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Cancer > Biological basis of cancer therapy > Flashcards

Biological basis of cancer therapy Flashcards

1
Q

Where is cancer incidence heavily concentrated

A

In the western world- better detection, unhealthy lifestyle

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2
Q

What are the top four most common cancer deaths in males worldwide (2008

A

Lung
Liver
Stomach
Colorectum

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3
Q

What are the top four most common cancer deaths in females worldwide (2008)

A

Breast
Lung
Colorectum
Cervix

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4
Q

Nowadays, why is the morality of breast and cervical cancers less than that of lung cancers

A

Better diagnosis and screening techniques for breast and cervical cancers.
Lung cancers often diagnosed late and so less patients can be treated surgically.

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5
Q

Describe how the incidence of cancers is set to change

A

22 million cases in 2030
Greater westernisation of developing countries will reduce infection-based cancers (cervical, stomach etc) and increase western cancers such as breast, colorectal, lung and prostate
Better screening and diagnostic techniques- A.I assisted mammography analyser

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6
Q

What are the 5 most common cancers worldwide

A 
Lung 
Breast 
Bowel 
Prostate 
Stomach
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7
Q

State the main anti-cancer treatment modalities

A

Radiotherapy
Chemotherapy
Surgery
Immunotherapy

May use radiotherapy/chemotherapy to down-stage the cancer before surgery if it has not yet spread or used when surgery is difficult (i.e too much bleeding, surgeon can’t get well demarcated edges to resect the cancer)

Not many immunotherapies to treat breast cancer.

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8
Q

Ultimately, what type of disease is cancer

A

Cancer is a disease of the genome

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9
Q

Describe the main types of genetic mutations that can cause 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

Often when the tumour is sequenced, many genetic mutations are evident.

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10
Q

What is important to remember about the genetics of cancer

A

Cancers are genetically “messy” – so attacking their DNA is a good idea
However, we want to minimise damage to normal DNA in the other normal cells too.

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11
Q

How was chemotherapy discovered

A

1943…John Harvey…100 tons mustard gas bombs…direct hit from German JU88 air raid….explosion..628 suffered from mustard gas…69 died within 2 weeks

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12
Q

What are the two different types of systemic therapies to treat cancers

A

Cytotoxic chemotherapies

Targeted therapies

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13
Q

What are the different classes of cytotoxic chemotherapies

A

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

Often use multiple different classes to minimise anti-cytoxic resistance.

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14
Q

What are the different types of targeted therapies

A

Small molecule inhibitors

Monoclonal antibodies

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15
Q

What do the cyto-toxic agents target

A

Cytotoxics “select” rapidly dividing cells by targeting their structures (mostly the DNA)- except for taxanes and vinca-alkaloids which target microtubules.

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16
Q

Describe the administration of cytotoxic chemotherapy

A

Given intravenously or by mouth (occasionally)
Works systemically
Non “targeted” – affects all rapidly dividing cells in the body
Will therefore lead to hair loss, bone marrow suppression , gut mucosa- can lead to mucositis (mouth ulcers)
Bone marrow suppression causing anaemia, neutropaenia and thrombocytopaenia

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17
Q

Describe the uses of cytotoxic chemotherapy

A

Given post-operatively: adjuvant- to get rid off any cells not removed by the surgery

Pre-operatively: neoadjuvant- chemosensitive cancer cells can shrink tumour before surgery- can lead to more manageable surgery i.e wide local excision instead of mastectomy
As monotherapy or in combination
with curative or palliative intent- but still can have prognosis of 3 years

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18
Q

Describe how 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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19
Q

State some examples of alkylating agents

A

Alkylating agents: Chlorambucil, cyclophosphamide, dacarbazine, temozolomide.

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20
Q

Describe how pseudo-alkylating agents work

A

Add platinum to guanine residues in DNA
Same mechanism of cell death as akylating agents
Examples: carboplatin, cisplatin, oxaliplatin

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21
Q

What are the side effects of alkylating and pseudo-alkylating agents

A

Side effects: cause hair loss (not carboplatin), nephrotoxicity, neurotoxicity, ototoxicity (platinums), nausea, vomiting, diarrhoea, immunosuppression, tiredness

Oncogenic- so risk of secondary malignancy bur benefit > risk

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22
Q

Summarise the mechanism of action of anti-metabolites

A

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

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23
Q

Describe the function of anti-metabolites

A

Block DNA replication (DNA-DNA) and transcription (DNA –RNA)
Can be purine (adenine and guanine), pyrimidine (thymine/uracil and cytosine) or folate antagonists (which inhibit dihydrofolate reductase required to make folic acid, an important building block for all nucleic acids – especially thymine)

Force the DNA into checkpoint — apoptosis

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24
Q

Describe some examples of anti-metabolites

A

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

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25
Q

Describe the side effects of anti-metabolites

A

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) -peeling and reddening of the skin
Fatigue

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26
Q

Describe the function of anthracyclines

A

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
Examples: doxorubicin, epirubicin

Intercalating agent (aromatic)

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27
Q

Describe the side effects of anthracyclines

A 
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”)
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28
Q

Describe how vinca alkaloids and taxanes work

A

Originally derived from natural sources
Work by inhibiting assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest

Vincas and indibulin- inhibit assembly
Taxane (paclitaxel)- inhibit dissasembly

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29
Q

Describe the side effects of microtubule targeting drugs

A

Nerve damage: peripheral neuropathy, autonomic neuropathy
Hair loss
Nausea
Vomiting
Bone marrow suppression (neutropenia, anaemia etc)
Arthralgia
Allergy

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30
Q

Describe the physiological role of topoisomerase

A

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
May induce apoptosis at checkpoints

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31
Q

Describe how topoisomerase inhibitors work

A

Drugs such as anthracyclines have anti-topoisomerase effects through their action on DNA
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

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32
Q

Describe the side effects of topoisomerase inhibitors

A 
(irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps and diaphoresis (sweating). Therefore given with atropine
Hair loss
Nausea, vomiting
Fatigue
Bone marrow suppression
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33
Q

What is the key difference between the action of topoisomerase and topoisomerase inhibitors

A

Topoisomerase is responsible for the unwinding of DNA and they induce temporary single and double strand breaks in the phosphodiester backbone
Topoisomerase inhibitors alter the binding of topoisomerase to DNA and allow permanent breaks in the DNA

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34
Q

Describe some specific and non-specific topoisomerase inhibitors

A

 Other drugs such as anthracyclines have anti-topoisomerase effects through their action on DNA.
 Specific topoisomerase inhibitor drugs – Topotecan, Irinotecan (topo1), Etoposide (topo2).

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35
Q

What will the DNA damage checkpoint and double strand breaks lead to

A

Apoptosis!

using p53, bcl-2

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36
Q

This lady received FEC chemotherapy, 5-fluorouracil, epirubicin and cyclophosphamide for her breast cancer

What is the expected benefit and what side effects should she expect?

A

Treatment will reduce her chance of relapse with the disease by 30% and chance of dying from the disease by 20%. Is it worth the toxicity?
We would say yes!
We have good therapies to deal with side effects

37
Q

How can we treat the side effects of anti-metabolites such as 5-FU

A

Pyridoxine (vitamin B6)
Antiemetics
Transfusions/ platelets / GCSF/ dose reduction
Mouth washes Loperamide

38
Q

How can we treat the side effects of anthracyclines such as epirubicin

A

Irreversible cardiac toxicity but can cap dosing
Scalp cooling

same as anti-metabolites

39
Q

Outline the timeline of systemic therapy

A 
1940-1950
Nitrogen mustards 
Alkylating agents
Antimetabolites 
1950s 
Vinca Alkaloids
1960s
Combination regimens
Taxanes and topoisomerase inhibitors
Cisplatin
1970s
Anthracyclines and topoisomerase inhibitors 
1980s 
Refinement of taxanes

1980s - 1990s
Better supportive care: GCSF, bone marrow transplants, anti-emetics
Hormone therapies: tamoxifen
Imatinib (Glivec)

40
Q

Describe how response rates to cytoxics in ovarian cancer patients has improved

A

Carboplatin / paclitaxel >80% from 1995

Up from 45% in 1965 with Chlorambuci

41
Q

Describe how survival retest cytotoxics with ovarian cancer has improved

A

now over 45 months

originally 20 months

42
Q

Describe some resistance mechanisms to cytotoxics

A

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 -negating the effects of double strand breaks.

43
Q

Summarise how we are manipulating what we know about cancer cells

A

Modern, targeted (ie non-cytotoxic) therapies seek to manipulate what we know about cancer cells
Mainly using monoclonal antibodies and small molecule inhibitors

44
Q

Summarise targeted chemotherapy

A

 Cancer cells have internal pathways which can be targeted in treatment.
o In monogenic cancers, this is fine and treatable.
o In others, parallel pathways or feedback cascades become activated- Upreg Ras/Raf and PI3K pathways

 “Dual kinase inhibitors” can prevent the feedback loop and this target not just monogenic cancers (picture).
Prevent feedback loops but increase toxicities – new therapeutic strategies required - as these pathways are important in all cells

45
Q

What were the original 6 hallmarks of cancer cells

A 
Self –sufficient
Insensitive to anti-growth signals
Anti-apoptotic
Pro-invasive and metastatic
Pro-angiogenic
Non-senescent
46
Q

Describe the current 10 hallmarks of cancer

A 
Self –sufficient
Insensitive to anti-growth signals
Anti-apoptotic
Pro-invasive and metastatic
Pro-angiogenic
Non-senescent
Dysregulated metabolism
Evades the immune system
Unstable DNA
 Inflammation
47
Q

Summarise the role of growth singnals

A

Normal cells need growth signals to move from a quiescent (resting) to active proliferating state
These signals are transmitted into the cell via growth factors binding transmembrane receptors and activating downstream signalling pathways

Cancer cells are self-sufficient in growth signals- once they become dysregulated- need growth factor initially

48
Q

Summarise the importance of receptor tyrosine kinase in cancers

A

 Receptor tyrosine kinase = >50% of human malignancies.

49
Q

Give some examples that are over expressed in cancers

A

HER2 – amplified and over-expressed in 25% breast cancer
EGFR – over-expressed in breast and colorectal cancer
PDGFR- glioma (brain cancer)

Kinase cascade and signal amplification will increase

50
Q

Describe some ligands that are over-expressed in cancers

A

VEGF – prostate cancer, kidney cancer, breast cancer

Kinase cascade and signal amplification will increase

51
Q

Describe constitutive (ligand independent) receptor activation in cancer

A

EGFR (lung cancer)
FGFR (head and neck cancers, myeloma)

Kinase cascade and signal amplification

52
Q

Describe the different types of monoclonal antibodies

A
  • momab (derived from mouse antibodies)
  • ximab (chimeric) e.g cetuximab
  • zumab (humanised) e.g. bevacizumab trastuzumab
  • mumab (fully human) e.g. panitumumab
53
Q

Describe the structure of humanised monoclonal antibodies

A 
Humanized monoclonal antibody, 
murine regions (black) interspersed within the light (light gray) and heavy (dark gray) chains of the Fab portion
54
Q

Describe the structure of murine monoclonal antibodies

A 
Chimeric antibody 
murine component (black) of the variable region of the Fab section is maintained integrally.
55
Q

What part of the receptor do monoclonal antibodies target

A

Monoclonal Antibodies target the extracellular component of the receptor

This can:
Neutralise the ligand

Prevent receptor dimerisation

Cause internalisation of receptor

56
Q

What else can mAbs target

A

mAbs also activate Fcγ-receptor-dependent phagocytosis or cytolysis induces complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC).

57
Q

Describe some examples of monoclonal antibodies used in cancer therapy

A

Bevacizumab binds and neutralises VEGF. Improves survival in colorectal cancer

Cetuximab targets EGFR

58
Q

How do small molecule inhibitors work

A

Bind to the kinase domain of the tyrosine kinase within the cytoplasm and block autophosphorylation and downstream signalling

59
Q

Describe Glivec (Imatinib) as the first targeted therapy

A

In 1973 the (9,22) chromosome translocation in patients with CML was discovered (Janet Rowley)
Found to create its own unique fusion protein called Bcr-abl, an enzyme which drove over-production of white cells
1996 Buchdunger et al published data on a drug that could specifically target bcr-abl (and not affect other proteins)
Fantastic clinical results (90% complete response rates in patients with CML) heralded the departure from “conventional cytotoxics” into a new era of “targeted therapies”
Example of “Oncogene Addiction” – uniquely hyperactive oncogene driving a tumour (Achilles’ Heel)

60
Q

Describe how Glivec works

A

Glivec is a small molecule inhibitor and targets the ATP binding region within the kinase domain

Ligand in ATP-binding site, inhibiting kinase activity of ABL1

Not all cancers are monogenic - i.e tyrosine kinase domain of ABL1

61
Q

Where can the small molecule inhibitors act

A

Small molecule inhibitors act on receptor TKs but also intracellular kinases – therefore can affect cell signalling pathways

62
Q

Describe the small molecule inhibitors which inhibit receptors

A

Examples of SMIs inhibiting receptors include erlotinib (EGFR), gefitinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR)

63
Q

Describe the SMIs which inhibit intracellular kinases

A

SMIs inhibiting intracellular kinases include:
Sorafinib (Raf kinase)
Dasatinib (Src kinase)
Torcinibs (mTOR inhibitors)

64
Q

Describe the benefits of targeted therapies over cytotoxic

A

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

65
Q

What are the advantages of mAbs

A 
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)
66
Q

What are the disadvantages of mAbs

A

Large and complex structure (low tumour or BBB penetration),
less useful against bulky tumours
Only useful against targets with extracellular domains
Not useful for constitutively activated receptors
Cause immunogenicity, allergy
Parenteral (IV) administration
Risky! (though humanisation reduces risk)
Expensive

67
Q

What are the advantages of small molecule inhibitors

A

Can target TKs without an extracellular domain or which are constitutively activated (ligand independent)
Pleiotropic targets (useful in heterogenic tumours/ cross talk)
Oral administration
Good tissue penetration
Cheap

68
Q

What are the disadvantages of small molecule inhibitors

A 
Shorter half-life, more frequent administration
Pleiotropic targets (more unexpected toxicity)
69
Q

What is a key issue with all of the targeted therapies

A

Resistance

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
70
Q

Describe anti-sense oligonucleotides

A

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
Very expensive

Can precent translation of ICAM-1

71
Q

Describe the use of RNAi

A

Single stranded complementary RNA
Has lagged behind anti-sense technology –especially in cancer therapy
Compounds have to be packaged to prevent degradation - nanotherapeutics
CALAA-01 targeted to M2 subunit of ribonucleotide reductase. Phase I clinical trials in cancer –results awaited
Again, very expensive

72
Q

Describe the regulation and funding of anti-cancer therapies

A

Licenced by European Medicines Agency

Approved by National Institute for Health & Care Excellence (NICE)

Cancer Drugs Fund - £340m/yr until March 2016

Regional differences in accès to drugs

73
Q

What is a major obstacle to the targeted approach

A

Tumour heterogeneity

74
Q

Describe actionable mutations and driver mutations

A

Drivers of heterogeneity- identify the driver events for genomic instability that may occur at the nexus of the trunk and branch may provide new approaches to limit tumour diversity and adaptation

Actionable mutations - early drivers of disease biology lead to ubiquitous somatic events present in every tumour sub clone and tumour region. such ubiquitous tumour mutations may present more robust therapeutic targets and optimal synthetic lethal targets

75
Q

Describe how we can track heterogeneity and bottlenecks

A

development of noninvasive techniques to monitor and track the sub clonal dynamics of tumour architecture through treatment may enhance understanding of resistance mechanisms as branches are pruned at the expense of outgrowth of other branches harbouring heterogeneous resistance mutations

76
Q

Describe tumour sampling bias

A

Biopsies in 1 region of a heterogenous primary or metastatic tumour will identify trunk events but may also identify as many or more heterogeneous events not shared by all regions of the tumour or by all tumour subtypes.
Comparison of paired primary/metastatic samples may enhance identification of trunk events for therapeutic targeting
Regional genetic ITH may have an impact on ex vivo assays of cell phenotypic function

77
Q

Describe the success story of targeting B-raf

A 
Activating mutations of 
B-Raf identified in 60% 
melanomas
Substitution of glutamic acid 
for valine (V600E) causes a 
500-fold increase in activity
B-Raf inhibitor (vemurafenib) 
showed dramatic Phase I activity 
in melanoma (80% PR or CR)
Extends life span of mutation holders by 7 months (Sosman et al, NEJM, 2012)
Side effects arthralgia, skin rash and photosensitivity
78
Q

Describe immune modulation via programmed cells eath 1 PD-1

A

Present on the surface of cancer cells
Required to maintain T cell activation
After binding the ligand PDL1, the body’s T cells can no longer recognise tumour cells as foreign
If either is blocked (ligand or receptor) , immune system is stimulated
Nivolumab (developed by BMS) is anti-PD1 antibody

79
Q

What can nivolumab be used to treat

A

In treatment-refractory melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC)
Saw overall response rates of 31% in melanoma (cf the usual 5-15%)
Median survival of 16 months (phase I trial)

80
Q

What is important to remember about cancer therapy

A

We now know that cancer is fundamentally a genetic disease
The mainstay of cancer treatment is cytotoxic chemotherapy, but this is toxic, non-specific and sometimes ineffective
Glivec was the first rationally-designed agent with impressive results in CML suggesting targeted drugs would replace cytotoxics
Targeted agents are generally monoclonal antibodies and small molecule inhibitors
Resistance develops to these drugs too, they can show toxicity and promiscuity
Can biopsies be believed?
Targeted therapies and “personalised oncology” are very expensive!

81
Q

What is meant by a bucket trial

A

Therapy against mutation not location of cancer

82
Q

Summarise personalised medicine

A

A 2012 Harris poll of 2760 US patients and physicians found that doctors had recommended personal genetic tests for only 4 per cent of patients (New Scientist, 2013)
In July 2013, the UK government announced that it would offer private companies a subsidy from a £300 million fund to encourage investment in its personalised medicine initiative
23andMe (banned by FDA, now approved by MHRA), DeCODEme (Iceland) and Knome (Ozzy Osbourne)

83
Q

Describe the impact of sequencing tumours prior to therapy

A

Depends on reliable methods – currently not being done (risk of false negative results)
Used to provide treatment as well as prognostic information
Concentrate on particular pathways for certain cancers?
Circulating biomarkers, tumour cells or DNA

84
Q

Describe some new therapeutic avenues

A

Nanotherapies – delivering cytotoxics more effectively
Virtual screening technologies to identify “undruggable” targets
Immunotherapies using antigen presenting cells to present “artificial antigens”
Targeting cancer metabolism

85
Q

Why do many cancer treatments cause side effects and how can we overcome these

A

Cytotoxic chemotherapy: cannot select only cancer cells so affects all rapidly dividing cells
Common side effects of all chemotherapy: and how to minimise
Hair loss - scalp cooling
Bone marrow suppression causing anaemia and neutropenia - transfusions/platelets/dose reduction and GCSF
Nausea and vomiting - antiemetics
Tiredness - cannot be avoided

86
Q

Explain the rational for new cancer drug development t

A

Tumour heterogeneity: major obstacle to targeted approach
Resistance mechanisms for cytotoxics:
Enhanced DNA repair
Drug efflux from cell using ATP-binding cassette (ABC) transporters
DNA adducts replaces by base excision repair using PARP
Resistance mechanisms for targeted therapy:
Mutations in ATP binding domains
Intrinsic resistance
Intragenic mutations
Upregulation of downstream pathways

87
Q

What are the most common cancers worldwide

A

 The most common cancers worldwide – lung, breast, bowel, prostate and stomach.
o Most common by gender – Lung in men, breast in women.
o “Western cancers” include – breast, colorectal, lung and prostate

88
Q

State the different mutations that can lead to cancer

A

o Chromosome translocation.
o Gene amplification (from copy number variations).
o Point mutations – in promotor/enhancer regions.
o Deletions/insertions.
o Epigenetic alterations.
o Heritable mutations.

Cancer (15 decks)

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