Cancer Flashcards
1
Q
Bcl2
A
Oncogene
Anti-apoptosis protein
2
Q
BCR and ABL
A
Oncogene
fused in chronic myeloid leukaemias
ABL is a tyr kinase
Reciprocal translocation between chromosomes 9 and 22
Forms the smaller Philadelphia chromosome
3
Q
Beta-catenin
A
Oncogene
Interacts with APC and mutated in small % colon cancers
Wnt signalling pathway
4
Q
BRAF
A
Oncogene
Downstream of Ras, mutated in melanomas and other tumours and activated by other mechanisms including fusion
V600E activation
Val –> glutamic acid
Adjacent to an activating phosphorylation site
Negative charge of glutamic acid mimics phosphorylation and so activates
5
Q
CCND1/CyclinD1
A
Oncogene
Activated by amplification in breast cancer
Controls Rb1 with CDK4
6
Q
EGFR/ERBB
ERBB2/HER2
A
Oncogenes
The ERBB family of RTKs includes ERBB aka EGF-receptor and ERBB2 aka HER2 - the target of breast cancer drug Herceptin
7
Q
ERG and TMPRSS2-ERG fusion
A
Oncogene
ERG is a TF involved in gene fusions in prostate cancers, leukaemias etc. TMPRSS2-ERG in 1/2 prostate cancers
Controls differentiation
8
Q
MLL
A
Oncogene
Histone methyltransferase, modifies histones, fused by translocation in leukaemias
9
Q
MYC family
A
Oncogene
TFs, clearly powerful and widely abnormal oncogenes (can be amplified), function unclear
Powerfully upreg many genes involved in proliferation, widely activated
10
Q
PIK3CA
A
Oncogene
Subunit of PI3Kinase, mutated in 1/3 breast, colorectal etc
Point mutated - one particularly common mutation changes a particularly -ve aa to +vely charged one
11
Q
Ras family, including KRAS
A
Oncogene
G proteins that carry signals from growth factor receptors to nucleus, activating the MAPkinase pathway. All become oncogenes when point mutated to active form in the same way
Blocks GTP hydrolysis, some by preventing access of GTP-ase activating proteins that complete the active site
12
Q
APC
A
Tumour suppressor gene
Large cytoplasmic protein that interacts with beta-catenin, component of the Wnt signalling pathway. Inactivated in most colon carcinomas. Inherited mutation gives polyposis coli
Normally indels
13
Q
BRCA1 and BRCA2
A
Tumour suppressor gene
Mutated in some families with strong hereditary predisposition to breast cancer. Component of homologous recombination DNA ds break repair. Protein unrelated to BRCA1 or 2.
14
Q
CDKN2A/INK4a/p16
A
Tumour suppressor gene
Inhibitor of Cdks, often deleted
15
Q
MLH1, MSH2
A
Tumour suppressor gene
Recognition proteins of the mismatch repair complex, mutated in some non-hereditary colon cancers and Lynch Syndrome families. MLH1 is an example of a gene frequently inactivated by DNA methylation of its promoter.
16
Q
p53
A
Tumour suppressor gen
Nuclear protein that arrests cell cycle in response to DNA damage and other insults. Mutated in 30-50% cancers
17
Q
PTEN
A
Tumour suppressor gene
Phosphatase that antagonises PI3KCA
Suffers inactivating point mutatiosn or deletions
18
Q
Rb-1
A
Tumour suppressor gene
Nuclear protein that regulates cell cycle. Discovered in retinoblastoma but also mutated in other human tumours
19
Q
Smad4
A
Tumour suppressor gene
Carries inhibitory signals in TGF-beta pathway. Mutated in some colon carcinomas and other cancers
20
Q
TGF-beta family
A
Tumour suppressor gene
Often inhibitory growth factors that regulate the differentiation of cells.
21
Q
Define cancer
A
A disease caused by alteration of a cell’s genes resulting in a failure of 3D growth and tissue repair
22
Q
Which gene changes can result in cancer?
A
Mutations
Epigenetic change including DNA methylation or histone modification
Tumour viruses bringing extra genes into a cell
23
Q
Define metastasis
A
Formation of new colonies of tumour in other parts of the body by the seeding of cells into the blood or lymphatics
24
Q
Define a benign tumour
A
Tumours incapable of metastasis unless subsequent metastasis turns them into a malignant tumour
25
Define a malignant tumour
Tumours capable of metastasis
26
How do you distinguish a malignant from a benign tumour down the microscope?
Benign has clearly defined boundaries, often with a capsule (connective tissue compressed by growing tumour), no invasion
Malignant ragged edges, infiltrating into surrounding tissue
27
Define invasion
Local metastasis, malignant tumours infiltrating into and growing in surrounding tissue
28
Define malignancy
The ability to metastasise
29
Give examples of benign tumours which are life threatening
Meningiomas
| Hormone-producing benign tumours in the pituitary or adrenal
30
+oma
benign
31
lipoma
benign fat
32
papilloma
wart
33
adenoma
benign glandular lump
34
+ sarcoma
malignant from mesenchyme
35
osteosarcoma
malignant bone tumour
36
leiomyosarcoma
malignant smooth muscle tissue
37
+ carcinoma
malignant from epithelium
38
malignant melanoma
don't use melanoma for benign molesbenign
39
benign mole?
nevus/nevi
40
malignant neural tumours?
neuroblastoma
| glioblastoma
41
leukaemia?
liquid haemopoietic neoplasm
42
lymphoma?
solid haemopoietic neoplasms, usually lymphocytes
43
How do metastases cause disease and death?
1. Interference with normal function
2. Metabolic effects
3. Death
44
How can metastases interfere with normal function?
1. Pressure e.g.meningioma, prostate obstructing urethra
2. Erosion e.g. bone --> fractures and pain
3. Epithelial ulceration e.g. colorectal bleeding --> anaemia
4. Competition with normal e.g. failure of normal bone marrow in leukaemia
45
Define cachexia
General systemic wasting seen in cancer. Mechanism unknown, other than competing for metabolic resources
46
What is more common, malignant tumours from epithelium or from mesenchyme?
Epithelium
47
Name the 4 most common malignant tumours from epithelia
Breast carcinoma
Colorectal/bowel
Lung (squamous carcinoma of the bronchus)
Prostate
48
How do patients present with tumours?
1. Tumour visible/palpable
2. Prostate: blockage of ureter
3. Colorectal: anaemia due to bleeding, obstruction of bowel, unexplained weight loss
49
Which virus and which proteins are cervical cancer associated with?
HPV 16 and 18, E6 and E7 proteins
50
How do you screen for cervical cancer?
Brush sample of cervix to try and detect benign pre-invasive lesions
51
How do you screen for colorectal cancer?
Faecal blood
| Endoscopy
52
How do you screen for breast cancer?
X-ray mammography
| but high false + rate leading to treatment of harmless lesions in 1/3 cases
53
How do you screen for prostate cancer?
PSA prostate specific antigen
| Detects malignant tumour
54
Define clonal expansion
A mutated cell outcompetiting neighbouring cells so that its progeny take over more than their normal share of tissue
55
Why may a tumour show heterogeneity?
Contains latest clone but also preceding clones and dead-end branches of the evolutionary tree.
56
What is the order of mutations in the model of colon cancer?
APC/beta catenin --> small adenoma --> CDC4/CIN and KRAS/BRAF --> large adenoma --> PIK3CA/PTEN, TP53/BAX, Smad4/TGF-betaRII --> carcinoma --> metastasis
57
What is the model of colon cancer called?
Vogelstein's
58
In which stages of the cell cycle is the cell diploid?
Go and Gi
59
What ploidy is the cell in G2?
Tetraploid
60
What controls the G1/S checkpoint?
Rb1 holds cycle at G1/S checkpoint (so inactivating mutations --> cancer)
Tumour suppressor gene
61
What inhibits Rb and so triggers progression through the G1/s checkpoint?
CDK4 complexed with CyclinD1 phosphorylates Rb1 (so activating mutations --> cancer)
Oncogenes
62
What inhibits CDK4 and cyclinD1 so inhibiting progression through G1/S checkpoint?
p21 aka CDKN1A, p16 aka CDKN2A
| so inactivating mutations --> cancer
63
Which genes controlling G1/S checkpoint progression are often mutated in breast cancer?
CCND1/cyclin D1 often overactive due to gene amplification
| p16/INK4a often inactivated
64
Define an oncogene
Genes that cause cancer by overactivity mutations
65
Define a tumour suppressor gene
Genes that cause cancer by loss of function mutations
66
Discuss p53 mutations
One copy lost has some effect, but losing bot has a stronger effect
Because it is a tetramer so mutating half the copies of the gene means that most of the tetramers are faulty
67
What is the evidence for cancers having specific defects that make them genetically unstable?
1. Individual cases of cancer show different kinds of genetic instability
68
What are the two main types of genetic instability? What causes them?
1. Microsatellite/Sequence instability - mutations that inactivate DNA mismatch repair e.g. MLH1, errors in replication e.g. pol epsilon mutation
2. Chromosomal instability - lots of rearranged chromosomes but normal rate of point mutation e.g. BRCA1 or BRCA2 failure of repair, or defective spindle attachment leading to lagging chromosomes
Not just a dichotomy
69
What are the main categories of DNA repair?
1. Fixing damaged bases (chemically damaged, UV-induced pyrimidine dimers) - either base excision or nucleotide excision
2. Mismatch repair
3. Two pathways that deal with DNA strand breaks and crosslinks
70
What does mismatch repair deal with?
Mismatched bases and small loops that occur when polymerases slip when replicating repeats and add or delete a copy of the repeat
71
What does mismatch repair mutation cause?
Slippage loops persist, expand or shrink these loops
Known as microsatellites
Higher point mutation rate as mismatched bases are overlooked
72
What percentage of colon cancers have failure of mismatch repair? Which mutations cause this?
15%
| MLH1 or MSH2 inactivation
73
What is mutated in HNPCC/Lynch Syndrome?
Mismatch repair
74
What are the 3 pathways to tackle DNA strand breaks?
1. Single strand break repair
2. Double strand break repair by end joining
3. Double strand break repair by homologous recombination
75
What is the pathway to treat interstrand cross links?
Fanconi Anaemia pathway
| Shares components with homologous recombination repair
76
How does homologous recombination work?
Uses the sister chromatid as a template to resynthesize the broken DNA
1. BRCA1 starts reaction
2. BRCA2 prepares the single strand ends for base pairing to the other helix
3. Base pair to other helix and copy the other template
77
List the types of mutations that lead to genetic instability
1. Mutations in DNA repair: mismatch repair - genetic instability
2. Mutations in DNA repair: homologous recombination - chromosomal instability
3. Mutations in cell cycle checkpoints: e.g. p53
4. Mutations affecting DNA synthesis: DNA pol epsilon proof reading domain
5. Defects in mitosis: errors in chromosome segregation (chromosome lagging)
78
How can you separate genetic instability from malignancy?
Give DNA cross linking agent e.g. cisplatin
Selects for cancer cells with revertant BRCA2 i.e. those that can repair the cross link by homologous recombination
This cancer still kills the patient, so BRCA2 must not be needed for malignancy
79
How are most predispositions to cancer inherited?
Inherit one mutated copy of a tumour suppressor gene
| inheriting an oncogene is unlikely as it would probably screw up development
80
What percentage chance do people with a BRCA2 mutation have of developing breast cancer during their life?
40-80%
Not mutated significantly in non-hereditary breast cancer. Also confers resistance to other cancers including ovarian and prostate
81
What is familial adenomatous polyposis?
Rare 1/10,000 condition causing 1000s of polyps then colon cancer
Mutations in APC
Tumour suppressor
82
What is hereditary non-polyposis colon cancer? What is it also known as?
Lynch syndrome
1% colon cancers
Colon cancer without lots of polyps
Inherit mutation in a mismatch repair gene e.g. MLH1
15% sporadic colon cancers have the same mutation
83
What is the significance of retinoblastoma in cancer research?
Knudson two-hit hypothesis
84
What are the hallmarks of cancer?
Loss of growth control:
1. Independence of growth-stimulating signals
2. Resistance to growth-inhibitory signals
3. Differentiation block
4. Resistance to apoptosis
5. Immortality
6. Genetic instability
Controversial:
7. Metabolic changes
8. Metastasis
9. Angiogenesis
10. Evasion of immune response
85
What is the Wnt signalling cascade?
Wnt - wnt receptor inhibits - APC inhibits- beta catenin - stimulates TCF4 - proliferation
86
What is most commonly mutated in the Wnt signalling pathway?
APC
87
Where is beta catenin normally mutated?
Point mutation in motif that the degradation machinery binds to
88
What is the MAP kinase signalling cascade?
EGF - EGFR - Grb 2 - SOS - Ras - B-Raf - MAPkinase
89
What is the AKT signalling cascade?
EGF - EGFR - PI3KCA - converts PIP2 to PIP3 - AKT - inhibit apoptosis
Uncommonly activating mutations in AKT
90
What does PTEN do?
PIP3 to PIP2 so allows apoptosis to occur
91
What is the TGFbeta signalling pathway?
TGFbeta - TGFbetaRII - SMADs - inhibit proliferation
92
What are chronic leukaemias?
Leukaemia arising in either fully differentiated lymphocytes, or progenitors that can still differentiate
93
What are acute leukaemias?
Leukaemia arising in stem cells in the blood with differentiation blocked
94
Where do myelomas arise?
Plasma cells
95
What is the hayflick limit?
Normal human somatic cells in culture only divide a fixed number of times before entering senescence/cycle arrest
50-100 divisions
96
What controls the division potential of a cell?
Telomere length
97
What turns on telomerase in cancers?
Point mutations in promoter of TERT gene, or chromosome rearrangement joining a strong promoter to the telomerase gene
98
What is the structure of a telomere?
TTAGGG repeats forming a loop
99
How much do telomeres shorten per cell cycle?
100bp
100
How do HPV viruses overcome cell senescence?
Synthesise proteins that inactivate Rb1 and p53
101
What is the experimental evidence that malignant cells can cross tissue?
1. Cells injected into capillary beds can be isolated in draining lymphatics
2. Cells injected in LV and tail vein give same eventual distribution of metastatic colonies
102
What has to happen for metastasis?
1. Entry into circulation
2. Survival in circulation
3. Arrest in organ
4. Extravasation
5. Survival of cells after extravasation
103
What is the major barrier for survival of a metastasis?
Survival and growth in the distant site
104
How did Weiss show experimentally that most primary tumour cells can cause metastasis?
Cells from metastases are equally metastatic as cells from the primary tumour
105
Define malignant cell
Cell that has acquired the ability to survive and grow in an alien tissue environment
106
Define passenger mutation
Irrelevant random mutations accumulated that do not give the cell a selective advantage
107
Define driver mutation
Mutations that do give a cell selective advantage
108
Name 4 mitogenic signalling pathways that can be affected in human colorectal cancer
```
Wnt signalling
RTK pathways
Rb control of cell cycle
Hedgehog pathway
Notch pathway
```
109
How is transcription controlled?
```
Transcription factors (e.g. p53, beta catenin TCF4 Wnt pathway, MYC and ETS families)
Chromatin modifiers - modify histones to turn genes on and off.
```
110
What is MLL?
Histone lysine methyltransferase, turns genes on
111
What is IDH1?
Isocitrate dehydrogenase (isocitrate --> alphaketoglutarate)
Enzyme in Krebs cycle
Turned on in some brain tumours
Changes enzyme specificity to make hydroxyglutarate, so blocks DNA methylation and blocks differentiation.
112
What is E-cadherin? How is it mutated?
Involved in cell-cell adhesion. Inactivated epigenetically by methylation of promoter DNA in lobular breast cancers.
113
Give examples of genes involved in colorectal cancer that are involved in small-scale sequence changes, and small-scale indels?
Sequence - RAS and p53
| Indel - APC truncated
114
Give examples of large scale gene changes?
```
Deletion
Inversion
Duplication
Amplification
Chromosome translocation
```
115
How do you study gene mutations?
Sequencing
1. Used to be done by PCR-amplifying a region of interest and Sanger sequencing
2. Increasingly replaced with Illumina (high throughput massive parallel sequencing) sequencing where millions of DNA fragments are attached to a glass slide and sequenced simultaneously. Find structural DNA rearrangements by finding sequence fragments that cross rearrangement junctions e.g. BCR-ABL fusion by finding DNA fragment from BCR at one end and ABL at the other
Rearrangements
3. Classically cytogenetics (microscopy). Arrest in metaphase, spread chromosomes on a slide and stain, can see translocations and large insertions or deletions.
4. FISH. Label DNA with fluorescence and hybridise to metaphase chromosomes.
5. Copy number measurement - measure large deletions and amplifications
116
What is FISH used for clinically?
Detect amplification of HER2 ERBB2 - the target of Herceptin therapy in breast cancer
117
What are the axes used for copy number measurement?
```
Y = log base 2 of ratio of tumour DNA to normal amount
X = genome position
```
118
What are the two other names for the EGF receptor?
ERBB
| Her-1
119
Give examples of point mutations found commonly in cancer
RAS
B-RAF
PIK3CA
PTEN
120
Give examples of a gene commonly affected by indels
APC
121
Give examples of genes affected by structural mutations: deletions
Deletions:
PTEN
p16/INK4a
122
Give examples of genes affected by structural mutations: duplications
Duplication:
| BRAF-KIAA1549 fusion in paediatric brain tumours
123
Give examples of genes amplified in cancer
EGFR in brain
ERBB2HER2 in 10-20% breas cancer
Cyclin D1 in breast
MYC
124
Give an example of a fusion gene found in a carcinoma. How is it formed?
TMPRSS2-ERG
50% prostate cancers
Formed by deletion between TMPRSS2 and ERG
125
Discuss 2 genes inactivated epigenetically
E-cadherin (cell adhesion) in lobular breast cancers
| MLH1 (mismatch repair) in colon cancer
126
Give an example of a retrotransposon
LINE-1
127
How did scientists prove that cyclinD1 is an oncogene?
Alter gene in animal model
Transgenic mouse made that expresses cyclin D1 from the MMTV promoter, which is active specifically in the mammary glands - mice get mammary hyperplasias that develop into tumours
128
How did scientists show the effect of APC?
Inactivated APC in mice
Showed that differentiation pattern of the crypt was changed so that the dividing cell compartment expanded and the cells were prevented from migrating up the villus and maturing
129
What percentage of cancer is said to be accounted for by smoking tobacco?
30%
130
What are the main cancer-causing agents?
```
UV
Ionising radiation
Chemical carcinogens
Asbestos
Viruses but also parasites and bacteria
```
131
What is the evidence that population differences in cancer incidence are more environmental than genetic?
Japanese migrants to West America swap from Japanese cancer pattern (high stomach, low breast), to American (reverse)
132
How does UV damage DNA?
Photoactivate pyrimidine residues in DNA so that they form dimers where two thymines or a thymine and a cytosine occur sequentially in DNA
Disrupts base pairing
133
What is the name of the disease where DNA excision repair is damaged? What is the effect?
Xeroderma pigmentosum
| UV sensitivity
134
Name some chemical carcinogens
Polycyclic hydrocarbons (smoke, tar, coal)
Beta-napthylamine (dye industry, smoke, tar)
Aflatoxin (natural product)
Dimethyl nitrosamine (meat products)
Mustard gas
135
How are chemical carcinogens activated?
P450 monooxygenases, hydratases, sugar conjugation
| Make more soluble
136
What is the activation schema of benzypyrene and where is this found?
```
Smoke
Benzoapyrene
P450 add O2
Epoxide hydratase add water
P450 add O2 again
Highly reactive 'ultimate carcinogen'
```
137
What is the activation and inactivation schema of beta-napthylamine and where is it found?
Dye industry, smoke, tar
Only relevant in species with glucuronidase so humans and dogs
Activated in liver by hydroxylation
Inactivated in liver by glycosylation with glucuronic acid
Reactivated in bladder where glucuronidase removes glucuronic acid
138
Aflatoxin B1
Most powerful natural carcinogen known to man
Warm damp peanut mould due to aspergillus flavus
Causes liver toxicity and liver cancer
Activated by oxidase to aflatoxin epoxide
139
Aristolochic acid
```
Chinese herbal mediciens, plant contamination of crops in Balkans
Natural product
Aristolochiaceae
Kidney toxicity, upper UT cancer
South East Asian liver cancers
```
140
Commonest base change of UV?
C --> T
141
Commonest base change of smoking?
C --> A
142
Commonest base change of aristolochic acid?
T --> A esp CT --> CA
143
Asbestos
Inhalation causes mesothelioma from mesothelial lining of pleural cavity
Probably promoter: fibres penetrate into lung, cause chronic inflammation and cell tunrover
144
Define tumour promoters
substances that promote the development of tumours without damaging DNA
Only cause tumours after an initiator has been applied
145
To cause a tumour, would you give a promoter or an initiator first?
Initiator
146
TPA
From seeds of croton tiglium
Residues mimic DAG, agonist for PKC
Natural promoter
147
What is the risk of breast cancer proportional to?
Interval between menarche and first pregnancy for childbearing women
148
How do you identify cancer causing agents?
Epidemiology
Mice and rat studies
Ames test in vitro
149
When can epidemiology be used to identify cancer-causing agents?
Clearly separate exposed from non-exposed
Prospective
Specific type of cancer caused
150
What is added to try and identify carcinogens that require metabolic activation?
Rat liver extract
151
Which agent has the risk of human exposure been estimated for?
Ionising radiation
152
What is the unit of exposure to radiation?
Amount of energy absorbed per unit of tissue
| The Gray = 100 rads = joules/kg
153
What is LET?
Linear energy transfer - describes the action of radiation on matter. Equal to retarding force acting on a charged ionising particle travelling through matter.
Diffusion cloud chamber with tracks of ionizing radiation that are made visible as strings of droplets.
High LET = alpha particles
Low LET = gamma rays.
154
How do we allow for different LET levels of radiations?
Multiply exposure level of radiation in Gray (Gy) by quality factor to give a measure of biological damage to give a dose equivalent in Sieverts Sv
155
What is the quality factor for X rays, gamma rays and alpha particles?
1 Gamma rays and X rays
| Up to 20 alpha rays
156
What is the average radiation exposure in the UK? What is it from?
2.5 mSv/year
1/8 medical
1/100 cosmic from long-haul flights
1/2 radon escaping from rocks
157
Where does most of the data come from for high doses of radiation?
Atomic bombs on Hiroshima and Nagasaki, people with Anklyosing spondylitis treated with X-rays for 20 years, uranium miners
158
What gives a convex, a concave curve or a straight line for cancer risk against dose of radiation?
```
Concave = mouse leukaemia. Plateau at high levels, presumably because some cells that could give leukaemias are killed.
Straight = neutrons
Convex = gamma rays, low levels of damage repaired more efficiently than high levels
```
159
Name some infectious disease that can cause cancer
Bacteria = helicobacter pylori
Parasites = schistosomiasis
Viruses =
160
What type of cancer is schistosomiasis associated with?
Bladder cancer
161
Which cancers are helicobacter pylori associated with?
```
Gastric adenocarcinoma
MALT lymphoma (mucosal-associated lymphoma)
```
162
Which cancers is EBV associated with?
```
Nasopharyngeaal carcinoma (especially in ethnic Chinese populations)
Burkitt's lymphoma - B cells(especially in malaria-endemic areas)
```
163
Which cancer is HBV associated with?
Hepatocellular carcinoma
| May act synergistically with aflatoxins
164
Which cancer is HHV8 human herpesvirus 8 associated with?
Kaposi's sarcoma
| Came to prominence in AIDS/HIV patients
165
Which cancer is HTLV1 human T-cell lymph tropic virus associated with?
T cell leukaemia and lymphoma
Retrovirus
Endemic in SW Japan, Caribbean, Africa and South America
166
Enzalutamide
Blocks androgen hormone, anti-cancer drug
167
Which drug is used to treat testicular cancer and with what success rate?
Cisplatin
| 70-90%
168
What do taxanes target?
The lagging mitotic spindle that leads to chromosome instability
169
What is the Waldmann experiment?
Made cancer cells that were defective in the p21 checkpoint (not seen in human tumours)
Grew as grafts on mice
X-irradiated them
X-radiation cured several checkpoint-defective tumours but no wild-type controls
Died of mitotic catastrophes when irradiated
170
What do PARP inhibitors do?
Damage DNA repair pathway so cells already defective in another pathway are more likely to be damaged than normal cells even by everyday spontaneous DNA damage e.g. BRCA2 -/- that have no homologous recombination pathway
Block ss break repair - end joining
So breaks accumulate
Halt replication as at the replication fork, the ss break becomes a ds break.
171
What does PARP stand for?
Poly ADPribose polymerase
| Put up a poly ADP ribose flag that DNA repair is needed
172
Which drugs act by creating blocked replication forks?
PARP inhibitors
| Cisplatin
173
What does imatinib inhibit?
BCR-ABL fusion gene
And also many other tyrosine kinases, including just Abl.
Chronic myeloid leukaemia.
174
Which of these can be targeted by small molecules: BRAF, RAS, MEK?
BRAF and MEK
| Not RAS
175
Vemurafenib
BRAF small molecule inhibitor, targets ATP-binding domain V600E domain
Treat melanomas
Resistance normally occurs by acquisition of RAS mutations or amplification of the mutant BRAF
176
Name an oncolytic virus
Adenovirus H101, and its predecessor Onyx-015
177
How do adenoviruses kill cancer cells?
Adenoviruses normally inactivate Rb1 and p53
Engineered viruses have deletions in E1B_55k gene so lose ability to inactivate p53
So only survive in p53-mutatnt cancers
178
Why did people think that the immune system protected us from cancer?
```
Experimental studies of tumour grafts in mice showed rejection
Macfarlane Burnet (established scientist) proposed that immune surveillance against tumours was the function of T cells
Later uncovered tumour-specific antigens in mouse models - actually retrovirus env proteins so not relevant in most cancers
```
179
In which types of cancer does the immune system play a role?
Those with a viral aetiology
Those in kidney transplant patients (perhaps due to drugs)
Maybe melanomas
180
Why do we not think the immune system plays a major role in cancer protection?
The immunosuppressed don't get more cancer
181
By what mechanism would tumour cells expressing mutant proteins not be eliminated by the immune system?
Peripheral tolerance
| NB normal cells have mutations and these aren't picked up
182
What are checkpoint inhibitors?
Monoclonal antibodies that block signals that hold back CTLs
CTLA-4 (binds to B7, displacing CD28 costimulatory), PD-L1 on dendritic cell + PD-1 on T cell (bind to each other to provide inhibitory signals)
183
What are the negatives of use of checkpoint inhibitors?
Treatment toxic - inflammation and autoimmunity
Doesn't work on everyone:
12% melanomas anti-CTLA4 (anti-PDIs may be better)
20% squamous cell lung cancers anti PD-L1
Response correlates with numbers of mutations per tumour
184
Ipilumumab
Anti CTLA-4 MAb
| Binds to B7, displacing costimulatory CD28
185
What are the problems with developing new drugs?
Takes a long time (phase III trials >5y)
Spenny (0.5-1 billion £)
Resistance usually develops
