ACVIM lectures Flashcards
(211 cards)
1
Q
What is the warburg effect?
A
aerobic glycosis
2
Q
T/F Cancer cells stop using oxidative phosphorylation in favor or glycosis
A
False- they continue to do same amount of oxidative phos AND additionally use glucose for glycolysis
3
Q
What is another substance that can be used for energy creation?
A
glutamine
4
Q
What effects dose lactate have on the tumor microenvironment?
A
- immune suppression/escape (impact APC, increase Tregs)
- enhance angiogensis (increased VEGF/IL8)
- enhance tumor cell migration/invasion (ECM/integrins)
5
Q
What impact does lactate have on patient outcome?
A
high lactate- worse outcome
6
Q
TKTL1 activity correlates to what activity of glycolysis?
A
increased so higher activity worse outcome (eval in mammary tumors once)
7
Q
18F-FDG-PETCT is sensitive or specific?
A
sensitive
8
Q
2-DG (inhibits glycolysis) results in what changes in invasion and metastasis?
A
reduced - possibly due to reduced cathepsin levels (which degrades ECM)
9
Q
Cancer stem cells can do what actions?
A
initiate and maintain tumor growth and produce heterogenous tumor population
10
Q
What is symmetric cell division with stem cells?
A
two identical daughter cells
11
Q
What is asymmetric cell division in stem cells?
A
stem cell and more differentiated progenitor cell (limited self renewal and lead to terminal differentiation)
12
Q
What are common stem cell markers via flow?
A
CD34, CD133, CD44
13
Q
T/F There are specific markers that differentiate normal from cancer stem cells
A
false
14
Q
What therapies are CSC more resistant to?
A
RT and chemo
15
Q
CSC have dysregulation in DNA repair via what mechaanisms?
A
p53, MDM2, gammaH2AX
16
Q
Inhibition of EGFR in CSC can lead to what response?
A
increased sensitivity to chemotherapy and radiation
17
Q
What is dedifferentiation?
A
loss of lineage committment and stem cell feature increase
18
Q
what is transdifferentiation?
A
change from one lineage (differentiated) to another
19
Q
Exposure of diff cell to OCT4, cMyc, SOX2, KLF4 results in what?
A
pluripotent stem cell production
20
Q
Hypoxia and subsequent HIF1 alpha production upregulates ___ and ____ which can promote dedifferentiation
A
Oct4 and Nanog
21
Q
ZEB, SNAIL, SLUG, TWIST transcription factors help to induce what process?
A
EMT
22
Q
What metabolic processes do CSC utilize?
A
either! plastic with ox phos and aerobic glycolysis and can switch
23
Q
what is metformin and how is it used in cancer research/therapy?
A
antidiabetic drug and blocks mitochondrial functon
24
Q
PGE2 mediates what inflammatory processes and cancer processes?
A
EGFR/VEGFR: proliferation, migration, angiogensis, mets
BCL-2NFkB - apoptosis inhibition
IL12 - immune suppression
MMP2/9 - mets/invasion
25
T/F PGE2 is a negative regulator of hematopoietic stem cell growth and development
False- PGE2 increases it
26
Rituximab targets what?
CD20
27
Herceptin targets what?
HER2
28
Avastin targets
VEGF
29
what is phenotype drug discovery?
look for change in cell/tumor then find target later
30
What is target based drug discovery?
ID target and create drug then test on tumor
31
T/F high throughput screening typically results in a drug
False- then look at hits and look for leads within those to confirm, increase potency/selectivity, reduced tox etc and then lead optimize the drug
32
what are the 4 types of ab formulations?
- Mouse
- chimeric
- caninized
- fully canine
33
what are three main methods for creation of monoclonal ab?
Hybridoma (using mouse)
phage display
transgenic mouse
34
What is time to development of animal health drug and how many early phase drugs make it to market?
6-8 years
| 1 in 10 drugs
35
what is fractional cell kill hypothesis?
drug kills constant fraction of cell population (independent # of cells)
36
overall results of chemo tx depends on what two conditions?
drug dose and number/freq of tx cycles
37
what two drug classes are impacted by rate of cell growth (don't work as well in tumors with non cycling cells)?
antimetabolites and antitumor antibiotics
38
what are benefits of initial tumor debulking in drug sensitiivty?
- smaller # starting cells (fractional cell kill)
- improved O2 delivery
- recruit quiescent cells to cycle
39
What are most common sites of alkylation for alkylators and end result?
N7 and O6 guanine and result in strand breakage when repair attempted
40
What DNA substitution occurs with alkylation of N7 guanine?
C to T (due to modified guanine)
41
what class of alkylators lead to crosslinks?
bifunctional
42
What are the nitrogen mustards (5)?
```
cytoxan
ifosfamide
mechlorethamine
chlorambucil
melphalan
```
43
What nitrogen mustards must be activated by P450?
cyotxan and ifosfamide
44
how does melphalan enter cells?
charged and hydrophilic so requires active uptake via AA transporter - via leucine transporter)
45
what are nitrosurea?
CCNU
| BCNU
46
what are methylating agents?
procarb
dacarab
TMZ
47
what other action does procarbazine have and what is main lesion caused by it?
MAO
| O6
48
what is main lesion for methylating aklyators?
O6
49
What alkylators cross BBB?
CCNU and TMZ
50
What is the role of methylguanine methyltransferase?
repair O6 alkylation
51
MMR overexpression or underexpression leads to resistance to alkylators?
underexpression
52
T/F ifosfamdie is given in single fractions because its metabolism can become saturated
False - given as multiple doses bc of saturation which reduced efficacy
53
Is doxorubicin or metabolite doxorubicinol more cardiotoxic?
Doxorubicinol
54
interaction of topo II and doxorubicin leads to what?
formation of cleavable complex - so unable to ligate the DS breaks created by topo II
55
what is MOA of actinomycin D?
intercalation DNA (in GC regions) and inhibition of RNA/protein synthesis
56
What is MOA of bleomycin?
binds to Fe intracellularly (Cu extracellularly) and then binds O2 and then cleaves DNA (up to 4/complex)
57
up or down regulation of TopoII alpha leads to resistance to dox?
downregulation
58
T/F Antimetabolites have high rate of secondary cancer
false b/c doesn't bind to DNA
59
What MTX form has most activity
MTX polyglutamates (also traps inside cell)
60
What are the cytidine analogs?
cytarabine and gemcitabine
61
what are actions of cytarabine?
inhibition DNA polymerase alpha and incorporate into DNA leading to chain elongation
62
gemcitabine has what actions?
inhibits RNR, incorporates into DNA, inhibits DNA polymerase
63
gemcitabine metabolites increase or decrease kinase enzyme actions?
increases - so more active drug made
64
What are actions of 5-FU?
inhibits DNA/RNA synthesis via incorporation and TS inhibition
65
what enzyme metabolizes 5-FU?
DPD
66
what is metabolism process of Rabacfosadine?
hydrolysis
deamination (RL step)
phosphorylation to PMEGpp (analog of dGTP)
67
what is action of Rabacfosadine?
competitive inhibitor DNA polymerase alpha, deta, episolon and incorporated into DNA
68
Vincas bind to - or + end of microtubules?
+ end = prevent assembly
69
taxanes bind where on microtubule?
interior surface
70
what is main excretion of vincaas?
hepatic
71
T/F alterations in alpha and beta tubulin leads to reduced affinity for vinca binding
false-makes tubulin more stable to microtubules are more stable (can lead to increased sensitivity to taxanes
72
What is most common binding site of platinums?
N7 purine (adenine or guanine)
73
Inter or intrastrand adducts are the main form of platinums?
intra, but interstrand is responsible for main cytotoxicity
74
Regarding "worst drug rule", which drug is "worst" and when is it used?
"worst" = use drug that has least cell kill against cell resistant to other drug
use first
75
For drugs with similar potency, which drug should be used?
more specific agent first and broader action longer
76
AUC of doxorubicin directly correlates with what in dogs?
absolute neutrophil count and outcome
77
what impacts acute and chronic cardiotoxicity of doxo?
max plasma concentration
78
what is max tolerated AUC for carbo in cats?
2.75-2.95mg*min/mL
79
What is calculation of feline carbo clearance?
GFR x 2.60
80
What are the routes of metastasis?
direct extension
lymphatic
hematogenous
permation
81
T/F E cadherin alone is a better prognostic factor compared to the ratio of type IV collagenases
false- ratio is better
82
metastasis is efficient or ineffecient?
inefficient
83
what can improved survival of tumor cells in circulation (3 things)?
homotypic tumor aggregation
heterotypic aggregation with lymphocytes/platelets
plasticity of cell membrane
84
what are two possible fates of disseminated tumors cells?
cell death - (immune recognition or incompatible soil)
| survive - (dormancy, recirculation, proliferation)
85
what is the seed and soil hypothesis?
certain organs are more suitable for metastatic growth based on tumor type
86
Does each tumor cell have the same metastatic capability?
No!
87
MDSC are pro or antiangiogenic?
pro
88
What is the foraging hypothesis?
less than ideal primary tumor environment (hypoxia, lack of nutrients ect) may drive metastasis
89
what do platelets produce that can activate survival, EMT and invasion pathways in tumor cells?
TGF beta (via SMAD in the tumor cell)
90
binding of platelets to tumor cells promotes or downregulates NFkB?
promotes
91
platelets release what factor that recruit immune cells that may help to create a niche for tumor metasasis?
chemokines
92
T/F circulating tumor cells is proof of metastasis
false - can have present w/o overt metastasis - also human with breast cancer in "remission" for 7-22 years can have circulating tumor cells detected w/o illness/progressive disease
93
Is there generally more inflammation in primary or metastatic leisons?
metastatic
94
Where are RTK's located?
cell membrane
95
what results after ligand binding to RTK?
ATP docks and results in phosphorylation
96
MAPK promotes what genes?
Cyclin D, fos/jun, p21
97
What is bound to RAS in active and inactive state?
GTP active
| GDP inactive
98
Activated RAS has what downstream effects?
RAF
PI3K
and several more
99
what main things does the PI3K signaling pathway impact?
cellular anabolism anad catabolism
100
Who many classes of PI3K are there?
class 1-4
101
which class of PI3K mainly activates AKT?
class 1
102
what is a critical downregulator of PI3K?
PTEN
103
what molecules are inhibited by AKT
MDM2, caspase 9, Ink4, BAD
104
What molecules are activated by AKT?
mTOR, GSK3B (inhibits cyclin D1 and alters cell proliferation)
105
What results in JAK activation?
cytokines binding to receptor resulting in dimerization/phosphorylation
106
TGF beta results in what phosphorylation?
serine/theronine
107
What are HSP90 responsible for?
folds new proteins to active form
108
If HSP90 is not active, what occurs to proteins?
protein is tagged for ubiquination and degraded
109
What is the role of XPO1?
exports tumor suppressor proteins from nucleus
110
what are 3 ways cell signaling is turned off?
- reduced growth factors/chemokines (internalization/degraded)
- intracellular phosphatases
- proteasome mediated degradation
111
what are 4 mechanisms of dysregulation of cell signaling?
- overexpression
- mutation
- chr. translocation
- autocrine loop activation
112
what are methods to inhibit RTK cell signaling?
- block ATP binding
| - mAb bind extracellular domain (result in endocytosis/ADCC to reduce signaling)
113
T/F aberrant expression of a protein indicates the tumor is relying on the protein for survival
False!!!
114
What are the main steps to drug development for targeted therapies?
- ID target
- Drug lead generation
- optimize the lead compound
- clinical trials
115
type 1 small molecule inhibitors bind when?
when kinase is in DFG-IN (ATP bound state) - turned on
116
What other area on the target do small molecular inhibitors bind to?
gatekeeper amino acid (near the ATP binding pocket)
117
type 2 small molecular inhibitor bind when?
DFG- out (inactive state)
118
where do type 3 and 4 small molecular inhibitors bind?
allosteric site -outside ATP binding site but block ATP binding (more unique binding sites vs type 1-2)
119
What are irreversible small molecule inhibitors?
covalent
120
what is most common tumor response to small molecular inhibitors?
PR
121
Are basket or umbrella trials more common for small molecular inhibitors?
basket
122
what are 3 types of resistance to small molecular inhibitors?
- mutation in target (can be gatekeeper)
- overexpression of target molecule
- additional mutations in other parts of pathway or other pathways
123
T/F - when resistance forms to small molecule inhibitors, additional drugs, even cytotoxic therapy may then be more effective
true
124
What are 3 methods to prevent resistance to small molecular inhibitors?
- combination therapy (RT, chemo, mAbs)
- combine w/ checkpoint inhibitors
- treat microscopic disease
125
What two main tumor types in pets express KIT mutations?
MCT, GIST, AML
126
What main tumor in pets has BRAF mutations?
TCC (>80%)
127
what are the targets of imatinib?
BCR-ABL, Kit, PDGFR
128
What are targets of toceranib?
KIT, PDGFR, VEGFR1 and 2, FLT3, CSF1 (at very high concentrations, VEGFR3, RET, ALK, AXL)
129
What are the targets of masitinib?
Kit and PDGFR (more selective than imatinib) and also Lyn and FGFR3
130
what is ORR of canine MCT to toceranib?
43% (70% if KIT mutation- early study)
131
In a retro eval, what other tumor types does toceranib have activity (outcome MCT)
head/neck carcinomas
agasaca
nasal tumor
thyroid carcinoma
132
what can act as a surrogate marker for toceranib activity vs taking a biopsy?
serum VEGF increase w/ inhibition of VEGFR2 pathway
133
An unpublished study of palladia vs RT vs combination for nasal carcinoma had what results?
RT alone MST 12mn
combination 20mn
palladia 8mn
134
What is impact of toceranib with microscopic met dz after SOC in OSA and HSA?
no impact
135
what has been shown to increase and decrease with toceranib treatment?
reduced Tregs and increased IFNgamma
136
RV1001 targets what?
PI3Kdelta
137
What is main toxicity noted with RV1001?
hepatotox gr 3-4 in all patients after 2-3 weeks
138
what was ORR to RV1001 in canine LSA?
77% (phase 2 study)
139
what is target of KPT335?
SINE (XPO1)
140
What is duration of benefit in canine LSA to KPT335?
1-3mn
141
What is target of Acalabrutinib?
BTK (covalent)
142
phase 1 study of acalabrutinib in DLBCL what was response?
no CR, some PR and more SD (ORR 25%- with PFS 22.5d)
143
Where is most common DNA methylation location?
Cytosine (5 position) followed by guanine
144
What occurs routinely to cytosine in DNA?
deaminated to uracil that is corrected
145
Is C followed by G common?
No - rare, but densely packed in CpG islands
146
Is methylation heritable?
yes
147
In cancer, what is the methylation status of promoters of TSG?
hypermethylation
148
MGMT expression induces resistance to what drug in dogs/cats in LSA?
CCNU
149
Open active chromatin has what histone modification?
hyperacetylation
150
T/F microRNAs code for a protein
false - silence protein expression
151
long non-coding RNA have what functions
- collect mRNA (prevent expression)
- form scaffolding for DNA
- mRNA stability to enhancing
- contribute to splicing mRNA
- impact translation mRNA
152
Canyons in DNA regions are hyper or hypomethylated?
hypomethylated
153
What genes are have been ID to have hypermethylation in cancers in dogs?
DAPK
p16
DLC1
TFPI1
154
What is bisulfite sequencing used for?
ID methylated CpG dinucleotides
155
what is digital restriction enzyme analysis of methylation?
Way to evaluate methylated regions of DNA (leaves only methylated sequences)
156
Methylation patterns may act as a biomarker of what?
predisposition ot cancer development
157
What are demethylating drugs evaluated in dog cell lines?
6-TG and Zeb
158
Valproic acid acts as what agent?
HDACi
159
T/F miRNAs are overexpressed only in cancer
False- can be over and underexpressed
160
What damage molecule represents steady state oxidative DNA damage?
8 -oxo-7- hdyrodeoxyguanosine
161
what is the p and q arm of a chromosome?
q long arm
| p short term
162
Myc-IgH translocation occurs in what disease?
Burkitt lymphoma
163
what is lost in CLL in humans and dogs?
Rb
164
what causes AML4-ALK mutation
inversion
165
What is the MC tumor type with ITD noted in dogs?
exon 11 of ckit in dogs
166
What is aneupolidy?
abnormla # chr (loss or gain)
167
what is polypoidy?
more than 2 complete sets of chr
168
In canine HS - what genes have losses?
Rb1 (more common in flat coats vs BMD), CDK2NA and PTEN
169
what are possible mechanisms of aneuploidy?
merotelic attachment, supranumerary centrosome, spindle assembly checkpoint defect and chromosome cohesion defects
170
microsatellite instability is whaat type of nucelotide instability?
insertion/deletion
171
what type of mutation occurs in adult tissue and doesn't pass to progeny?
somatic
172
what type of mutation occurs in germinal tissue and present in every cell?
germline
173
what are different types of DNA damage stx changes?
DSB
SSB
adduct
base pairing abnormalities
174
MRE11, RAD50, NBS1 respond to SS or DS breaks?
DSB
175
ATR kinase is activated in what DNA damage?
SSB and alkylation/adducts
176
AMT kinase is activated in what type of DNA damage?
DSB
177
ATM and ATR phosphorylate what substances
H2AX (histone)
| p53
178
which DNA repair pathway is active in G1 phase?
ATM
179
what DNA repair pathways are active in S and G2 phases?
ATM, ATR
180
When is HR vs NHEJ repair used?
S and G2 for HR and all phase G1
| HR requires template strand
181
which DNA repair mechanisms is slower and most accurate?
HR
182
what activates NHEJ?
DNA-PKcs (with Ku70 and Ku80 interaction)
183
what is needed for RAD51 to bind appropriately for ATM?
BRCA2
184
PARP assist with which type of DNA breaks?
SS
185
what repair process is activated when fanconi proteins identify interstrand crosslinks?
HR and NER
186
oxidized bases are repaired by what method?
BER
187
UV lesions and alkyl adducts are repaired by what method?
NER
188
MMR deficiency have increases in what?
microsatellite instabilities
189
hypoxia increase or reduced effects of genomic instability?
increases
190
Knockout of ATM or ATR will result in fatal changes?
ATR
191
what is the only genetic driver of human and canine LSA is conserved?
P53
192
What are main components of the TME across most tumors?
```
CSC
ECM
stromal fibroblasts
blood vessels networks
lymph vessel networks
stromal adipocytes
inflammatory macs
immunosuppressive cells
innate immune cells
adaptive immune cells
```
193
what is an important event that initiates TME?
changes in normal stromal cells due to interactions w/ CSC
194
T/F normal ECM promotes spread of tumor cells
false! usually inhibits
195
The following are characteristics what
- increased stiffness
- fragmented hyaluronic acid
- increased Tenascin C
- increased IL6 and pro inflammatory cytokines
tumor associated ECM
196
decreased CAV-1, increased SMA, vimentin, FAP and MCT4 are markers on what cells?
CAF
197
what does MCT4 do?
export lactate
198
what immunomodulatory factors do CAFs release?
IDO
TGFbeta
Arg
199
under normoxic condition how do VHL and HIF interact?
VHL degrades HIFalpha
200
what is the most potent stimulator of angiogenesis?
VEGFA
201
Which VEGFR is more responsible for tumor associated neoangiogensis
VEGFR2
202
What is role of Tie 2 when bound to Ang1 and Ang2?
Ang1 binding maintains current state
| Ang2 binding results in new vasculature (less stable though)
203
what are methods to target angiogensis pathway?
blocked VEGFA
block VEGF R or other RTKs (PDGFR, EGFR, MET R)
target downstream pathways (MAPK pathway ex)
204
what is the goal of anti-angiogentic tx?
normalize tumor associated vasculature
205
what factors control lymphangiogenesis?
VEGFC and D (bind VEGFR3)
206
what do adipocytes provide to TME?
support angiogenesis
provide energy for tumor cells
encourages pro-inflammatory state
207
TAMs that are M1 and M2 have what role?
M1: pro immune
M2: pro tumor
208
Is state of TAM static/discrete?
No
209
Adenovirus FASL overcomes what tumor feature?
immunosuppressive barrier
210
what is eBAT?
EGF and uPA targeted carrier of pseudomonas exotoxin
211
what are the main effects of eBAT?
EGFR/uPAR+ tumor cells
uPAR+ stromal environment
uPAR+ macs
