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Cancer 9: Biological basis of cancer therapy Flashcards

1
Q

Which old drugs are being looked at for cancer treatment

A

Aspirin and

metformin (to reduce tumour glycolysis)

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2
Q

What is the most common cause of cancer death in the UK for male and female

A

Both lung

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3
Q

What are the 4 pillars of cancer theerapy

A

Surgery

Radiotherapy

Chemotherapy

Immunotherapy

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4
Q

What are the 6 most common cancers worldwide

A

Six most common cancers worldwide are lung, breast, bowel, prostate, and stomach

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5
Q

State the types of genetic mutations causing cancer

A

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

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6
Q

What are the 2 types of systemic therapy

A

Cytotoxic chemotherapy

Targeted therapies

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7
Q

Give examples of cytotioxic chemotherapy

A

1) Alkylating agents
2) Antimetabolites
3) Anthracyclines
4) Vinca alkaloids and taxanes
5) Topoisomerase inhibitors

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8
Q

What are the target therapies

A

Small molecule inhibitors

Monoclonal antibodies

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9
Q

How do cytotoxics work generally

A

Cytotoxics “select” rapidly dividing cells by targeting their structures (mostly the DNA)

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10
Q

….

A

…..

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11
Q

How can cytotoxic chemo be given

A

Given intravenously or by mouth (occasionally)

Non “targeted” – affects all rapidly dividing cells in the body

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12
Q

When can cytotoxic chem be given

A

Given post-operatively: adjuvant

Pre-operatively: neoadjuvant

As monotherapy or in combination with curative or palliative intent

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13
Q

How do alkylating agents work

A

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

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14
Q

What are pseudo-alkylating agents

A

Add platinum to guanine residues in DNA

Same mechanism of cell death as akylating agents

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15
Q

Give examples of pseudo-alkylating episodes

A

carboplatin, cisplatin, oxaliplatin

sounds like platin-um

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16
Q

Give examples of alkylating agens

A

Chlorambucil, cyclophosphamide, dacarbazine, temozolomide.

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17
Q

What are the side effects of Alkylating and pseudoalkylating agents

A

cause hair loss (not carboplatin),

nephrotoxicity,

neurotoxicity,

ototoxicity (platinums),

nausea,

vomiting,

diarrhoea,

immunosuppression,

tiredness

BrainEarTirednessHairlossImmunosuppressionNauseaKidneys

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18
Q

How does cisplatin work

A

Enters through copper channel (CTR1)

Hydrolises in low Cl- environment, then binds guanine residues cross links DNA

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19
Q

What are the effects of intra- and inter-strand cross-links created by cisplatin

A

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

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20
Q

How do antimetaboites work

A

Masquerade as purine or pyrimidine residues leading to inhibition of DNA synthesis, DNA double strand breaks and apoptosis

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21
Q

Which checkpoints are involve in detecting damage due to cancer drugds

A

anti-metabolites: DNA checkpoint –> apoptosis

same for alkylating

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22
Q

What do anti-metabolites block

A

Block DNA replication (DNA-DNA) and transcription (DNA –RNA)

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23
Q

What can anti-metabolites be antagonsits of

A

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)

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24
Q

Give examples of anti-metabolites

A

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)

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25
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
26
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
27
Give examples of anthracyclines
doxorubicin, epirubicin -cin (remember cos cyclin has c)
28
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”)
29
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
30
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
31
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
32
Which drugs have anti-topoisomerae effets
Drugs such as anthracyclines have anti-topoisomerase effects through their action on DNA
33
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
34
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
35
Which drug might help with side effects of topoisomerase inhibitors
Atropine
36
What must be watched out for with patients on chemotherapy
Septic neutropaenia If a patient with cancer has fever, they would need antibiotics immediately
37
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)
38
What are targeted therapies
monoclonal antibodies and small molecule inhibitors
39
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
40
How can dual kinase inhibitors help
Prevent feedback loops (which could compensate fr the blocked muation) but increase toxicities – new therapeutic strategies required
41
What arethe 6 hallmarks of cancer
``` Self –sufficient Insensitive to anti-growth signals Anti-apoptotic Pro-invasive and metastatic Pro-angiogenic Non-senescent ```
42
What are the 4 new hallmarks of cancer
Dysregulated metabolism Evades the immune system Unstable DNA Inflammation
43
What must normal cells have to divide (move out of G0)
Growth factor binding
44
What percentage of receptor tyrosine kinases are assoiated with human malignancies
>50% associated with human malignancies
45
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)
46
Give an example of when a receptor tyrosine kinase LIGAND ie overexpressed
VEGF – prostate cancer, kidney cancer, breast cancer
47
Give examples of faulty receptors leading to constitutive (ligand independent) receptor activation
EGFR (lung cancer) | FGFR (head and neck cancers, myeloma)
48
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
49
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
50
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)
51
How do mAbs work
Target the extracellular component of the receptor Neutralise the ligand Prevent receptor dimerisation Cause internalisation of receptor
52
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).
53
mABs can also target what, other than receptors
The ligand
54
Give 2 examples of monoclonal antibodyes
Bevacizumab binds and neutralises VEGF. Improves survival in colorectal cancer Cetuximab targets EGFR
55
What do small molecule ihibitors do
Bind to the kinase domain of the tyrosine kinase within the cytoplasm and block autophosphorylation and downstream signalling
56
What was the first targeted therapy
Glivex (i.e. imatinib) to work on CML due to BCR-ABL
57
How does glivec work
Glivec is a small molecule inhibitor and targets the ATP binding region within the kinase domain
58
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
59
Give examples of SMI inhibiting receptors
erlotinib (EGFR), gefitinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR)
60
Give examples of SMIs affecting intracelllar kinases
Sorafinib (Raf kinase) Dasatinib (Src kinase) Torcinibs (mTOR inhibitors)
61
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)
62
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
63
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
64
mABs is especially good for which malignancies
Haem
65
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
66
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
67
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
68
How might RNA interference be useful in cancer therapy
Single stranded complementary RNA Compounds have to be packaged to prevent degradation - nanotherapeutics
69
What are the obstacles in the way o fthe targeted approach
Tumour heterogeneity is a major obstacle to the targeted approach
70
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
71
Which mutation of b-RAF is commonly found in melanoma
Substitution of glutamic acid for valine (V600E) causes a 500-fold increase in activity
72
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
73
What is nivolumab, is it effective?
anti-PD1 antibody delivered lasting responses
74
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

Canc (16 decks)

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