
A
down-regulation of hypothalamus-pituitary axis
20
Q
What’s important to know when starting LHRH agonist tx?
A
There’s an initial “flare” response
21
Q
What can be Rx’ed to tx the initial flare from LHRH agonists?
A
bicalutamide for 14-30d
22
Q
What LHRH antagonist is used for prostate cancer?
A
degarelix
23
Q
MOA of degarelix?
A
blocks pituitary receptors > reduces LH and FSH secretion > rapid decrease in testosterone production
24
Q
T or F: Degarelix causes an initial flare.
A
F
25
What's abiraterone?
androgen biosynthesis inhibitor
26
MOA of abiraterone
Inhibits CYP17 > blocks androgen production in testes, adrenal glands, and tumour
27
What unique AE does abiraterone cause as a result of its MOA?
Reduces cortisol production > causes increased ACTH > causes accumulation of mineralocorticoids > HTN, hypokalemia, edema
28
What's given in combo with abiraterone? Why?
Prednisone > prevents compensatory rise in ACTH
29
Name 4 androgen receptor blockers
Bicalutamide, flutamide, enzalutamide, apalutamide
30
Androgen deprivation tx's: AEs
Urinary sx's, gynecomastia, hot flashes, reduced libido and ED, fatigue, wt gain, loss of muscle mass, osteopenia/-porosis, MI/increased QT
31
Name the 5 classes of small molecule drugs (and the suffixes used in each drug class)
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)
32
Tyrosine kinase inhibitor MOA?
Intracellularly block signals from activated trans-membrane proteins by competing w/ ATP for the TK region of the trans-membrane receptor
33
Epidermal growth factors receptors - list them
HER1/2/3/4
34
Another name for HER1 receptors?
EGFR
35
What do the epidermal growth factors receptors do?
They ctrl cell differentiation, proliferation, and survival
36
Through which pathway do the epidermal growth factors receptors act?
Tyrosine kinase pathway (TKP)
37
4 EGFR inhibitors for non-small cell lung carcinoma:
1. erlotinib
2. gefitinib
3. afatinib
4. osimertinib
38
These two EGFR inhibitors target the EGFR tyrosine kinase cytosolic domain
erlotinib, gefitinib
39
This EGFR inhibitor targets EGFR, HER2, HER4, and HER3 (transphorylation of it)
afatinib
40
Which EGFR inhibitor isn't used often?
osimertinib
41
Diarrhea is a huge AE of this EGFR inhibitor
afatinib
42
HER2 is overexpressed in what types of cancers?
15% of breast cancer cases, and some gastroesophageal cancers
43
AEs of HER2 agents?
rash, D, cardiotox, hepatotox
44
Specific HER-2 agents?
lapatinib
45
Name VEGF inhibitors
axitinib
46
What do VEGF inhibitors do?
Reduce/prevent angiogenesis of tumors
47
What kind of cancer is tx'ed w/ VEGF inhibitors?
Renal cell carcinoma
48
AEs of VEGF inhibitors?
HTN, bleeding, impaired wound healing
49
What do multikinase inhibitors target?
> 1 tyrosine kinase region in the cytoplasmic side of transmembrane protein receptors
50
What're sunitinib and pazopanib?
multikinase inhibitors
51
sunitinib and pazopanib: how do they help tx cancer?
inhibit tumor growth, cellular proliferation, and angiogenesis
52
What're sunitinib and pazopanib used to tx?
renal cell carcinoma
53
Unique AEs of sunitinib and pazopanib?
1. hand foot skin rxn (HFSR) aka plantar palmar erythrodysethesia (PPE)
2. discoloration of nails and/or hair (yellow or white)
54
Why is bleeding an AE of sunitinib and pazopanib?
Due to VEGF-inhibition activity
55
How do sorafenib and regorafenib work?
inhibit cellular proliferation and tumor angiogensis
56
What's sorafenib used for?
hepatocellular carcinoma, renal cell carcinoma
57
What's regorafenib used for?
Gastrointestinal Stromal Tumor (GIST), hepatocellular carcinoma
58
Unique AEs of sorafenib and regorafenib?
HFSR aka PPE
Severe rash, mild skin discoloration
59
What's a "Philadelphia Chromosome"?
An oncogene that's formed when the BCR portion of chromosome 22 fuses w/ the ABL portion of chromosome 9
60
The "Philadelphia chromosome" is found in this cancer
CML (chronic myelogenous leukemia)
61
List the BCR-ABL inhibitors
imatinib, dasatinib, nilotinib, bosutinib, ponatinib
62
What is wrong with the protein made by the BCR-ABL protein in CML (chronic myeloid leukemia)?
It's an abnormal tyrosine kinase, hence the need for a tyrosine kinase inhibitor
63
List the tyrosine kinase inhibitors (classes):
EGFR inhibitors, HER2 inhibitors, VEGF inhibitors, multikinase inhibitors, BCR-ABL inhibitors
64
List the two cyclin dependent kinase (CDK) inhibitors
palbociclib, ribociclib
65
CDK inhibitors: what kind(s) of cancer are they used in?
Estrogen-receptor positive breast cancers
66
CDK inhibitors: MOA
Inhibit CDK (cyclin dependent kinase) > decrease breast cancer cell proliferation > induce senescence (i.e. it halts proliferation)
67
CDK inhibitors can be used synergistically with what type of chemotx?
anti-estrogen tx's (e.g. estrogen receptor antagonists, aromatase inhibitors)
68
AEs of CDK inhibitors
Neutropenia, stomatitis, N, fatigue
69
Name a poly ADP-ribose polymerase (PARP) inhibitor
Olaparib
70
What proteins are responsible for repairing daily DNA damage?
PARP, BRCA1 and BRCA2
71
MOA of PARP inhibitors?
Inhibits PARP > DNA repair is prevented > cancer cell death
72
When would PARP inhibitors be used?
In cancers where BRCA1/2 is damaged/not working properly
73
AEs of PARP inhibitors
N/V, fatigue, anemia
74
Name the proteasome inhibitors
bortezomib, carfilzomib, ixazomib
75
Proteasome inhibitors are used in these types of cancers
hematologic cancers
76
What kind of cancers are tx'ed by proteasome inhibitors?
multiple myeloma, non-Hodgkin lymphoma
77
MOA of proteasome inhibitors
Damaged proteins and other substrates cannot be degraded by 20S proteasome > toxic metabolites buildup in cancer cell > cancer cell ruptures
78
Anaplastic lymphoma kinase gene mutation: most common pt population?
young pts who're NON-smokers
79
ALK inhibitors: list them
crizotinib, alectinib, ceritinib
80
One of this ALK inhibitor's AEs includes vision disorder
ceritinib
81
There're 3 types of non-small cell lung cancer. What're they?
squamous cell carcinoma, large cell carcinoma, adenocarcinoma
82
What kinds of mutations drive NSCLC adenocarcinoma and large cell carcinoma?
PD-L1, EGFR, AKL, ROS
83
BRAF kinase inhibitors: list them
vemurafenib, dabrafenib
84
BRAF kinase inhibitors: indication
melanoma ONLY
85
BRAF kinase inhibitor MOA:
Block BRAF kinase > stop cancer cells from growing
86
AEs of BRAF kinase inhibitors
alopecia, N, rash, photosensitivity, severe hypersensitivity, cutaneous squamous cell carcinoma
87
How do we reduce the risk of cutaneous squamous cell carcinoma when tx'ing pts w/ BRAF kinase inhibitors?
Combine the BRAF kinase inhibitor w/ MEK inhibitors
88
MEK inhibitors: AEs
acneiform rash, cardiotox's, ocular tox
89
mTOR (mamallian target of rapamycin) - what is it?
serine/threonine protein kinase that ctrls cell cycle progression, cell proliferation, and angiogenesis
90
Name mTOR inhibitors
temsirolimus, everolimus
91
What kinds of cancers are tx'ed using mTOR inhibitors?
renal cell carcinoma, pNET (pancreatic neuroendocrine tumor), breast cancer (historical)
92
What's the hedgehog pathway?
Cell differentiation and organ development pathway that's active in vertebrate embryonic development
93
What role does the hedgehog pathway play in adults?
Tissue maintenance and repair only (or differentiation/organ development)
94
Inappropriate reactivation of the hedgehog pathway in adults is assoc w/ what kind of cancer?
basal cell skin cancer
95
Name a hedgehog pathway inhibitor
vismodegib (only one with "-gib" suffix)
96
AEs of vismodegib:
GI effects, loss of taste, alopecia, arthralgia
97
Which two targeted tx's are assoc w/ alopecia?
hedgehog pathway inhibitors and BRAF inhibitors
98
hedgehog pathway inhibitor CI
pregnancy (teratogen)
99
Bruton's tyrosine kinase (BTK) inhibitors: name them
ibrutinib, acalabrutinib
100
BTK inhibitors: used to tx which cancers?
chronic lymphocytic leukemia (CLL)
relapsed mantel cell lymphoma (MCL)
101
MOA of BTK inhibitors
Inhibition of B-cell receptor and cytokine receptor pathways > inhibits proliferation and survival of malignant B-cells
102
AEs of BTK inhibitors
arrhytmias, PR prolongation, tumor lysis syndrome, bleeding, Hep B reactivation
103
Phosphoinositide-3-kinase (PI3K) inhibitors: name it
idelalisib
104
MOA of idelalisib:
inhibits B-cell signaling > reduced B-cell migration to lymph nodes and bone marrow
ALSO induces malignant B-cell apoptosis
105
Idelalisib (a PI3K) is combined with this to tx CLL (chronic lymphocytic leukemia)
rituximab
106
idelalisib AE
GI, infections, rash, myelosuppression, pneumonia/pneumonitis, hepatotoxicity
107
BCL-2 inhibitors - name it
venetoclax
108
What is BCL-2?
B-cell lymphoma-2 = anti-apoptotic protein overexpressed in chronic lymphocytic leukemia (CLL) cells
109
Major AE of venetoclax (BCL-2 inhibitor)
Tumor lysis syndrome/hyperuricemia
110
Name the monoclonal antibody targets for cancer tx
CD20 antigen, EGFR (HER1), HER2, VEGF
111
Name the two anti-CD2- mabs
rituximab, obinutuzumab
112
MOA of anti-CD20 mabs (rituximab, obinutuzumab)
CD20 antigen found on malignant and nonmalignant B cells > mabs recruit other immune mediators enabling cell destruction and apoptosis
113
AEs of anti-CD20 mab tx?
infusion rxns (facial flushing, hypotension, fever, dyspnea, chest pain), tumor lysis syndrome, Hep B reactivation
114
CIs of anti-CD20 mab tx?
live vaccines 6mths before and after tx
115
anti-CD20 mab tx can cause tumor lysis syndrome - how to deal w/ this?
Premedicate w/ hydration and allopurinol
116
EGFR (HER1) mab drugs:
cetuximab, panitumumab
117
What's cetuximab used for?
head and neck cancers
118
What's panitumumab used for?
colorectal cancer
119
MOA of EGFR (HER1) mab drugs?
bind to extracellular ligands > stops intracellular tyrosine kinase pathways
120
Major AE assoc w/ EGFR mab drugs
Significant Mg2+ level drop
121
This EGFR mab drug is assoc w/ interstitial pneumonitis
panitumumab
122
Name the HER2 mab drugs
trastuzumab, pertuzumab
123
MOA of trastuzumab
blocks HER-2 dimerization > reduces cell replication
124
MOA of pertuzumab
blocks HER-2 heterodimerization > reduces cell replication
125
trastuzumab is also used in these cancers
GI cancers that overexpress HER2
126
Name the VEGF mab drugs
bevacizumab, ramicirumab,
127
bevacizumab MOA:
binds all circulating VEGF > prevents activation of VEGF receptors
128
bevacizumab is used for what types of cancers
advanced colorectal cancer, NSCLC, glioblastoma, gynecologic cancers
129
bevacizumab: AEs
HTN, bleeding, cerebral infarction, MI, proteinuria
130
ramicirumab MOA:
binds to VEGF receptor 2 specifically
131
What's ramicirumab used for?
advanced gastric cancer and gastroesophageal adenocarcinomas
132
Name 3 antibody-drug conjugates
DM1, trastuzumab emtansine, brentuximab vedotin, and ibritumomab tiuxetan,
133
DM1 MOA
microtubule inhibitor
134
Name two other microtubule inhibitors
taxanes and vinca alkaloids
135
Why isn't DM1 used anymore for cancer tx?
Too toxic
136
How is DM1 given nowadays?
As trastuzumab emtansine
137
T or F: trastuzumab emtansine is given at the same dose as DM1
F
It would kill the pt; half the dose is given
138
MOA of trastuzumab emtansine
trastuzumab brings emtansine to cancer cell > emtansine (containing DM1) gets taken up > causes tumor cell death
139
What kind of cancer is tx'ed w/ brentuximab vedotin
refractory Hodgkin dz and refractory anaplastic lg cell lymphoma
140
What kind of cancer is tx'ed w/ ibritumomab tiuxetan?
relapsed refractory follicular lymphoma
