biological basis of cancer therapy Flashcards
epidemiology of cancer *
14 million cases a yr
concentrated in west - perhaps because of better diagnosis and detection, or a more unhealthy lifestyle
what are the main cancer causes of death *
men - lung - diagnosed late so few people have surgery then liver then stomach
women - breast then lung then colorectum
describe the predicted incidence of cancers *
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
what are the 4 main cancer treatment modalities &
surgery
radiotherapy
chemo
immunotherapy
using breast cancer explain 4 anti-cancer modalities *
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
what types of genetic mutation cause cancer *
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)
how can we use the genetic mutations causing cancer *
because cancer is genetically messy - can target the DNA - but dont want to target the normal DNA
what are the 2 types of systemic therapy *
cytotoxic chemo
targeted therapy
types of cytotoxic chemo *
alkylating therapies
antimetabolites
anthracyclins
vinca alkaloids and taxanes
topoisomerase inhibitors
(to tackle resistance, use drugs from different categories)
types of targeted therapies *
small molecule inhibitors
monoclonal antibodies
mechanism of cytotoxic chemo *
select rapidly dividing cells by targeting their structures
alkalating agents, antimetabolites, anthracyclins, topoisomerase inhibitors target intrinsic tumour DNA
texanes and vinca alkaloids attack microtubules
describe cytotoxic chemo *
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
mechanism of alkylating agents *
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
describe pseudo-alkylating agents *
add platinum to guanine residues in DNA
same mechanism of cell death as alkylating agents
eg carboplatin, cisplatin, oxaliplatin
SE of alkylating agents or pseudoalkylating agents *
hair loss (not carboplatin)
nephrotoxicity
neurotoxicity
ototoxicity (platinums)
neusea, vom, diarrhoea - most common
immunosuppression
tiredness
mechanism of antemetabolites *
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)
SE for anti-metabolites *
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
mechanism of anthracyclins *
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
se of anthracyclins *
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’
describe vinca alkaloids and taxanes *
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
se of microtubule targeting drugs *
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
describe topoisomerase inhibitors *
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
SE of topoisomerase inhibitors*
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
treatment for SE for anti-metabolites *
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
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
treatment for alkylating agent se *
alopecia - scalp cooling
nausea and vom- anti-emetics
diahorrea - loperamide
immunosuppression - transfusion, platelet, GCSF, dose reduction
how have response rates to cytotoxics for ovarian cancer changed over time
increased from 50% to 80%
now still use carboplatin/paclitaxel
how have survival rates to cytotoxics for ovarian cancer changed
improved but still under 50%
why do we need to develop new drug targets *
resistance of cells to treatment
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
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
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
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
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
what are the new 4 hallmarks of cancer *
deregulating cellular energetics
avoiding immune destruction
tumour promoting inflammation
genome instability and mutation
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
describe the growth factor receptor pathway *
GF binds to ligand binding site
causes dimerisation
and downstream signalling of the kinase cascade adn signal amplification
describe the growth factor receptor *
has extracellular ligand binding site
kinase domain intracellularly
C-terminal region with tyrosines for autophosphorylation
problem with receptor tyrosine kinases *
>50% of them are associated with human malignancies
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
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
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
explain the suffixes for monoclonal Ab
momab - from mouse Ab
ximab - chimeric eg cetuximab
zumab - humanised eg bevacizumab
mumab - fully human eg panitumuab
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
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
mechanism of bevacizumab *
binds and neutralises VEGF
improves survival in colorectal cancer
mechanism of cetuximab *
targets EGFR
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
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
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)
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
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)
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
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
DISADVANTAGES OF SMALL MOLECULES *
SHORTER HALF LIFE - MORE FREQUENT ADMIN
PELITROPIC TARGETS - MORE EXPECTED TOXICITY
RESISTANCE
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
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
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
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
problem with drug fundung *
it is a post code lottery
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
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
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
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
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
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
benefit of the 100 genome project
increase genetic screening so more likely to do genetic tests for patients
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
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
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
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
