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cancer - year 2 > biological basis of cancer therapy > Flashcards

biological basis of cancer therapy Flashcards

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1
Q

epidemiology of cancer *

A

14 million cases a yr

concentrated in west - perhaps because of better diagnosis and detection, or a more unhealthy lifestyle

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2
Q

what are the main cancer causes of death *

A

men - lung - diagnosed late so few people have surgery then liver then stomach

women - breast then lung then colorectum

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3
Q

describe the predicted incidence of cancers *

A

set to increase to 22million caes by 2030

greater westernisation of developing countries will reduce infection based cancers - cervical, stomach ands increase western cancers ie breast, colorectal, lung and prostate

have AI that will be able to improve detection of tumours and see patterns

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4
Q

what are the 4 main cancer treatment modalities &

A

surgery

radiotherapy

chemo

immunotherapy

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5
Q

using breast cancer explain 4 anti-cancer modalities *

A

surgery - but surgeons might not be able to get a clean margin

maybe give radiotherapy or chemotherapy to downsize tumour - as long as it hasnt spread

immunotherapy is not common in breast

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6
Q

what types of genetic mutation cause cancer *

A

chromosome translocation

gene amplification

point mutation within promotor or enhancer region of genes

deletions or insertions

epigenetic anterations to gene expressions

(when sequence tumour find many abnormalities)

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7
Q

how can we use the genetic mutations causing cancer *

A

because cancer is genetically messy - can target the DNA - but dont want to target the normal DNA

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8
Q

what are the 2 types of systemic therapy *

A

cytotoxic chemo

targeted therapy

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9
Q

types of cytotoxic chemo *

A

alkylating therapies

antimetabolites

anthracyclins

vinca alkaloids and taxanes

topoisomerase inhibitors

(to tackle resistance, use drugs from different categories)

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10
Q

types of targeted therapies *

A

small molecule inhibitors

monoclonal antibodies

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11
Q

mechanism of cytotoxic chemo *

A

select rapidly dividing cells by targeting their structures

alkalating agents, antimetabolites, anthracyclins, topoisomerase inhibitors target intrinsic tumour DNA

texanes and vinca alkaloids attack microtubules

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12
Q

describe cytotoxic chemo *

A

given iv or by moyth (occaisionally)

works systematically

non-targeted - ie affects all rapidly dividing cells in the body - gut mucosa, bone marrow = bone marrow suppression and mouth ulcers

given post op - adjuvant - insurance policy to mop up any remaining cells - improve prognosis and cure

given preop - neoadjuvant - downsatge to prep surgery eg to aboid masectomy

as monotherapy or in combination

with curative/palliative intent

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13
Q

mechanism of alkylating agents *

A

add alkyl groups to guanine residues in DNA

cross link (intra, inter, DNA-protein) DNA strands = prevention of DNA uncoiling at replication

triggers apoptosis via checkpoint pathway

however - encourage mispairing = onchogenic - risk of 2nd malignancy - usually benefit outweighs risk

eg chlorambucil, cyclophosphamide, decarbazine, temozolomide

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14
Q

describe pseudo-alkylating agents *

A

add platinum to guanine residues in DNA

same mechanism of cell death as alkylating agents

eg carboplatin, cisplatin, oxaliplatin

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15
Q

SE of alkylating agents or pseudoalkylating agents *

A

hair loss (not carboplatin)

nephrotoxicity

neurotoxicity

ototoxicity (platinums)

neusea, vom, diarrhoea - most common

immunosuppression

tiredness

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16
Q

mechanism of antemetabolites *

A

masqeurade as purine or pyrimidine residues or are folate antagonists (inhibit dihydrofolate reductase needed to make folic acid)

= inhibition of dna synthesis (block replication and transcription), dna double strand breaks and apoptosis

eg methotrexate (folate), 6-mercaptopurine, decarbazine and fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)

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17
Q

SE for anti-metabolites *

A

hair loss (alopecia) - not 5-flurouracil or capecitabine

bone marrow suppression causing anaemia, neutropenia, thrombocytopenia

increased risk of neuropenic sepsis or bleeding

nausea and vom= dehydration

mucositis and diarrhoea

palmar-plantar erythrodysedthesia - red feet and hands and skin peels

fatigue

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18
Q

mechanism of anthracyclins *

A

inhibit transcription and replication by intercalating nuceotides within the DNA/RNA strand

they block DNA repair - mutagenic

create DNA and cell membrane damaging free radicals

eg doxorubicin, epirubicin

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19
Q

se of anthracyclins *

A

cardiac toxicity - arrhythmia/HF - probablu due to damage induced by free radicals - need to measure heart function before you prescribe them

alopecia

neutropenia

nausea and vom

fatigue

skin changes

red urine - doxorubicin ‘the red devil’

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20
Q

describe vinca alkaloids and taxanes *

A

they are origenally derived from natural sources

work by inhibiting assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules

cause cells to go into mitotic arrest

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21
Q

se of microtubule targeting drugs *

A

nerve damage: peripheral neuropathy (numb hands and feet), autonomic neuropathy (BP and GI problems)

hair loss

nausea

vom

bone marrow suppression = neutropenia and anaemia

arthralgia - joint pain

allergy

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22
Q

describe topoisomerase inhibitors *

A

topoisomerases are needed to prevent DNA tortional strain during DNA replication and transcription

topoisomerases induce temporary single strand (topo1) or double strand (topo2) breaks in phosphodiester backbone

they protect the free ends of dna from aberrent recombination events

drugs eg anthracyclins have anti-topoisomerase effects through their action on DNA

specific topoisomerase inhibitors inc topotectan and irinotecan (topo1) and etoposide (topoII) - they alter the binding of the complex to the DNA and cause perm DNA breaks

cause apoptosis

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23
Q

SE of topoisomerase inhibitors*

A

irinotecan - acute cholinergic like syndrome ie diarrhoea, abdo cramps, flushing, and diaphoresis (sweating) - given with atropine to avoid this

hair loss

nausea vom

fatugue

marrow suppression

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24
Q

treatment for SE for anti-metabolites *

A

pyridoxine (vit B6) for PPE

antiemetics for nausea and vom

transfusions/platelets/GCSF/dose reduction - for marrow suppression

mouth washes for mucositis

loperamide - stop diarrhoea

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25
treatment for anthracyclin se \*
cardiac toxicity is irreversible but can limit dose scalp cooling for alopecia transfusions, platelets, dose reduction and GCSF for neutropenia antiemetics - for nausea and vom
26
treatment for alkylating agent se \*
alopecia - scalp cooling nausea and vom- anti-emetics diahorrea - loperamide immunosuppression - transfusion, platelet, GCSF, dose reduction
27
how have response rates to cytotoxics for ovarian cancer changed over time
increased from 50% to 80% now still use carboplatin/paclitaxel
28
how have survival rates to cytotoxics for ovarian cancer changed
improved but still under 50%
29
why do we need to develop new drug targets \*
resistance of cells to treatment
30
how can a cell be resistant to cancer treatment \*
may have DNA repair mechanisms upregulated and DNA damage is repaired - so dont get the double strand breaks may use PARP which replaces DNA adducts by base excision repair or drug could be effluxed from cell by ATP binding cassette (ABC) transporters heterogenity of cells and ability to overcome treatments
31
what is the aim of modern targeted therapies \*
they use what we know aboput cancer cells to manipulate them - mainly using monoclonal antibodies and small molecule inhibitors
32
what is the problem of interfering with the wiring in the cancer cells \*
it is fine in monogenic cancer for others - it causes upregulation of parallel pathways or feedback cascades
33
how have we reduced the upregulation of feedback pathways \*
use dual kinase inhibitors so the same drug blocks the feedback pathway this kills more cancer cells but also leads to more toxicity need to find the balance more therapy stategies needed
34
what are the 6 hallmarks of the cancer cell \*
self sufficient insensitive to anti-growth signals anti-apoptotic pro-invasive and metastatic pro-angiogenic non-senescent
35
what are the new 4 hallmarks of cancer \*
deregulating cellular energetics avoiding immune destruction tumour promoting inflammation genome instability and mutation
36
what do normal cells need to move from a quiescent stage to active proliferating stage \*
growth signals they are transmitted into the cell by growth factors binding transmembrane receptors and activating downstream signalling pathways
37
describe the growth factor receptor pathway \*
GF binds to ligand binding site causes dimerisation and downstream signalling of the kinase cascade adn signal amplification
38
describe the growth factor receptor \*
has extracellular ligand binding site kinase domain intracellularly C-terminal region with tyrosines for autophosphorylation
39
problem with receptor tyrosine kinases \*
\>50% of them are associated with human malignancies
40
describe the effect of over expression of receptors in GF receptor pathway \*
HER2 is overexpressed in 25% of breast cancer - it is part of EGFR family which is over expressed in breast and colorectal cancer PDGFR is overexpressed in brain cancer this causes an increase in the kinase cascade and signal amplification - this is a target for cancer treatment
41
describe over-expression of the ligand in the GF receptor pathway \*
VEGF is overexpressed in prostate, kidney, breast this causes an increase in the kinase cascade and signal amplification - this is a target for cancer treatment
42
describe consitutive receptor activation \*
eg with EGFR in lung cancer and FGFR (fibroblast GF receptor) oin head, neck and myeloma increase kinase cascade and signal amplification
43
explain the suffixes for monoclonal Ab
momab - from mouse Ab ximab - chimeric eg cetuximab zumab - humanised eg bevacizumab mumab - fully human eg panitumuab
44
describe the difference between humanized monoclonal Ab and chimeric \*
murine regions are interspersed within light and heavy chains of Fab in humanised in chimeric - murine component of variable region is maintained integrally
45
describe the mechanism of monoclonal Ab \*
they target teh extracellular component of the receptor - neutralise the ligand - this prevents receptor dimerisation = internalisation of the receptor and prevents down stream signalling also target Fcy-receptor dependant phagocytosis or cytolysis - this induces complement dependant cytotoxity or Ab dependant cytotoxicuty - this is an immune response
46
mechanism of bevacizumab \*
binds and neutralises VEGF improves survival in colorectal cancer
47
mechanism of cetuximab \*
targets EGFR
48
describe the mechanism of small molecule inhibitors \*
bind to the kinase domain of the tyrosine kinase within the cytoplasm and block auto-phosphorylation and downstream signalling
49
describe glivec \*
the 9,22 chromosome translocation in pts withCML was discovered found to create own fusion protein - Bcr-abl an enzyme which drove over production of white cells glivec targets this Bcr-abl without targetting other proteins - 90% complete response rates in pts with CML reduced use of cytotoxics and encouraged targetted therapy this is an example of oncogene addiction - uniquely active onchogene driving a tumour glivec targets the ATP binding region in the kinase domain - inhibiting the kinase activity of the enzyme
50
what are the 2 target sites for small molecule inhibitors and egs of what targets each one \*
act on tyrosine kinases - erlotinib (EGFR), geftinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR) act on intracellular kinases so affect signalling pathways - sorafinib (blocks Raf Kinase), dasatinib (Scr kinase) torcinibs (mTOR inhibitors)
51
what is the principle of targeted therapies \*
act in receptors so block hallmarks of cancer eg VEGF inhibitor block blood flow to tumour, AKT inhibitors block apoptosis resistance mechanisms without the toxicity seen in cytotoxics
52
what are the advantages of monoclonal Ab \*
* High target specificity * Cause ADCC, complement mediated cytotoxicity and apoptosis induction * Can be radiolabelled * Cause target receptor internalisation * Long half-life (lower dosing frequency) * Good for haematological malignancies * Liked by regualatory authorities (FDA)
53
disadvantages of monoclonal Ab\*
large anc complex structure - low tumour or BBB penetration less useul against bulky structures only useful against targets with extracellular domains not used against constituently activated receptors caus immunogenity, allergy iv admn risky - although human form reduces the risk expensive RESISTANCE
54
advantage of small molecules \*
can target TKs without an extracellular domain or which is constitutively activated - ligand independant pleiotropic targts - useful in heterogenic tumours/cross talk oral admin good tissue penetration cheap
55
DISADVANTAGES OF SMALL MOLECULES \*
SHORTER HALF LIFE - MORE FREQUENT ADMIN PELITROPIC TARGETS - MORE EXPECTED TOXICITY RESISTANCE
56
describe the reistance mechanisms to targeted therapies \*
mutations in ATP=binding domian (eg BCR-Abl fusion gene and ALK gene) intrinsic resistance - herceptin ( a monoclonal ab) is effective in 85% HER2+ bvreast cancers - suggesting other driving pathways intragenic mutations upregulation of downsteam or parallel pathways
57
describe anti-sense oligonucleoties \*
new drugs still in trials single, stranded chem modified DNA-like molecule 17-22 nucelotids in length complemetary nucleic acid hybridisation to target gene - hinder translation of specific mRNA they recruit RNase H to cleave mRNA good for undruggable targets
58
describe RNA interference \*
single stranded comp RNA compounds have to be packaged to prevent degradation - this is nanotherapeutics CALAA-01 targeted to M2 subunit of ribonucleotide reductase phase 1 clinical trials
59
how are drugs approved
by EMA approved and funded by NICE can get funded by cancer drugs fund £340m/yr until march 2013 - if not funded by NICE
60
problem with drug fundung \*
it is a post code lottery
61
describe hoe we target b-Raf \*
in 60% of melanomas b-Raf has an active mutation it substitutes glutamic acid for valine adn causes a 500fold increase in activity b-Raf inhibitor (vemurafenib) showed dramatric phase 1 activity in melanoma extends life of mutation holder by 7 months looking at PET scans where radiolabelled glucose is taken up - massive improvement over weeks
62
describe immune modulationvia programmed cell death \*
PD-1 present on surface of cancer cells - required to maintain T cell activation after bindingthe ligand PDL1, the body's T cell dont recognise the tumour as foreign if either is blocked - the immun system is activated eg nivolumab: delievered increased overall survival in treatment-refractory melanoma, non-small cell lung cancer, renal cell carcinoma saw overall response rates of 31% in melaoma median survival of 16 months in pase 1 trial can get collitis, thyroiditis, pit problems, pneumonitis
63
what are genetic predictive ssays \*
take genetic assay of a tumour before give chemo and if that person is found to have a high risk of relapse then they're offered chemo in many cases can offer endocrine therpay alone - much less toxic
64
can we believe biopsies \*
may not be representative of the whole tumour eg primary might be different from the met - breast cancer can switch from being hormone resistant to hormone sensitive have to rebiopsy if people recur
65
what is a bucket trial \*
rather than treating cancer at the same site with the same drug - treat cancer with the same mutation with the same drug
66
describe the adaptive approach \*
fluid - start with all arms of therapy and then if see a signal from a certain type of cancer, should target that
67
benefit of the 100 genome project
increase genetic screening so more likely to do genetic tests for patients
68
Describe sequencing tumours prior to starting therapy \*
not currently done - risk of false -ve used to provide treatment and prognostic info concentrate on particular pathways for certain cancers circulating biomarkers, tumour cells or dna - tumour cells and dna are only found at late stages so might not be able to detect primary cancers
69
describe new therapeutic avenues \*
nanotherapies to deliver cytotoxics more effectively virtual screening technologies to identify undruggable targets immunotherapies using antigen presenting cells to present artificial antigens - not effective in some cancers target cancer met
70
describe how heterogenity is an obsticle to targeted approach \*
tracking heterogenity and bottlenecks - development of non-invasive techniques to monitor subclonal dynamics of tumour architecture through treatment may enhance understanding of resistance mechanisms as branches are 'pruned' at teh expense of outgrowth of other branches habouring heterogenous resistance mutations eg t790M gatekeeper mutation tumour sampling bias - biopsies in 1 region of a heterogenous primary or met will identify trunk events not shared by all regions of the tumour/all tumour subclones - comparision of paired samples may enhance identification of trunk events for therapeutic targetting. regional genetic ITH might have an impact on ex vivo assays of cell phenotypic function drivers of herteogenity - identification of the drivers of genomic instability that may occur at the trunk and branch may provide new approaches to limit tumour diversity and adaption actionable mutations - early drivers of disease lesd to somatic events in every subclone and tumour region - such mutations present a more robust therapeutic target and optimal synthetic lethal targets develop methods to quantify intratumour herterogenity - evidence emerging in breast and renal cancer suggests that herterogenous branched mutation may outnumber common trunk mutations
71
if treatment reduces chance of relapse of disease by 30% and dying by 20% even though there is high toxicity is it worth taking the treatment \*
yes some toxicity is rare, and drugs can be given to target the others

cancer - year 2 (18 decks)

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