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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
Q

how are cellular stress signals mediated

A

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

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26
Q

how does a mutated p53 react in response to DNA damage

A

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
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27
Q

what is required to cause most cancers

A

multiple lesions

e.g. model of progression of colorectal carcinoma

sequence of genetic events in progression of normal epithelial cell to carcinoma

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28
Q

tumours are __________

A

heterogenous

can spread

cycling and resting cells

genetic info can vary in cells of the same tumour

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29
Q

therapeutic potential

A
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30
Q

MOA of nitrogen mustards

in use

A

DNA alkylation

cyclophosphamide

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31
Q

antimetabolites MOA

in use

A

folic acid analogue active on leukaemia

MOA = DNA and RNA synthesis

IN USE = metotrexate, 5-FU, gemcitabine

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32
Q

cellular screening for cytotoxic compounds - mechanisms

in use

A

mechanisms target essential cellular components and processes - DNA, microtubules, enzymes

in use = cisplatinum, doxorubicine, taxanes

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33
Q

targeted therapy

in use

A

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

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34
Q

history of chemotherapeutics

A
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35
Q

a chemotherapeutic agent (drug) =

A

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

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36
Q

Pro-drug

A

drug is not the active substance

drug needs to be activated modified by either tumour cell or by the host organism

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37
Q

4 classifications of therapeutics

A

chemical type/nature

mechanism

molecular target

cellular/tumour response

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38
Q

chemical type/nature

A

small molecule

de novo chemical synthesis

natural products

antibody

39
Q

molecular target

A

kinase inhibitors

topoisomerase inhibitors

40
Q

mechanism

A

alkylating agents - bind to DNA

antimetabolites

cell cycle and/or mitotic inhibitors

anti-angiogenesis

endocrine agents

41
Q

cellular/tumour response

A

cytotoxic or cytostatic

42
Q

curative - goal of chemo

A

early stage sensitive tumours e.g. testicular cancers, lymphomas

43
Q

adjuvant goals of chemo

A

after surgery or radiotherapy to minimise recurrences - mostly solid tumours

44
Q

neoadjuvant goals of chemo

A

before surgery to reduce tumour size

45
Q

activty of a drug is defined by

A

its therapeutic window

TW is the ratio between toxic conc and active conc

lethal dose50/effective dose50

generally a single digit number

46
Q

toxicological liabilities - mechanism related and drug specific

A

mechanism related - affecting normal proliferating cells - GI and bone marrow

drug specific i.e. neurotoxicity of taxanes, cardiotoxicity of doxorubicine

47
Q

taxanes

A

neurotoxicity

48
Q

doxorubicine

A

cardiotoxicity

49
Q

alkylating agents

what do they do

e.g.

A

covalently modify DNA

cyclophosphamides, cisplatin

50
Q

intercalating agents

what do they do

e.g.

A

bind with bases and to minor groove of the DNA, NOT to backbone of DNA

doxorubicin

51
Q

antimetabolites

what do they do

e.g.

A

inhibit supply of dNTPs

block DNA (and RNA) synthesis

5-flourouracil, gemcitabine

52
Q

drug approved for pancreatic cancer

A

gemcitabine

active metabolites inhibit RNR (ribonucleotide reductase) and are incorporated into the DNA during replication

active in a broad range of tumours

53
Q

microtubule dynamics as a target of cancer therapy

A
54
Q

example of drug resistance mechanisms developed by tumours

A

Decrease accumulation

Decrease activation

Change in met causing increase in activation

** target of drug is transformed - kinase inhibitors

55
Q

how cells respond to anticancer drugs

A
56
Q

benefit of combination of drugs as treatment

A

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
Q

molecular targeted therapeutics - MTT

A
  • What are the signalling pathways involved in getting to cancerous phenotypes*
  • Learn which are key proteins important for mediating process*
58
Q

Bcr-Abl

type of mutation

results in

A

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
Q

Gleevec/Imatinib

A

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
Q

how does resistance to Gleevec therapy arise

A

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
Q

targeting tumour suppressors - what is it necessary to do

A

synthetic/combined lethality

62
Q

PARP

A

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
Q

mode of action of PARP inhibitors

A

SS breaks are not repaired

64
Q

BRCA mutations and PARP inhibitors

A

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
Q

mechanisms of resistance to PARPi

A
66
Q

oncology drug discovery process

A
67
Q

screening funnel

A
68
Q

considerations for choosing a good target in oncology - biological

A

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
Q

considerations for choosing a good target in oncology - technical

A

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
Q

business considerations for oncogotherapeutics

A
71
Q

compound collections for screening can be

A
72
Q

biochemical kinetic assays

A
73
Q

HTS

A

high throughput screening

74
Q

virtual screening for new ligands

A
  1. target structure known
  2. computational docking of molecules into target’s active site
  3. ID of potential binders
  4. experimental test predictions
75
Q

functions of cell proliferation assays

A

to verify the antiproliferative activity of selected cpds

to compare potency among different cpds

to compare potency among different cell lines

76
Q

IC50 and IC90

A
77
Q

RB pathway

A

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
Q

xenografted mouse models

A

immunosuppressed animal (nu/nu)

human cancer cells implanted subcuteneously

79
Q

orthotropic implanted mouse models

A

human tumour cells surgically implanted in their normal contest

80
Q

patient derived xenografts (PDX)

A

immunosuppressed animals (nu/nu)

small tumours derived from patients

81
Q

spontaneous (induced) models

A

DMBA rats

female are dosed intragastrically with DMBA

after approx 2 months animals develop mammary carcinoma

82
Q

transgenic mouse models - MMTV/v-Ha-Ras

A

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
Q

transgenic mouse models - TRAMP

A

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
Q

transgenic mouse models - p53 knockout

A

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
Q

xenograft of human solid tumours

A
86
Q

xenografts - advantages and disadvantages

A
87
Q

transgenic, spontaneous models, PDX

advantages and disadvantages

A
88
Q

phase 1, 2 and 3 of clinical studies

A
89
Q

Phase I - 2 years

A
90
Q

phase I testing

A
91
Q

phase II testing - 2+ years

A
92
Q

phase III testing - 2+ years

A
93
Q

probability of success - oncology vs non-oncology

A

Molecular Medicine (7 decks)

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