Final Exam Flashcards
1
Q
Neoplasm
A
new growth, may be benign or malignant
2
Q
Tumor
A
nonspecific term meaning lump or swelling
3
Q
Cancer
A
any malignant neoplasm
4
Q
Hyperplasia
A
increase in organ or tissue size due to an increase in the number of cells (BPH)
5
Q
Metaplasia
A
an adaptive, substitution of one type of adult tissue to another type of adult tissue
6
Q
Dysplasia
A
an abnormal cellular proliferation is which there is loss of normal architecture
7
Q
Anaplasia
A
loss of structural differentiation, cells dedifferentiate (leiomyoma)
8
Q
What is the epithelial origin of carcinoma?
A
neoplasm of squamous epithelial cell origin
9
Q
What is the benign version of a carcinoma?
A
papilloma
10
Q
What is the epithelial origin of an adenocarcinoma?
A
neoplasm of glandular tissue
11
Q
What is the benign version of an adenocarcinoma?
A
adenoma
12
Q
What is the epithelial origin of a sarcoma
A
neoplasm with origin in mesenchymal tissues or derivatives (bone, muscle, fat)
13
Q
What is the epithelial origin of lymphoma and leukemia
A
hematopoietic tissues
14
Q
What is the epithelial origin of melanoma?
A
cancer of pigment producing cells in the skin or the eye
15
Q
What is the epithelial origin of a blastoma?
A
in precursor cells called blasts, which are more common in children
16
Q
What is the epithelial origin of a teratoma?
A
germ cell neoplasm made of several different differentiated cell/tissue types
17
Q
What cells are affected in myeloid leukemias?
A
common myeloid progenitor
18
Q
What cells are affected in lymphocytic leukemias?
A
common lymphoid progenitor
19
Q
What cells are affected in lymphomas?
A
small lymphocytes (T,B)
20
Q
Cancer is characterized by what three things?
A
- uncontrolled cellular growth (benign,cancer)
- tissue invasion (cancer)
- metastasis (cancer)
21
Q
What are the hallmarks of cancer?
A
- sustaining proliferative signaling
- avoiding immune destruction
- enabling replicative immortality
- activating invasion and metastasis
- inducing or accessing vasculature
- genome instability and mutation
- resisting cell death
22
Q
What is an oncogene?
A
any gene in a healthy cell capable of promoting tumor growth
23
Q
What is the genetic basis of cancer?
A
some cancers can result of mutation or deletion of a single potent tumor suppressor (retinoblastoma)
24
Q
2-hit Hypothesis
A
- assumption that hereditary retinoblastoma has a single deletion of the RB1 tumor suppressor
- heterozygous mutations can increase susceptibility to cancers
25
What kind of genes are BRCA 1/2?
tumor suppressors
26
BRCA mutations in breast cancer increase susceptibility to what type of inhibitors?
PARP inhibitors (synthetic lethality)
27
PARP inhibitors
- trap PARP to DNA, unable to uncouple from DNA
- olaparib, rucaparib, niraparib
28
What happens during G0/G1?
- cell is quiescent or accumulating building blocks required for division
- cellular contents are duplicated
29
What happens during S phase?
- each of the 46 chromosomes is duplicated by the cell
30
What happens during the G2 phase?
- the cell "double checks" the duplicated chromosomes for error, making any needed repairs
31
What determines when the cells move from one phase of the cell cycle to the next?
cell cycle clock driven by cyclins paired with cyclin-dependent kinases
32
Non-cell specific agents
DNA damaging agents
- alkylators
- intercalaters
33
G1-specific agents
Mitogenic signaling
- kinase inhibitors
- hormone inhibitors
34
S-specific agents
DNA replication
- anti-metabolites
- anti-folates
- Topo I inhibitors
35
G2-specific agents
Sister Chromatid Separation
- Topo II inhibitors
36
M-specific agents
Chromosome Segregation
- microtubule inhibitors
37
Common Oncogenes
- KRAS
- PI3K
38
Common Tumor Suppressors
- TP53, p16, RB1
39
Palbociclib Target
CDK4/6 (approved for BRACA 1/2)
40
Palbociclib Class of Drug
Kinase Inhibitor
41
Palbociclib Cell Cycle Target
G1
42
Palbociclib Dose Limiting Side Effects
- neutropenia
- N/V/D
- fatigue
- similar to traditional chemotherapies
43
Drugs that are more effective against cycling cells at many phases of the cell cycle are called what?
- cell cycle non-specific
- alkylating agents and DNA intercalation agents
44
Limitation of cell kill in phase specific drugs
- higher drug doses may not result in greater tumor cell killing
45
Increased cell kills requires what?
- prolonged exposure
- one way to increase the number of cells present in the sensitive phase is to maintain therapeutic levels of a drug over a long period of time
46
Dose limiting toxicities of cancer chemotherapies?
Hematopoietic
- Infections
- hemostasis
- anemia
GI
- N/V
- Loss of appetite
47
Designing Chemotherapy Regimens
- combination of drugs with different mechanisms of action
- no additive toxicity for drugs with non-overlapping toxicity
- increased cell killing
48
What is the CHOP regimen
- Cyclophosphamide (alkylating agent)
- Doxorubicin (anthracycline)
- Vincristine (microtubule inhibitor)
- Prednisone (steroid)
49
What are the causes altered drug metabolism?
- increased transport of drugs out of the cell through efflux pumps (PgP, MRP)
- reduced transport into the cell (loss of drug importer, decreased membrane permeability)
- Decreased activation of prodrug
- Increased detoxification of drug molecule
50
What causes changes in drug target or function?
- increased expression of drug target through gene amplification (upregulation makes it harder to inhibit)
- emergence of mutant, structurally altered taraget
- emergence of cells bearing alterations in genes whose products are functionally redundant with the drug target
51
What causes physiological changes that promote resistance?
- metastasis
- massive stromalization
- changes in cell state such as EMT
52
What causes cell survival mechanisms?
- activation of anti-apoptoic regulators
- increased repair of damage caused by chemotherapies
53
What is the most common reason for resistance to multiple chemos at once?
drug transport out of cell
54
What are the two major strategies to endocrine therapy?
- stop steroid receptor function
- decrease production of steroids
55
Tamoxifen MOA
- selective estrogen receptor modulator
- blocks estrogen-dependent breast cancer cell proliferation
- estrogen agonist effects
- acts as antagonist and agonists
56
SERM (Tamoxifen) Receptor Target
ER/PR +
57
SERM (Tamoxifen) Side Effects
- hot flashes due to anti-estrogen effects
- incidence of cancer increased 3-fold
58
SERM (Tamoxifen) Pre or Post menopausal?
- pre and post menopausal
59
Tamoxifen Drug Interaction
Less effective in patients with a common CYP2D6 varient
60
Tamoxifen vs Raloxifene
Tamoxifen
- antiproliferative to Breast
- blocks bone resporption
- endometrial hyperplasia
Raloxifene
- no endometrial hyperplasia
- increases bone mass in osteoporosis
61
Selective Estrogen Receptor Down Modulator (Fluvestrant and Elacestrant) MOA
- Fluvestrant has pure ER antagonist that has no agonist effects
- Elacestrant acts as partial agonist at low doses and full SERD at high dose
62
SERD (Fluvestrant/Elacestrant) Receptor Target
ER
63
SERD Indication (Fluvestrant/Elacestrant)
- ER+ metastatic breast cancer in postmenopausal women who have progressed on other anti-estrogen therapy
64
What does Aromatase convert?
- Androstenedione to estrone
- testosterone to estradiol
65
What do aromatase inhibitors block?
- synthesis of estrogens
- not the synthesis of androgens or progestrone
66
Non-steroidal aromatase inhibitors MOA
- Letrozole and Anastrozole
- potent and selective competitive inhibitor of aromatase activity
67
Indication of Non-steroidal aromatase inhibitors
- treatment of breast cancer in postmenopausal women
- first line or when started after 3-5 years of tamoxifen
68
Steroidal Aromatase inhibitor MOA
- acts as false substrate that aromatase converts to reactive intermediate
- binds irreversibly at active site and inactivates enzyme
69
Indication of Steroidal Aromatase Inhibitor
ER+ breast cancer in postmenopausal women who have progressed on anti-estrogen therapy
70
Which anti-estrogen compound directly inhibits the activity of the estrogen receptor throughout the body?
Fulvestrant (directly binds to ER)
71
Chronic administration of GnRH analogs ____ pituitary GnRH receptors and leads to pituitary _____
down regulates, desensitization
72
GnRH Analogs MOA
- acute admin induces surge of LH and FSH (agonist effect)
- chronic administration downregulates pituitary GnRH and decreases synthesis of estrogen
73
Toxicity of GnRH analogs
- transient worsening of symptoms related to initial agonists
- long term side effects include hot flashes, sexual dysfunction, gynecomastia
74
Indication of GnRH analogs in breast cancer
- premenopausal breast cancer
75
Medications for postmenopausal women with ER+ disease
- tamoxifen
- Nonsteroidal aromatase inhibitors
- steroidal aromatase inhibitor (exemestane)
- pure anti-estrogens (fulvestrant)
76
Medications for premenopausal breast cancer
- GnRH agonists
- Surgical oophorectomy
- Tamoxifen
77
Important enzyme in steroid hormone biosynthesis for prostate cancer
Type II 5-alpha reductase
- testosterone --> DHT in prostate cells
17 alpha-hydrolyse and C17,20 lyase
- conversion of pregnenolone and progesterone to DHEA and androstenedione
78
Importance of DHT in prostate cancer
- DHT binds to androgen receptor (AR) in prostate cells
- binding of AR to DHT leads to translocation to the nucleus and action of genes that drive cell
79
Degareliz/Relugolix versus Leuprolide/Goselerin
- Degarelix/relugolix will not cuase flare of testosterone production
- long term side effects are the same
80
Abiraterone MOA
- inhibits the function of 17-alpha hydroylase and C17,20 lyase
- inhibits the conversion of pregnenolone and progesterone to DHEA and androstenedion
81
Abiraterone side effect
- increased levels of cholesterol
82
AR Receptor Antagonists
- enzalutamide
- apalutamide
- darolutamide
83
AR Receptor Antagonist MOA
- bind to AR to prevent AR translocation to the nucleus
84
AR Receptor Antagonist Target
androgen receptor
85
AR Indication
- metastatic and non metastatic prostate cancer
86
What is unique about the action of Tamoxifen vs Fluvestrant?
- it activates ER in the bone
87
Which compounds act directly on AR?
AR antagonists (enzalutamide)
88
What is cell signaling largely driven by?
the transfer of phosphate by a kinase to a target protein
89
What are the common targets of several kinases?
- serine
- tyrosine
- threonine
90
What balances the activity of kinases by removing phosphates?
Phosphatases
91
Type I Kinase inhibitors
bind to the active conformation of the kinase
92
Type II kinase inhibitor
bind and stabilize the inactive conformation of the kinase
93
Type III kinase inhibitor
occupy the allosteric pocket outside of the ATP binding pocket
94
Competitive kinase inhibitors
bind kinase in a reversible fashion and must compete with ATP for binding
95
Covalent kinase inhibitors
covalently bind with reactive nucleophilic cysteine residue proximal to the ATP-binding site, resulting in the blockage of the ATP site and irreversible inhibition
96
Gefitinib Target
EGFR
97
Gefitinib MOA
- Type I TKI
- competitively inhibits the enzyme by binding to the ATP binding site in the kinase domain
- inhibition of kinase activity turns off signal to proliferate
98
Gefitinib Indication
- patients with metastatic NSCLC whose tumors have EGFR exon 19 or exon 21 (L8585R) mutations
99
Gefitinib Toxicities
- fatigue
- rash
- diarrhea
100
Afatinib Target
All ErbB receptors (EGFR)
101
Afatinib MOA
- covalent kinase inhibitor inhibitor
102
Common toxicities for drugs targeting EGFR
EGFR inhibitor associated rash
103
Common resistance mutation to Gefitinib
T790M
104
Osimertinib MOA
covalent third generation EGFR inhbitor
105
Osimertinib indication
- effective against T790M mutant EGFR
106
What two genes are genomically amplified in breast cancer?
HER2 and EGFR
107
Lapatinib MOA
- reversible inhibitor of EGFR and HER2
108
Lapatinib targets
EGFR and HER2
109
Side Effects of Lapatinib
- N/V/D
- decompensated heart failure
110
Tucatinib MOA
- TKI that preferentially binds to HER2
111
Tucatinib Target
HER2
112
FLT3 mutations
- cytokine receptor important for hematopoietic cell survival and proliferation
- mutations lead to increased proliferation and decreased apoptosis
- acute myloid leukemia
113
First generation FLT3 inhibitor
- midostaurin (broad kinase inhibitor)
- type I
114
Second generation FLT3 inhibitor
- crenolanib (more specific than first generation midostaurin)
- type I
115
Type II FLT3 inhibitors
Quizartinib (specifc for ITD mutations)
116
What target is not driven by molecular diagnosticcs
- VEGFR (tumor angiogenesis)
- limited impact on disease
117
Imatinib MOA
Type II small molecule inhibitor of the Abl tyrosine kinase to decreased proliferation and enhance apoptotic cell death in CML and GIST
118
Imatinib Toxicities
- n/v
- fluid retention and edema
- neutropenia and thrombocytopenia
119
Treatment length for imatinib
life long
120
Ponatinib MOA
- BCR-Abl inhibitor
- effective against all the major mutant forms of BCR-Abl
121
Indication for Ponatinib
- inhibits the gatekeeper mutation of T315I that is resistant to all other BCR-Abl compounds
122
Major drivers of Lung Cancer
- Unknown
- EGFR
- KRAS
- EML4-ALK
123
EML4-ALK translocation
- When ALK becomes inappropriately fused to ELM4 it becomes cytoplasmic and constitutively active
124
Alectinib MOA
tyrosine kinase inhibitor of ALK
125
Dabrafenib MOA
second generation BRAF-V600 inhibitor
126
Indication of Dabrafenib
- combination with trametinib for treatment of BRAF V600E/K mutant metastatic melanoma
127
Trametinib MOA
- inhibts the kinase activity of MEK1 and MEK2
- Type III allosteric inhibitor
128
Trametinib adverse reactiosn
- rash
- diarrhea
- lymphedema
129
Limitation of Trametinib use
- not indicated for the treatment of patients who have received prior BRAF inhibitor therapy
130
Bruton's Tyrosine Kinase
- important for normal B cell activity and B cell tumor growth
131
What type of kinase inhibitor is Ibrutinib?
Covalent
132
BTK inhibitors
Ibrutinib
Acalabrutinib
133
Acalabrutinib MOA
- second generation covalent BTK inhibitor
- also targets Cys481
- more potent and selective than ibrutinib
134
What type of kinase inhibitor is acalabrutinib
covaleng
135
Rapamycin Analogues
- sirolimus
- everolimus
136
What do rapamycin analogues target
mTOR (serine-threonine kinase)
137
Everolimus target
only mTORC1, not mTORC2
138
Oncotype Dx
helps to predict recurrence and therefore can prevent overtreatment, do not drive indications for specific therapies
139
What is the most dose-limiting toxicity of antimetabolites?
Myelosuppression
140
What target DNA and RNA precursors
anti-metabolites target the synthesis of essential molecules in proliferating cells
141
Purines
guanine, adenine
142
Pyridines
thymine, cytosine
143
MOA of pyrimidine analogs
- interfere with pyrimidine nucleotide synthesis (5-FU, capecitabine)
- Inhibition of DNA polymerase (Ara-C, Gemcitabine)
144
Uridine analogs
- primarily inhibit thymidine synthesis from uracil
145
5-FU MOA
- 5-FU is converted to FdUMP, which is an anlog of dUMP
- FdUMP forms ternary complex with thymidylate synthase and tetrahydrofolate
- this reaction cannot go to completion and thymidylate synthase is trapped
- TMP cannot be produced
- 5-FU also is converted into 5-UTP, which is incorporated into RNA and cannot be processed, affecting RNA stability
146
5-FU resistance
- downregulation of activating enzymes that convert 5-FU to FdUMP
- upregulating thymidylate synthase
147
5-FU susceptibility
~ 5% of the population has gene polymorphisms that result in deficiencyc of enzyme DPD which breaksdown 5-FU
- toxicity buildup
148
Drug Rescue For 5-FU
Thymidine
149
Drug Synergy of 5-FU
Leucovorate (increases the amount of covalent ternary complex with thymidylate synthase)
150
Capecitabine MOA
orally active prodrug of 5-FU
151
Cytosine Analogs MOA
primarily inhibit DNA synthesis
152
Cytarabine (Ara-C)
- Coverted to Ara-CTP intracellularly
- Ara-CTP is a competitive inhibitor of DNA polymerase alpha
- Cytidine deaminase converse cytarabine to non-toxic uracil arabinoside
- decreased levels of cytidine deaminase in the CNS makes Ara-C highly toxic in meningeal leukemia and lymphoma
153
Resistance mechanisms of cytarabine
- downregulation of activating enzymes
- upregulation of cytidine deaminase
- downregulation of transporter to move drug into cells
154
Gemcitabine vs Cytarabine
- increased cell permeability
- greater affinity for activating enzyme
- better evasion of DNA repair enzymes
- greater potency
155
Synergy Cytarabine
Tetrahydrouridine (cytidine deaminase inhibitor) to increase efficaccy and decrease resistance
156
Which drug is a nucleoside analog
Cytarabine
157
Purine analogs
6-MP
158
6-MP MOA
- inhibits multiple enzymes in the de novo purine biosynthesis pathway
- blocks synthesis of purine nucleotides
159
6-MP Metabolism
- TPMT polymophisms increase risk of toxicity
160
6-MP drug interactions
Xanthine oxidase inhibitors (allopurinol),
prevents the breakdown of 6-MP increasing toxicity
161
Which drug does allopurinol not block the breakdown of
6-TG
162
Importance of Folic Acid
- enters folate pool as dihydrofolate (FH2)
- reduction to tetrahydrofolate by DHFR
163
Inhibition of DHFR
- reduces tetrahydrofolate pools
- dihydrofolate (inactive folate) accumulates
164
Methotrexate MOA
mimics folic acid, bind and inhibit DHFR
165
Resistance to MTX
- amplification of DHFR gene or mutation of DHFR
- decreased polygultamation
166
Pemetrexed
- inhibitor of DHFR, thymidylate synthase, and glycinamide ribunucleotide formyltransferase
- decreased risk of drug resistance
167
Drug Rescue MTX
Leucovorin (increases intracellular pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition)
168
What are alkylating agents?
drugs that generate reactive electrophilic (electron deficient) intermediates that react with nucleophilic (electron rich) groups on DNA and proteins
169
What is the most common site of alkylation
Guanine N7
170
Most effective anti-cancer drugs are what?
bifunctional akylating agents that produce DNA intra- and interstrand linkages
171
What part of the cell cycle do alkylating agents impact
not cell-cycle phase specific
172
What in cells can react with alkylating agents and "quench" their activity?
Glutathione
173
Side effects of alkylating agents
- mutagenic and carcinogenic (second malignancies/leukemias)
- normal cell populations rapidly proliferating (gut, bone marrow)
- N/V, myelosuppresion, carcinogenic and teratogenic
174
Chlorambucil
decrease nucelophilicity of nitrogen by adding aryl groups
175
Cyclophosphamide MOA
chemically stable prodrug that requires hydroxylation of hepatic ccytochrome P450
176
What byproduct does cyclophosphamide produce?
acrolein
177
Toxicities of cyclophosphamide
- mild bone marrow toxicity
- hemorrhagic cystitis
178
Treating bladder toxicities caused by cyclophosphamide
mesna
179
Mitomycin C (mutamycine)
- aziridine containing natural product
- funcctions as alkylating agent
- bifunctional adducts
- myelosuppression
180
Platinum drugs
- covalent crosslinkers, but not alkylating agents
- often intrastrand
181
Cisplatin MOA
aquo form is highly reacctive and a potent electrophile, reacts especially with thiols
182
Dose limiting toxicity of ccisplatin
nephrotoxicity (proximal tubule
183
other toxcities of cisplatin
- severe N/V
- minimal bone marrow toxicity
- peripheral neuropathy dose related
- ototoxicity
184
Drug resistancce of cisplatin
- increased intracellular concentration of non-protein thiols, especially glutathione
- increased expression of cellular GST
185
Mechanism of Action of Topoisomerase I Inhibitors
- bind to and form ternary drug-enzyme-DNA complex, blocks DNA religation
186
What phase of the cell cycle is most sensitive to Topo I
S phase
187
Drug resistance to Topo I Inhibitors
- Glutathione S-transferase overexpression (most important)
- PGP overexpression
- MRP overexpression
- topoisomerase downregulation or mutation to prevent inhibitor binding
188
Topo I Inhibitor Drugs
topotecan
irinotecan
189
Ininotecan Mutation
SN-38 polymorphisms that cause low expression of UGT1A1, causing increased toxicity of Irinotecan
190
Topo II Inhibitor MOA
inhibits Topo II to relieve torsional strain and untangles DNA
191
What type of compounds are Topo 2 Inhibitors
only ones that produce double stranded DNA breaks
192
Topo 2 Inhibitor Drugs
Anthracyclines (doxorubicin)
Etoposide
193
Topo 2 Inhibitor mechanisms of toxicity
- intercalators (AC)
- free radical causes DNA damage
- inhibition of Topo II presumed to be most important therapeutically
194
What causes the cardiotoxicity seen with anthracycliens
free radical damage
195
What part of the cell cycle do AC topo II inhibitors impact
non-cell cycle dependent
196
Toxicities of doxorubicin
- cardiotoxicity
- severe local tissue damage if extravasated
- read color
197
Which topo II AC has less cardiotoxicity?
epirubicin
198
Drug that mediates toxicity of anthracyclines
- Dexrazoxane
- protects against AC induced cardiotoxicity
199
Etoposide MOA
Topo 2 inhibitor that does not intercalate
200
What part of the cell cycle does etoposide topo 2 inhibitors impact
G2
201
Resistance to Topo II Inhibitors
- Glutathione S transferase overexpression (doxorubicin only)
- pgp overexpression
- MRP overexpression
- topo 2 downregulation or mutation
- increased DNA damage repair
202
What part of the cell cycle does bleomycin impact
G2 and M phases
203
What is a dose limiting toxicity of bleomycin
- pulmonary (myelosuppression is minimal)
- skin rash
- bleomycin is inactivated by bleomycin aminohydrolyase, which is in high concentrations everywhere but skin and lung
204
What is dynamic instability?
- shrinking and growing of microtubules
- polymerization (build)
-depolymerization (fall apart)
205
What is bleomycin
Topo 2 intercalator
206
Vinca alkaloids MOA
prevent microtubule assembly
207
Taxanes MOA
prevent microtubule disassembly
208
What drug requires a specific transporter to get into cells?
Vinca alkaloids (PGP)
209
Vinca Alkaloids dose limiting toxicity
peripheral neuropathy
(myelosuppression rare)
210
Eribulin vs vincristine
lower rate of neurotoxicity
211
Microtubule Stabilzers
Taxanes and epothilones
212
Taxanes MOA
blocks depolymerization and segregation of sister chromatids to daughter cells
213
Resistance of Taxanes
PGP
214
Dose limiting side effects of paclitaxel
- myelosuppression
- sensory neuropathy is reversible
215
Cabazitaxel vs Paclitaxel
- poor binding to PGP and MDR
- more efficacious in multi drug resistant tumors
216
Epothilones vs Taxanes
- not cross resistant with taxanes
- poor PGP substrate
217
Epothilones toxicity
- neurotoxicity like taxanes (reversible)
218
mAb nomenclature: o
mouse
219
mAb nomenclature: xi
chimeric
220
mAb nomenclature: zu
humanized
221
mAb nomenclature: u
fully human
222
Binding of several antibodies to a receptor on the surface of a cancer cell can lead to what?
CDC and antibody-dependent cellular toxicity (ADC)
223
Trastuzumab MOA
recombinant humanized monoclonal antibody specific for HER2
224
Trastuzumab Target
binds to HER2 receptor and induces recepter internalization and degredation
225
Trastuzumab Toxicities
- flu like symptoms
- cardiomyopathy
- risk of hypersensitivity reactions
226
Pertuzumab MOA
recombanized humanized monoclonal antibody specific for HER2
227
Pertuzumab Target
binds to HER2 and inhibitors dimerization (decreases signal)
228
Indication of Pertuzumab
used in combination with Trastuzumab
229
Cetuximab MOA
- competitively inhibits binding of EGF and TGF-alpha
- blocks phosphorylation and activation of receptor associated kinases
- leads to inhibition of cell growth and induction of apoptosis
230
Where does cetuximab and panitumumab bind to?
extracellular domain of the EGF receptor
231
Toxicities of Cetuximab
- severe infusion reactions in first dose
- acneiform rash
- asthenias
- fever
232
Bevacizumab MOA
- Binds to VEGF and blocks interaction with endothelial receptors
- blocks endothelial cell proliferation and new blood vessel formation
233
Is VEGF mutated in cancer?
no!, not an oncogene
234
Can bevacizumab be used as a monotherapy?
No, no evidence of efficacy as a single agnet
235
Bevacizumab vs Ramucirumab
- bevacizumab binds to the ligand
- ramucirumab binds to the receptor
236
What does rituximab target?
CD20 in B-cell non-hodgkin's lymphoma
237
What does daratumumab target?
Cd38 in multiple myeloma
238
Trastuzumab Emtansine (T-DM1, Kadcyla) MOA
ADC consisting of cytotoxic agent emtansine linked to mAb trastuzumab
239
Adverse effects of trastuzumab emtansine
- AEs of trastuzumab
- thrombocytopenia
- hepatotoxicity
240
Trastuzumab/Derextecan MOA
ADC consisting of Topo I inhibitor and mAb
241
What is negative selection
strong affinity of immature T cell ans self MHC molecules that causes apoptosis
242
What is positive selection
binding is just right where T cells survive
243
Central tolerance
- all high avidity self reactive T cells have been
- need to empower T cells to kill cancers, which are often very different from self
244
Strategies to overcome central tolerance
- redirect T cells to cancer using genetic means
- redirect T cells to cancer using recombinant proteins
- lower the threshold to allow for targeting neo agents
245
BiTE target
CD3/CD19
246
BiTE drug
blinatumomab
247
Blinatumomab MOA
bind CD3 to physically bring an activated T cell in proximity with CD19
248
are BiTE drugs chimeric antibodies
NO
249
what do CTLA-4 and PD1 act as?
brakes or checkpoints on the immune system
250
Ipilimumab MOA
bind CTLA-4 receptor and reverses the CTL inhibition
251
What may be required with Ipilimumab?
high dose corticosteroids
252
Pembrolizumab MOA
bind PD-1 receptor blocks interaction with PDL-1 which is expressed on T cells
253
Sipulcel-T
PAP-GM-CSF to stimulate a patient's own immune system to attack the cancer
254
Side effects Sipulcel-T
flu like symptoms
possible increased risk of stroke
255
CAR-T cell target
CD19
