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Molecular Medicine > Unit 5 - From Oncogenes and TSGs to Drugs > Flashcards

Unit 5 - From Oncogenes and TSGs to Drugs Flashcards

1
Q

genetic disease

A

irreversible

SNP

gross chr rearrangement

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2
Q

epigenetic

A

reversible - affects ways in which genes can be transcribed, how many copies of mRNA you can make

DNA methylation - affecting gene exp

histone modifications - methylation, acetylation - affecting gene exp

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3
Q

Point mutations

A

single nucleotide base changes

present in DNA, transcribed into RNA - can result in the encoded protein

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4
Q

nonsense mutation

A

altered codon encodes a termination codon

inappropriate termination of translation

shortened (truncated) protein

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5
Q

missense mutation

A

altered codon encodes a different AA

protein will contain an incorrect AA - missense mutation

could result in a non-functional (most) or hyperactive protein

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6
Q

silent mutation

A

altered codon encodes for the same AA

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7
Q

gross chr rearrangement

A

increased/decreased copy numbeer and gene expression

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8
Q

how is DNA organised

A

into chromatin by DNA binding proteins (histones)

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9
Q
A

Nucleosomes and histones

Protein in middle - DNA around

tails are piece of protein of histones - stick out - highly modified - charged

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10
Q

changes in chromatin conformation

A
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11
Q

what is RB

A

a transcriptional repressor

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12
Q

RB pathway

A

RB binds to the transcriptional activator E2F

E2F promote the expression of genes involved in cell proliferation

mutations in both alleles of RB1 lead to the retinal cancer -retinoblastoma

RB1 is a tumour suppressor

RB pathway is de-regulated in virtually every human cancer

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13
Q

role of INK4 family

A
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14
Q

2 types of genes altered in cancer cells

A

oncogenes e.g. myc, ras, abl

protein products act as ACCELERATORS of cell division or promote the cancer phenotype

tumour suppressor genes (TSG) e.g. RB, p53, BRCA1, BRCA2

protein products normally act as BRAKES on cell division or counteract the cancer phenotype

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15
Q

inheritance pattern - oncogenes vs TSGs

A

oncogenes = dominant

TSGs = recessive

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16
Q

what is RAS

A

a proto-oncogene and a central node of multiple pathways relevant to cancer

Mediates signalling through tyrosine kinase receptors

In order to activate another pathway

Survival - cell cycle progression - when active, promotes phenotypes related to cancer

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17
Q

normal vs mutant RAS gene

A

this mutant protein lacks GTPase activity, so it is active (on) all the time

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18
Q

mutations in RAS gene - what does the gene encode

what does mutation lead to

A

encodes RAS GTPase protein

leads to production of an altered RAS protein that binds GTP but cannot break it down to GDP

so RAS protein is active (on) all the time

RAS signalling pathway is continuously activated

cell proliferation is stimulated - promotes tumour formation

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19
Q

prevalence of mutations in RAS

A
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20
Q

c-MYC and Burkitt’s lymphoma

cancer of what type of cell

type of mutation

results in

A

cancer of lymphocytes - common in parts of Africa

caused by translocation of gene for c-MYC transcription factor

c-MYC gene translocated from chr 8 → chr 14

enhanced production of c-myc protein

stimulates cell proliferation - tumour formation

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21
Q

how does Myc regulate proliferation

A

through CDKs

Myc is a TRANSCRIPTION FACTOR

Protein that binds to DNA in order to promote transcription

Works with MAX to activate transcription of genes

Transcribe - cyclin D and CDK4 (promote cell cycle progression)

Excess of kinase it binds and sequesters the KIP protein - causes its degradation - cyclin kinase inhibitor - inhibits cyclin E

MYC + MAX = transcriptional activator

However when myc binds MIZ1 it is a transcriptional repressor

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22
Q

MYC + MAX =

A

transcriptional activator

but when myc binds MIZ1 it is a transcriptional repressor

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23
Q

MYC promotes function of

A

CDK4

promotes inhibitor

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24
Q

Li-Fraumeni Syndrome

pattern of inheritance

A

rare cancer-prone syndrome

inherit 1 mutated copy (allele) of p53

somatic mutations in other copy (allele) of p53 gene

early onset of variety of cancers - blood, breast, bone, lung, skin

both copies (alleles) of a TSG must be inactivated for a phenotype to result

p53 gene codes for p53 protein - named bacuase protein is 53 kDa - transcription factor

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25
how are cellular stress signals mediated
by the p53 transcription factor Downstream of a lot of signalling - tells cells we're under stress - lack of O2, loss of signalling factors etc
26
how does a mutated p53 react in response to DNA damage
loss of ability to arrest cell cycle progression after DNA damage cell continues to divide in the presence of DNA damage increase in mutations in genome - genome instability cells lacking p53 also fail to undergo apoptosis (cell death) after DNA damage * because transcription of certain gene products required for apoptosis does not occur * also become resistant to some chemotherapeutic agents
27
what is required to cause most cancers
multiple lesions e.g. model of progression of colorectal carcinoma sequence of genetic events in progression of normal epithelial cell to carcinoma
28
tumours are \_\_\_\_\_\_\_\_\_\_
heterogenous can spread cycling and resting cells genetic info can vary in cells of the same tumour
29
therapeutic potential
30
MOA of nitrogen mustards in use
DNA alkylation cyclophosphamide
31
antimetabolites MOA in use
folic acid analogue active on leukaemia MOA = DNA and RNA synthesis IN USE = metotrexate, 5-FU, gemcitabine
32
cellular screening for cytotoxic compounds - mechanisms in use
mechanisms target essential cellular components and processes - DNA, microtubules, enzymes in use = cisplatinum, doxorubicine, taxanes
33
targeted therapy in use
molecular target defined upfront and then drugs that act through that target are identified potential for better selectivity versus cancer cells in use - Gleevec, Avastin
34
history of chemotherapeutics
35
a chemotherapeutic agent (drug) =
a substance that has been demonstrated to give benefit to cancer patients in controlled clinical studies clinical benefit is defined according to the specific disease - cure, prolonged lifespan (survival time), improved side effects/increased quality of life
36
Pro-drug
drug is not the active substance drug needs to be activated modified by either tumour cell or by the host organism
37
4 classifications of therapeutics
chemical type/nature mechanism molecular target cellular/tumour response
38
chemical type/nature
small molecule de novo chemical synthesis natural products antibody
39
molecular target
kinase inhibitors topoisomerase inhibitors
40
mechanism
alkylating agents - bind to DNA antimetabolites cell cycle and/or mitotic inhibitors anti-angiogenesis endocrine agents
41
cellular/tumour response
cytotoxic or cytostatic
42
curative - goal of chemo
early stage sensitive tumours e.g. testicular cancers, lymphomas
43
adjuvant goals of chemo
after surgery or radiotherapy to minimise recurrences - mostly solid tumours
44
neoadjuvant goals of chemo
before surgery to reduce tumour size
45
activty of a drug is defined by
its therapeutic window TW is the ratio between toxic conc and active conc lethal dose50/effective dose50 generally a single digit number
46
toxicological liabilities - mechanism related and drug specific
mechanism related - affecting normal proliferating cells - GI and bone marrow drug specific i.e. neurotoxicity of taxanes, cardiotoxicity of doxorubicine
47
taxanes
neurotoxicity
48
doxorubicine
cardiotoxicity
49
alkylating agents what do they do e.g.
covalently modify DNA cyclophosphamides, cisplatin
50
intercalating agents what do they do e.g.
bind with bases and to minor groove of the DNA, NOT to backbone of DNA doxorubicin
51
antimetabolites what do they do e.g.
inhibit supply of dNTPs block DNA (and RNA) synthesis 5-flourouracil, gemcitabine
52
drug approved for pancreatic cancer
gemcitabine active metabolites inhibit RNR (ribonucleotide reductase) and are incorporated into the DNA during replication active in a broad range of tumours
53
microtubule dynamics as a target of cancer therapy
54
example of drug resistance mechanisms developed by tumours
Decrease accumulation Decrease activation Change in met causing increase in activation \*\* target of drug is transformed - kinase inhibitors
55
how cells respond to anticancer drugs
56
benefit of combination of drugs as treatment
2+ drugs delivered to a patient increase cell killing by using different mechanisms minimise risks of resistance reduce peaks of toxicities of single drugs
57
molecular targeted therapeutics - MTT
* What are the signalling pathways involved in getting to cancerous phenotypes* * Learn which are key proteins important for mediating process*
58
Bcr-Abl type of mutation results in
reciprocal translocation between chr 9-22 causes the expression of chimeric Bcr-Abl protein with tyrosine kinase activity loss of -ve regulation gain of protein-protein interaction domains POTENT ONCOGENE - sufficient for cellular transformation by activating multiple molecular pathways present in 95% of patients with CML, 15-30% with ALL, 2% with AML
59
Gleevec/Imatinib
first successful MTT complete remission of Bcr-Abl+ leukaemia 95% 5 year survival before Gleevec was available, 50% of patients progressed to the more advanced stages of Ph+ CML after only 3-5 years and survival was generally shorter for these patients
60
how does resistance to Gleevec therapy arise
from mutations in Bcr-Abl kinase domain mutations in the ATP pocket strongly reduce the affinity for Gleevec 2nd generation of compounds that inhibit mutant forms has been developed
61
targeting tumour suppressors - what is it necessary to do
synthetic/combined lethality
62
PARP
poly (ADP-ribose) polymerase Allow chromatin to be more relaxed Enzyme - chain of adiporibose on chromatin histones - allow chromatin to be more relaxed to allow DNA repair protein to be relocated to help in DNA repair
63
mode of action of PARP inhibitors
SS breaks are not repaired
64
BRCA mutations and PARP inhibitors
BRCA1 and 2 - TSGs often mutated in breast and ovarian cancers they have deficient HR DNA repair - cells are dependent of Base Excision repair PARP inhibitors block the repair of DNA SS breaks and BE repair normal cells are insensitive to PARP inhibitors BRCA cells are 1000x more sensitive to PARP inhibitors
65
mechanisms of resistance to PARPi
66
oncology drug discovery process
67
screening funnel
68
considerations for choosing a good target in oncology - biological
BIOLOGICAL NB disease progression essential for tumour growth - target in tumour cells, external target specificity fro tumour - only expressed in tumour, hyperactive in tumour (activating mutations in target, normal -ve regulation is lost in tumour) different cellular response in tumour vs normal cells - genetic background strongly influence outcome of treatment defined patient population
69
considerations for choosing a good target in oncology - technical
druggable - a small molecule can block target function enzymes - normally have a catalytic pocket protein-protein interactions - only if small defined surface is involved availability of cellular and animal models availability of specific technologies and reagents - targeted chemical libraries, screening methods
70
business considerations for oncogotherapeutics
71
compound collections for screening can be
72
biochemical kinetic assays
73
HTS
high throughput screening
74
virtual screening for new ligands
1. target structure known 2. computational docking of molecules into target's active site 3. ID of potential binders 4. experimental test predictions
75
functions of cell proliferation assays
to verify the antiproliferative activity of selected cpds to compare potency among different cpds to compare potency among different cell lines
76
IC50 and IC90
77
RB pathway
no absolute specificity off target events may be prevalent E.g. CDK4 inhibitors But microtubule inhibitors can also block cell cycle progression - what you're looking for is a marker that is as close as possible to action of target e.g. P of RB
78
xenografted mouse models
immunosuppressed animal (nu/nu) human cancer cells implanted subcuteneously
79
orthotropic implanted mouse models
human tumour cells surgically implanted in their normal contest
80
patient derived xenografts (PDX)
immunosuppressed animals (nu/nu) small tumours derived from patients
81
spontaneous (induced) models
DMBA rats female are dosed intragastrically with DMBA after approx 2 months animals develop mammary carcinoma
82
transgenic mouse models - MMTV/v-Ha-Ras
expressing v-Ha-Ras oncogene in the mammary and salivary epithelium mice develop malignant adenocarcinomas of the mammary and salivary gland with 16-24 weeks of age
83
transgenic mouse models - TRAMP
transgenic adenocarcinoma mouse prostate, Probasin-SV40 T antigen expressing the SV40 T antigen in the prostatic epithelium TRAMP mice develop prostatic adenocarcinomas by 18 weeks of age by 24-30 weeks of age metastasis are commonly detected in the lymph nodes and lungs
84
transgenic mouse models - p53 knockout
mice carry a null mutation in the p53 tumour suppressor gene mice are prone to spontaneous development of different tumours before they reach 20 weeks, particularly lymphomas and sarcomas
85
xenograft of human solid tumours
86
xenografts - advantages and disadvantages
87
transgenic, spontaneous models, PDX advantages and disadvantages
88
phase 1, 2 and 3 of clinical studies
89
Phase I - 2 years
90
phase I testing
91
phase II testing - 2+ years
92
phase III testing - 2+ years
93
probability of success - oncology vs non-oncology

Molecular Medicine (7 decks)

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