W15 Molecular/targeted therapy of cancer Flashcards
1
Q
_____ vectors have a better safety profile than retroviral vectors and are more efficient at delivering genes to non-dividing cells.
A
Lentiviral
2
Q
_____ delivery of virus is hindered by rapid clearance of viruses from body by the immune and complement systems.
A
Systemic
3
Q
Cationic liposomes are microscopic vesicles that enter cells by endocytosis and have been used to deliver genes to tumor cells. They have a selectivity for ____ cells.
A
endothelial
4
Q
______ is a modification of “naked” plasmid DNA gene delivery using particles. DNA is absorbed into gold particles and fired into tissues under high pressure. It is inefficient and cannot be given systemically.
A
gene gun
5
Q
________ are inefficient at delivering genes compared to viruses.
A
plasmids
6
Q
_______ is a type of cancer gene targeted therapy that involves surface modification to allow delivery and/or entry to cells via specific surface receptors and is largely applied to _____ vectors.
A
transductional targeting
adenoviral
7
Q
______ are composed of 2 single-chain antibodies with one recognizing the fiber knob and the other a tumor-associated antigen. This adaptor targets adenovirus to a specific tumor type.
A
bispecific fusion proteins (diabodies)
8
Q
________ is a type of cancer gene targeted therapy that exploits unique gene expression in specific cell types once the vector has entered the cell.
A
transcriptional targeting
9
Q
Replication-competent oncolytic viruses are viruses that _____________.
A
conditionally replicate in cancer cells
10
Q
ONYX-015 vector is a ____-deleted adenovirus that conditionally replicates in cells with non-functional ____ gene.
A
E1b
p53
11
Q
_____ has the potential to shut down cell cycling when infected with wild-type adenovirus but is prevented from doing so through actions of the product of ____.
A
p53
E1b
12
Q
____-deficient viruses cannot replicate in normal cells with p53 intact, however, in cells that have no functional p53 protein, viral replication can proceed and cause cell lysis.
A
E1b
13
Q
Newly developed gene editing approaches, such as ______ and ______ provide novel ways to manipulate the genome.
A
TALENS and CRISPR
14
Q
Delivery and use of ________ molecules to cancer cells can be used to ablate the deleterious effects of activated oncogenes.
A
small interfering dsRNA (siRNA)
15
Q
Exogenously delivered _______ is directed to RNA-induced silencing complex (RISC). This complex is then directed to the target mRNA of the offending gene. By degradation of mRNA, expression of the target gene is suppressed, which is known as _____________.
A
- siRNA
- posttranscriptional gene silencing
16
Q
What is the major advantage of RNAi?
A
potential to target multiple genes of various pathways involved in tumor progression
17
Q
siRNA can be delivered directly to tumors because systemic delivery is vulnerable to what?
A
enzymatic inactivation and renal clearance
18
Q
What gene therapy has the ability to convert a relatively non-toxic prodrug to an active compound within a cancer cell?
A
delivery of a suicide gene, usually viral or bacterial enzyme
19
Q
Success of suicide gene therapy largely depends on the extent of ___________.
A
the bystander effect
20
Q
What are the 5 basic mechanisms that mediate the bystander effect?
A
- Release of activated soluble factors as cells die
- Passive diffusion of toxic factors from intact cells
- Transference of toxic compounds through gap junctions
- Phagocytosis of apoptotic bodies released from transduced cells
- Stimulation of host immune response in TME
21
Q
The cytokine, IL-18, promotes _______.
A
cell mediated responses
22
Q
Delivery of cytokine genes and a pro-drug activating gene can be delivered to cancer cells, which has been studied in canine ________ which used cells to deliver IL-2 to tumors with encouraging results.
A
melanoma
23
Q
______- directed CAR T-cells has been used in dogs and showed:
A
CD20
feasibility but only modest clinical responses
24
Q
Based on the studies does with humans and mice, which complications or limitations could or did occur in regards to the cloning of the MDR gene for delivery to normal bone marrow cells to protect them against cytotoxic effects of conventional chemotherapy?
A
- did not protect against GI cells
- MDR gene could transfer to malignant cells, rendering them insensitive to effects of standard drugs
25
The transcription factor _____ has been identified as a potential mediator of radio-resistance and has been found to have an anti-apoptotic effects. A study demonstrated that modulation of expression of this TF by siRNA affected oral SCC sensitivity to RT through upregulation of ______________.
- slug
- p53 upregulated modulator of apoptosis (PUMA)
26
Inhibition of _____ and _____ pathways in cancer have been shown to modulate chemotherapy and radiosensitivity.
Notch and EGF
27
Recent pilot studies have been performed in dogs using what 2 systemically delivered oncolytic viruses?
- reovirus and vesicular stomatitis virus
28
What is a risk factor for naked DNA?
Auto-immunity
29
In humans, BRAF mutations have been found in ________ and _______.
cutaneous melanoma and papillary thyroid carcinoma
30
AKT phosphorylation activates _____, a transcription factor that has antiapoptotic properties.
NF-kB
31
AKT also phosphorylates the proteins _____, ____, _____, and ___, leading to redistribution of these proteins either in or out of the nucleus, ultimately inhibiting apoptosis while promoting cell cycling.
mTOR, p21, p27, and GSK3
32
Mutations in PTEN have been documented in canine cancers, _______ and ____.
OSA and melanoma
33
Broadly describe 2 mutations documented in kinases.
- point mutations: single amino acid change
- internal tandem duplications: deletion of amino acids or insertion of amino acids
34
A _______ mutation occurs in the BRAF gene in approximately ____% of human cutaneous melanoma. This mutation causes a conformational change in BRAF, mimicking its activated form.
point mutation
60%
35
RAS is dysregulated through _____ mutation in several hematopoietic neoplasms.
point mutation
36
KIT is a RTK normally expressed on _____, _____, ____ and ______ cells.
hematopoietic stem cells, melanocytes, in the CNS, and mast cells
37
In ___% of canine grade 2 and grade 3 mast cell tumors, mutations consisting of ______ are found in exon _____ in the juxtamembrane domain of KIT. Additional activating mutations in the extracellular domain of KIT, specifically exons ____ and ____, have also been identified.
- 30%
- internal tandem duplications
- 11
- 8 and 9
38
KIT mutations consisting of _________ in the ____ region are found in 50% of human patients with GISTs and are also found in canine GISTs.
deletions in the JM domain
39
What RTK mutation is seen in human AML, lung carcinoma, and several types of carcinoma?
- FLT3 ITDs in AML
- EGFR point mutations in lung carcinoma
- PI3K-alpha mutations in several types of carcinomas
40
What type of RTK mutation is seen in HER2 in human breast and ovarian cancers?
overexpression
41
Is ABL or BCL the cytoplasmic TK that is dysregulated in CML?
ABL
42
Describe 2 autocrine loops that lead to kinase dysregulation in dogs with cancer.
- OSA: MET and its ligand, HGF
- HSA: coexpression of KIT and its ligand, SCF
43
Single-agent therapy with trastuzumab (Herceptin) for HER2+ breast cancer patients result in response rate of ___% in the setting of metastatic disease. Response rates approach ___% when combined with chemotherapy.
- 25%
- 50%
44
Small molecule inhibitors work primarily by _____________.
blocking ATP binding site of kinases
45
Imatinib (Gleevec) is orally administered and binds to the ATP pocket of ____, ____, and _____.
KIT
ABL
PDGFRa
46
In the chronic phase of CML, imatinib induces remission rate of ___% and most patients remain in remission for longer than 1 year. The remission rate for patients in blast crisis range from ___-___% and often last less than ______.
- 95%
- 25-50%
- 10 months
47
Name 4 mechanisms of resistance to imatinib in patients with CML. Which is the most common?
1. Development of point mutation in ABL that preclude drug binding (MOST COMMON)
2. Upregulation of ABCB1 and increased efflux of the drug
3. BCR-ABL1-independent pathways of signal transduction
4. BCR-ABL gene amplification
48
Treatment of human GISTs with imatinib result in response rates of ___-___%. A small number of GISTs have activating mutations in ______ instead of KIT.
- 50-70%
- PDGFRa
49
A subset of people with NSCLC have tumors with activating mutations in EGFR (exons ____ and ___) that respond to _____ or ____ - small molecule inhibitors of EGFR. Resistance is often mediated by a second mutation at codon 790. _____ is a protein kinase inhibitor that targets this specific resistance mutation. Be sure to include their brand names.
- exons 19 and 21
- erlotinib (Tarceva)
- gefitinib (Iressa)
- osimertinib (Tagrisso)
50
Name a chromosomal translocation seen in a small number of patients with NSCLC and a small molecular inhibitor that has demonstrated significant activity for these patients.
- EML4-ALK translocation
- crizotinib (Xalkori)
51
________ is a small molecular inhibitor of BRAF that has significant activity against cutaneous malignant melanomas that possess this mutation. Response rates for BRAF mutant melanoma patients exceed ____%, compared to <5% for patients treated with dacarbazine.
- vemurafinib (Zelboraf)
- 50%
52
What is the brand name for rapamycin?
Rapamune
53
_________ and ______ are rapamycin analogs approved for use in patients with metastatic renal carcinoma.
temisorlimus (Torisel) and everolimus (Zortress)
54
______ is a BTK inhibitor, which is a cytoplasmic kinase that is critical for B cell receptor activity. It is approved for the use in several B-cell malignancies, including _______, ______, and _________. Response rates typically exceed ___-___%.
- ibrutinib (Imbruvica)
- CLL, folicular LSA, Waldenstroms macroglobulinemia
- 70-80%
55
________ and _______ are small molecular inhibitors of PI3K-gamma-delta that have shown some activity against peripheral and cutaneous T cell LSAs.
tenalisib and duvelisib
56
Sunitinib (Sutent) is a small molecule inhibitor of several RTKs. Name them.
- VEGFR1/2
- PDGFRa/b
- CSFR1
- KIT
- FLT3
- RET
57
Palladia is a multitargeted inhibitor closely related to _____ that exhibits a similar target profile. Name the targets.
- sunitinib
- VEGFR1
- PDGFRB
- KIT
- FLT3
- CSFR1
58
In the phase I study for Palladia in dogs with spontaneous malignancies. ____% experienced an objective response, ___% achieved stable disease, and overall clinical benefit was ___%.
- OR: 28%
- SD: 26%
- OCB: 54%
59
A study evaluating Palladia in dogs with recurrent or metastatic intermediate or high-grade MCTs was performed. The ORR was ___% and the overall clinical benefit was ___%. Dogs whose MCTs harbored activating mutations in KIT had a response rate of ___% compared to those without mutations ___%.
- ORR: 43%
- OCB: 60%
- KIT mutations: 69%
- No KIT mutations: 37%
60
Name the targets of Masitinib (Kinavet, Masivet).
- KIT
- PDGFRa/b
- Lyn
- Fyn
- FGFR3
61
Long-term treatment with masitinib (2 years), resulted in increased number of dogs with MCTs with long-term disease control (___% alive) compared with those treated with placebo (___% alive).
- 40%
- 15%
62
RV1001 is a _______ inhibitor that has demonstrated significant activity against naive and relapsed T- and B-cell LSA in dogs. In phase I and II clinical trials, ORR ranged from ___-___% with the DLT of ______.
- PI3K-delta inhibitor
- ORR 62-77%
- Hepatotoxicity
63
Verdinexor (KPT-335, Laverdia) is an orally bioavailable small molecule inhibitor of ____. It has been evaluated in phase I and phase II studies in dogs with LSA. The ORR in both studies was ___% and the DLT was ______, _______, and _______.
- XPO-1
- 35%
- hyporexia, weight loss, and hepatotoxicity
64
Blockage of XPO1 forces retention of proteins, including ____, ____, ___, ____, and ____, allowing their function.
- p53
- p21
- RB
- FOXO
- NFkB
65
Name 3 drugs that inhibit VEGF RTK pathway making them anti-angiogenic.
- Bevacizumab (Avastin)
- Sunitinib (Sutent)
- Toceranib (Palladia)
66
What was the response rate to the thrombospondin-1 mimetic peptide, ABT-898, in 28 dogs with soft tissue sarcoma?
32%
67
A prospective randomized placebo-controlled clinical trial in dogs with multicentric LSA treated at first relapse with ABT-526 combined with lomustine was performed. What were the findings?
- significantly improved time to tumor progression and remission duration but NOT remission rate compared to lomustine alone
- No toxicities were noted
68
A pilot study in 13 dogs with _____ treated with endogenous endostatin delivered via liposome-DNA complexes was performed. There was non-specific anti-tumor activity.
STS
69
A phage vector delivering tumor necrosis factor alpha (RGD-A-TNF) to alphaV integrins on tumor endothelium to promote local cytotoxicity to the tumor endothelium was performed in tumor-bearing dogs in a dose-escalation trial. ___% achieved a partial response and ___% achieved stable disease.
PR: 14%
SD: 43%
70
Clinical evaluation of compounds that inhibit MMPs have been largely unrewarding. A large randomized trial of 303 dogs with ____ were treated with MMP inhibitor Bay-12-9566 or placebo following DOX chemotherapy. Results did not improve survival.
OSA
71
In a study of 18 dogs with TCC, piroxicam treatment was associated with reduced urinary concentrations of proangiogenic growth factor _______ and induction of apoptosis. A subsequent study evaluated these parameters in 12 dogs with TCC treated with piroxicam in combination with cisplatin. Reductions in urinary ____ and ______ were associated with response to combination regimen.
- bFGF
- BFGF and VEGF
72
_____ is an agent with antiangiogenic effects that has been approved for treatment of human multiple myeloma.
thalidomide
73
Name 4 mechanisms of action of metronomic chemotherapy.
1. inhibition of tumor angiogenesis
2. activation of antitumor immunity
3. induction of tumor dormancy
4. inhibition of cancer stem cells
74
Upregulation of ______ occurs during treatment with metronomic Cytoxan and othes.
thrombospondin-1
75
_____ cells may be most influential in rebuilding tumor cells during break period after the acute damage of MTD chemotherapy. Preclinical models have demonstrated that these cells acutely decrease with MTD treatment only to rapidly rebound during break period.
CEPs
76
_________ and _______ are two major immune cells that are key players in immunoediting.
Tregs and MDSCs
77
Name 3 immunostimulatory effects of metronomic Cytoxan.
1. Decreases in number and function of Tregs
2. Dendritic cell activation
3. Stimulation of tumor specific cytotoxic T cells
78
In a study in dogs, circulating Tregs were significantly decreased when ______ was given alone or in combination with _____. Dogs receiving combination therapy concurrently had significant increases in serum concentrations of ____ that were inversely correlated with Treg numbers after 6 weeks of therapy.
- Cytoxan
- Palladia
- IFNg
79
Low doses of ____ to mice with metastatic lung tumors led to a selective decrease in Treg number and function without interfering with tumor-specific cytotoxic T cell function.
paclitaxel
80
______ appears to decrease MDSC accumulation within tumor tissues, likely in part through the differentiation into functionally active immunostimulatory DCs.
gemcitabine
81
What alkylator besides Cytoxan has shown to reduce circulating Tregs in human cancer patients.
temozolomide
82
Daily low dose TMZ therapy in 30 tumor-bearing dogs either alone or in combo with daily low-dose Cytoxan has been evaluated. Dogs receiving Cytoxan or the combination with TMZ had significantly lower percentages of _______. Dogs receiving TMZ alone _______. Neither drug nor the combo was found to influence plasma concentrations of ____ and _____.
- Tregs
- did not have lower Tregs
- TSP-1 and VEGF
83
_______ is a stage of tumor development in which viable neoplastic cells are present but inactive as a result of dynamic equilibrium between apoptosis and proliferation.
Dormancy
84
Give 3 examples of non-cytotoxic drugs that indirectly target angiogenesis.
1. COX-inhibitor
2. thalidomide
3. tetracycline
85
An early trial tested administration of oral Cytoxan alternating with etoposide and combined with daily piroxicam for the adjuvant treatment of dogs with splenic HSA. What were the findings?
Similar efficacy and less toxicity compared to control dogs receiving DOX
86
A study comparing metronomic Cytoxan versus DOX for splenic HSA in dogs found a MST of ___ for dogs receiving either treatment.
3.4 months
87
Dogs with HSA were treated with maintenance metronomic Cytoxan + and NSAID following splenectomy and 6 doses of DOX. What were the findings?
No effect on PFS or overall survival time
88
Dogs with OSA were treated with daily Cytoxan and NSAID after limb amputation and carboplatin. What were the findings?
no difference in outcome compared to amp + carbo alone
89
In a larger, multicenter study, dogs with OSA were randomized to receive piroxicam and Cytoxan with or without Palladia after limb amputation and carboplatin. What were the findings?
Compared to historical controls that received amp + carbo alone, there was no difference in outcome
90
When administration of lomustine at a daily oral dose of 2.84 mg/m2 was tested in 84 dogs with various malignancies, a high incidence of adverse effects occurred and led to discontinuation of the therapy in ___%.
30%
91
Chlorambucil combined with monthly doses of lomustine in 8 dogs with glioma was well tolerated. What were the notable side effects?
grade 1 or 2 thrombocytopenia after chronic therapy in 25% of patients
92
In dogs with various malignancies, the combination of MTD DOX with concurrent metronomic Cytoxan was evaluated in a phase I study. What were the findings?
- well tolerated
- administration of DOX associated with non-selective depletion of circulating lymphocytes thus the potential benefit of Treg depletion by Cytoxan would have been lost
93
A study of 50 dogs with macroscopic STS treated with 5 x 6Gy hypofractionated RT followed by daily oral oral piroxicam and thalidomide plus every other day oral Cytoxan in 20 dogs was performed. The addition of MC protocol had no effect on PFS but MST of treated dogs was _____ compared to RT alone at _____.
MST MC: 25 months
MST RT alone: 10 months
94
Intra-tumoral IL-2 therapy with daily oral Cytoxan in 6 dogs found a decrease in ______ as well as an increase in ____ compared to baseline.
- Tregs
- TSP-1
95
Anti-angiogenic RTK inhibitors have found a risk of metastatic conditioning. This phenomenon has been observed with ________.
sunitinib
96
Name 4 antiangiogenic biomarkers.
1. VEGF
2. Treg
3. CEC/CEPs
4. Hypertension (surrogate)
97
Tumor DNA in dogs and other mammals is globally _______, specifically in ______ satellite sequences, which leads to genomic instability. Cancer cells also acquire sequence-specific promoter ________ and transcriptional repression in normally unmethylated regions, several of which have been shown to be associated with known TSGs: ____, ____, ___, and _____.
- hypomethylated
- hypermethylation
- p16, VHL, Rb, p73
98
Methylation of DNA is controlled by four known DNA methyltransferases (DNMT), _____ is the most important in cancer.
DNMT1
99
_________ and _____ are nucleoside analogs that incorporate into DNA and inhibit DNMT activity, but allow replication to proceed and are FDA approved for treatment of _________.
- 5-azacytidine (Vidaza) and 5-aza-deoxycytidine (Dacogen)
- myelodysplastic syndrome
100
The commonly used cardiac medications ______ and _____ also possess demethylating activity.
procainamide and hydralazine
101
Hydralazine-valproic acid (VPA) combinations have demonstrated activity in _______ and ________ in early human trials.
myelodysplastic syndrome and cutaneous T-cell LSA
102
A phase I clinical trial of the demethylating agent 5-azacytidine has been performed in dogs with ________. No responses or correlation between gene methylation were reported
urothelial carcinoma
103
What are 2 potential problems with DMNT inhibitors?
1. Increase genomic instability
2. trigger metastatic phenotype
104
What are 4 benefits of HDAC inhibitors?
1. Decreases angiogenesis
2. Increases apoptosis
3. increases differentiation in cancer cells
4. Enhances efficacy of therapy.
105
Name 4 mechanisms where HDAC inhibitors can inhibit angiogenesis.
1. Upregulation of VHL --> inhibition of HIF-1a and VEGF
2. Decreased expression of pro-angiogenic factors, bFGF ANG2, and Tie-2
3. Inhibition of endothelial NO synthase and endothelial cell proliferation and tube formation
4. Inhibition of commitment of endothelial progenitor cell to endothelial lineage
106
Name 2 HDAC inhibitors that are approved by FDA for treatment of cutaneous T cell LSA.
Vorinostat (Zolinza) and Romidepsin (Istodax)
107
Inhibition of canine prostate cancer metastasis to bone was observed after HDAC inhibitor ______ treatment in a murine xenograft model.
AR-42
108
Synergy between ______ and the DNMT inhibitor _____ has been observed in canine OSA cell lines.
vorinostat and zebularine
109
The commercially available anti-convulsant drug VPA can function as both a _______ and ______.
DNMT and HDAC inhibitors
110
VPA was recently shown to enhance the efficacy of ____ in canine OSA cell lines and to synergize with ______ in a canine OSA xenograft.
DOX
DOX
111
Studies have demonstrated a _____- fold increase in susceptibility to proteasome inhibitor-associated apoptosis when comparing tumor cells with corresponding normal tissues.
3-40-fold
112
______ and _______ are the only two proteosome inhibitors that have received FDA approval for treatment of human multiple myeloma and mantle cell LSA.
Bortezomib (Velcade) and carfilzomib (Kyprolis)
113
Toxicology studies for bortezomib have been performed in dogs and a biologically effective and tolerable dose established for treatment of _________.
Golden retriever muscular dystrophy
114
_______ is a molecular chaperone responsible for the conformational maturation of many proteins involved in diverse oncogenic activities.
Heat shock protein 90 (HSP-90)
115
The best studied inhibitors of HSP-90 are ______ antibiotics of the ____ class
- ansamycin antibiotics
- geldanamycin class
116
The HSP-90 derived from most tumor cells has a binding affinity for the HSP-90 inhibitor ______ approximately ____-fold higher than HSP-90 derived from normal cells. This is likely due to overaccumulation of _________ in tumor cells leading to increased HSP-90 activity.
- 17-AAG
- 100-fold
- misfolded proteins
117
What RTKs or other proteins do geldanamycins (HSP-90 inhibitors) inhibit?
- KIT
- MET
- PDGFR
- IGF-1R
- HIF-1
- Mutant p53
- survivin
118
What are the negative effects of HSP-90 inhibitors?
- protect colon carcinoma cells from cisplatin
- potentiated bone-specific mammary carcinoma metastasis in one murine model
119
STA-1474 in a _____ inhibitor that has been evaluated in a phase I clinical trial in dogs with spontaneous cancer. Clinical responses were observed in dogs with _____, ______, ______, and ________.
- HSP-90 inhibitor
- MCT, OSA, melanoma, thyroid carcinoma
120
_______ is a "nick-sensor" that signals the presence of DNA damage and facilitates DNA repair.
PARP
121
_____ is the main enzyme in catabolizing PAR to ADP-ribose.
PARG
122
When PARP binds to DNA strand breaks, it activates an enzyme causing shuttling of PARP, and, subsequently, opening up chromatin to allow ______ to enter the nucleus, move PARP substrate, and DNA strand breaks are repaired. Due to excessive ______, PAR decreases and thus chromatin returns to its original structure.
PARG
PARG
123
______, ________, and ____ are FDA approved PARP inhibitors for BRCA-mutant breast and ovarian cancer patients.
- Olaparib (AstraZeneca)
- Rucaparib (Rubraca)
- Niraparib (Zejula)
124
______ is responsible for the nuclear export of a broad variety of target proteins, including a large number of known suppressor proteins ______, _____, _____, _____ and _____.
- exportin 1 (XPO1)
- p53, survivin, Rb, p21, and IkB
125
_____ inactivates XPO1 and has shown considerable selective anti-proliferative and proapoptotic activity in multiple solid and hematopoietic tumor types.
Small molecule elective inhibitors of nuclear export (SINE)
126
Laverdia (KPT-335) has shwon in vitro antiproliferative activity in canine tumor cell lines derived from ___, ____, ____ and _____.
LSA, MCT, OSA, melanoma
127
Name 4 RTKs that have been found to be overexpressed in canine OSA cell lines?
- Met/RON
- C-kit
- EFGR
- PDGFR
128
