Cancer 9: Biological basis of cancer therapy Flashcards
Which old drugs are being looked at for cancer treatment
Aspirin and
metformin (to reduce tumour glycolysis)
What is the most common cause of cancer death in the UK for male and female
Both lung
What are the 4 pillars of cancer theerapy
Surgery
Radiotherapy
Chemotherapy
Immunotherapy
What are the 6 most common cancers worldwide
Six most common cancers worldwide are lung, breast, bowel, prostate, and stomach
State the types of genetic mutations causing cancer
Chromosome translocation
Gene amplification (copy number variation)
Point mutations within promoter or enhancer regions of genes
Deletions or insertions
Epigenetic alterations to gene expression
Can be inherited
What are the 2 types of systemic therapy
Cytotoxic chemotherapy
Targeted therapies
Give examples of cytotioxic chemotherapy
1) Alkylating agents
2) Antimetabolites
3) Anthracyclines
4) Vinca alkaloids and taxanes
5) Topoisomerase inhibitors
What are the target therapies
Small molecule inhibitors
Monoclonal antibodies
How do cytotoxics work generally
Cytotoxics “select” rapidly dividing cells by targeting their structures (mostly the DNA)
….
…..
How can cytotoxic chemo be given
Given intravenously or by mouth (occasionally)
Non “targeted” – affects all rapidly dividing cells in the body
When can cytotoxic chem be given
Given post-operatively: adjuvant
Pre-operatively: neoadjuvant
As monotherapy or in combination with curative or palliative intent
How do alkylating agents work
Add alkyl (CNH2N+1) groups to guanine residues in DNA
Cross-link (intra, inter, DNA-protein) DNA strands and prevents DNA from uncoiling at replication
Trigger apoptosis (via checkpoint pathway)
Encourage miss-pairing - oncogenic
What are pseudo-alkylating agents
Add platinum to guanine residues in DNA
Same mechanism of cell death as akylating agents
Give examples of pseudo-alkylating episodes
carboplatin, cisplatin, oxaliplatin
sounds like platin-um
Give examples of alkylating agens
Chlorambucil, cyclophosphamide, dacarbazine, temozolomide.
What are the side effects of Alkylating and pseudoalkylating agents
cause hair loss (not carboplatin),
nephrotoxicity,
neurotoxicity,
ototoxicity (platinums),
nausea,
vomiting,
diarrhoea,
immunosuppression,
tiredness
BrainEarTirednessHairlossImmunosuppressionNauseaKidneys
How does cisplatin work
Enters through copper channel (CTR1)
Hydrolises in low Cl- environment, then binds guanine residues cross links DNA
What are the effects of intra- and inter-strand cross-links created by cisplatin
At the DNA damage checkpoin,
nucleotide excision repair attempts to excise the lesions
Mismatch repair pathway activated (these are a type of during, or post replication repair)
At the DNA damage checkpoimnt, apoptotic cell death due to p53
How do antimetaboites work
Masquerade as purine or pyrimidine residues leading to inhibition of DNA synthesis, DNA double strand breaks and apoptosis
Which checkpoints are involve in detecting damage due to cancer drugds
anti-metabolites: DNA checkpoint –> apoptosis
same for alkylating
What do anti-metabolites block
Block DNA replication (DNA-DNA) and transcription (DNA –RNA)
What can anti-metabolites be antagonsits of
Purine antagonist (adenine and guanine)
Pyrimidine antagonist (thymine/uracil and cytosine)
Folate antagonists (which inhibit dihydrofolate reductase required to make folic acid, building block for all nucleic acids – especially thymine)
Give examples of anti-metabolites
methotrexate (folate), 6-mercaptopurine, decarbazine and fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)
(mostly -bine, or has base name…. for folate it has -ate at the end)
What are the side effects of anti-metabolites
Hair loss (alopecia) – not 5FU or capecitabine
Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
Increased risk of neutropenic sepsis (and death) or bleeding
Nausea and vomiting (dehydration)
Mucositis and diarrhoea
Palmar-plantar erythrodysesthesia (PPE)
Fatigue
How do anthracyclins work
Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within the DNA/RNA strand.
Also block DNA repair - mutagenic
They create DNA and cell membrane damaging free oxygen radicals
Give examples of anthracyclines
doxorubicin, epirubicin
-cin (remember cos cyclin has c)
What are the side effects of anthracyclines
Cardiac toxicity (arrythmias, heart failure) – probably due to damage induced by free radicals
Alopecia
Neutropenia
Nausea and Vomiting
Fatigue
Skin changes
Red urine (doxorubicin “the red devil”)
What vinca alkaloids and taxanes. How does each work
Work by inhibiting assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest
What are the side effects of microtubule targeting drugs (eg. vinca alkaloids and taxanes)
Nerve damage: peripheral neuropathy, autonomic neuropathy
Hair loss
Nausea
Vomiting
Bone marrow suppression (neutropenia, anaemia etc)
Arthralgia
Allergy
What are topoisomerases. How do they work
Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription
They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA
They protect the free ends of DNA from aberrant recombination events
Which drugs have anti-topoisomerae effets
Drugs such as anthracyclines have anti-topoisomerase effects through their action on DNA
As well as anthracyclines, which other drugs also have anti-topoisoerase effects
Specific topoisomerase inhibitors include Topotecan and irinotecan (topo I) and etoposide (topo II) alter binding of the complex to DNA and allow permanent DNA breaks
What are the side effects of topositomerase
(irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps and diaphoresis (sweating).
Hair loss
Nausea, vomiting
Fatigue
Bone marrow suppression
Which drug might help with side effects of topoisomerase inhibitors
Atropine
What must be watched out for with patients on chemotherapy
Septic neutropaenia
If a patient with cancer has fever, they would need antibiotics immediately
What are the methds of cancer cell resistance to chemo drugs
Drug effluxed from the cell by ATP-binding cassette (ABC) transporters
DNA adducts replaced by Base Excision repair (using PARP)
DNA repair mechanisms upregulated and DNA damage is repaired (so no DNA double strand breaks)
What are targeted therapies
monoclonal antibodies and small molecule inhibitors
Why can monogenic cancers be treated easier
You can “cut the wiring” (mutation) in monogenic cancers but for others, parallel pathways or feedback cascades are activated
How can dual kinase inhibitors help
Prevent feedback loops (which could compensate fr the blocked muation) but increase toxicities – new therapeutic strategies required
What arethe 6 hallmarks of cancer
Self –sufficient Insensitive to anti-growth signals Anti-apoptotic Pro-invasive and metastatic Pro-angiogenic Non-senescent
What are the 4 new hallmarks of cancer
Dysregulated metabolism
Evades the immune system
Unstable DNA
Inflammation
What must normal cells have to divide (move out of G0)
Growth factor binding
What percentage of receptor tyrosine kinases are assoiated with human malignancies
> 50% associated with human malignancies
In which cancers are receptors over expressed
HER2 – amplified and over-expressed in 25% breast cancer
EGFR – over-expressed in breast and colorectal cancer
PDGFR- glioma (brain cancer)
Give an example of when a receptor tyrosine kinase LIGAND ie overexpressed
VEGF – prostate cancer, kidney cancer, breast cancer
Give examples of faulty receptors leading to constitutive (ligand independent) receptor activation
EGFR (lung cancer)
FGFR (head and neck cancers, myeloma)
State three ways in which receptors can lead to unregulated proliferation
Over expression of receptor tyrosine kinase
Faulty receptor sleading to constitutive receptor activation
Overexpression of receptor ligand
Outline what each of the following suffixes mean
- momab
- ximab
- zumab
- mumab
-momab (derived from mouse antibodies)
-ximab (chimeric= from animal) e.g
cetuximab
- zumab (humanised) e.g. bevacizumab trastuzumab
- mumab (fully human) e.g. panitumumab
Differentiate humanised monoclonal antibodies and chimeric monoclonal antibodies
HUMANISED:
Murine (i.e. rodent) regions insterpsed with the heavy and light chains of the Fab portion of the antibody
CHIMAERIC antibody
Murine compoent of the variable region of the Fab section is maintained integrally (not interspersed)
How do mAbs work
Target the extracellular component of the receptor
Neutralise the ligand
Prevent receptor dimerisation
Cause internalisation of receptor
In addition to targeting the EC component of the receptor, what else can mABs do?
mAbs also activate Fcγ-receptor-dependent phagocytosis or cytolysis
induces complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC).
mABs can also target what, other than receptors
The ligand
Give 2 examples of monoclonal antibodyes
Bevacizumab binds and neutralises VEGF. Improves survival in colorectal cancer
Cetuximab targets EGFR
What do small molecule ihibitors do
Bind to the kinase domain of the tyrosine kinase within the cytoplasm and block autophosphorylation and downstream signalling
What was the first targeted therapy
Glivex (i.e. imatinib) to work on CML due to BCR-ABL
How does glivec work
Glivec is a small molecule inhibitor and targets the ATP binding region within the kinase domain
T/f small molecule inhibiors only act on receptor TKs
F
Small molecule inhibitors act on receptor TKs but also intracellular kinases – therefore can affect cell signalling pathways
Give examples of SMI inhibiting receptors
erlotinib (EGFR), gefitinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR)
Give examples of SMIs affecting intracelllar kinases
Sorafinib (Raf kinase)
Dasatinib (Src kinase)
Torcinibs (mTOR inhibitors)
How can SMIs work, by acting on receptors
block cancer hallmarks (e.g VEGF inhibitors alter blood flow to a tumour, AKT inhibitors block apoptosis resistance mechanisms)
T/F targeted therapy has slightly reduced toxicity relative to systemic therapy
F
By acting on receptors (either externally or internally), targeted therapies block cancer hallmarks (e.g VEGF inhibitors alter blood flow to a tumour, AKT inhibitors block apoptosis resistance mechanisms) WITHOUT the toxicity observed with cytotoxics
What is advantage of mABs compared to SMI
mABs:
High specificity, caused ADCC, complement mediated cytotoxicity and apopotisis induction, can be radiolabelled, longer half life
SMI:
Can target TKs without EC domain or which are constitutively actiated (ligand independent), pleiotropic targets, oral administration, good penetration, cheap
mABs is especially good for which malignancies
Haem
What are disadvantages when comapirng mABs and SMIs
mABs:
Large/comlex structure (low tumour/BBB penetration), less usefula gainst bulky tumours, only useful against targets with EC domains, not useful for constitutivel activated receptors, cause allergy, IV admin, risky, expensive
SMI:
Shorter half life, more frequent admin. , mor eunexpected toxiity due to pleiotropic targets
Outline the mechanism of resistance to targeted therapies
Mutations in ATP-binding domain (e.g BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively)
Intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways)
Intragenic mutations
Upregulation of downstream or parallel pathways
How are anti-sense oligonucelotides useful in cancer treatment
Single stranded, chemically modified DNA-like molecule 17-22 nucleotides in length
Complementary nucleic acid hybridisation to target gene hindering translation of specific mRNA
Recruits RNase H to cleave target mRNA
Good for “undruggable” targets
How might RNA interference be useful in cancer therapy
Single stranded complementary RNA
Compounds have to be packaged to prevent degradation - nanotherapeutics
What are the obstacles in the way o fthe targeted approach
Tumour heterogeneity is a major obstacle to the targeted approach
Outline the success story involving b-RAF
What are the side effects of the drug
Activating mutations of
B-Raf identified in 60%
melanomas
B-Raf inhibitor (vemurafenib)
showed dramatic Phase I activity
in melanoma (80% PR or CR)
Extends life span of mutation holders by 7 months
arthralgia, skin rash and photosensitivity
Which mutation of b-RAF is commonly found in melanoma
Substitution of glutamic acid
for valine (V600E) causes a
500-fold increase in activity
Outline the success story involving immune modulation via programmed cell death 1 (PD-1)
PD1 present on tumour cell surface
Required to maintain T cell activation
But after binding to the ligand PDL1, the body’s T cell could not recognise the tumour as foreign anymore
Blocking PDL1 or its receptor PD-1, immune system is stimulated again
Nivolumab (developed by BMS) is anti-PD1 antibody
What is nivolumab, is it effective?
anti-PD1 antibody
delivered lasting responses
What could be new therapeitoc avenes in cancer therapy
Nanotherapies – delivering cytotoxics more effectively
Virtual screening technologies to identify “undruggable” targets
Immunotherapies using antigen presenting cells to present “artificial antigens”
Targeting cancer metabolism
