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MBB334 - Biochemical Basis of Human Disease > Staton - Cancer > Flashcards

Staton - Cancer Flashcards

1
Q

What is the cellular basis of cancer?

A
  • when cell escapes normal growth constraints and begins to prolif in uncontrolled fashion
  • balance disrupted –> mutations accum, usually takes 5-15 mutations in key genes
  • disruption can result from uncontrolled cell growth or loss of ability to undergo apoptosis
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2
Q

What are key genes involved in that are gen mutated in cancers?

A
  • prolif, switching off apoptosis, cell cycle, DNA repair etc.
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3
Q

In normal tissues how is a balance kept?

A
  • rates of new cell growth and old cell death are kept in balance (apoptosis)
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4
Q

What is a neoplasm?

A
  • new growth

- abnormal mass or tissue, where growth exceeds and not coord w/ normal tissue (not necessarily cancer at this stage)

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5
Q

What is a tumour?

A
  • non specific term meaning lump or swelling, often syn for neoplasm, or can just mean cancer
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6
Q

What is cancer?

A
  • any malignant (growing and has alt DNA) neoplasm or tumour
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7
Q

What is metastasis?

A
  • discontinuous spread of malignant neoplasm to other sites (can be local, or all over)
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8
Q

How is carcinogenesis characterised at the cellular level?

A
  • excessive cellular prolif
  • uncoord growth
  • tissue infiltration
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9
Q

How is carcinogenesis characterised at the molecular level?

A
  • disorder of growth regulatory genes

- dev in multi-step fashion

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10
Q

How are mutations involved in cancer dev?

A
  • cells continuously exposed to DNA damaging events –> spont mutations
  • repair machinery efficient so only small prop retained
  • for dev of most cancer gen req 5-15 ‘driver’ mutations
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11
Q

Why is not an issue that we all have many mutations, and when is it an issue?

A
  • have lots of diff types of prots, so if KO 1 often something else can take over, lots of redundancy and compensation in body
  • but mutation in gene coding for prots w/ key role in cell division more dangerous
  • genes code for prots and it’s the alt prot that has role in cancer
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12
Q

Whats happens to cells after they have been through the cell cycle?

A
  • either exit cycle and become differentiated (never divide again)
  • or in quiescent state ready to re-enter when receive signal to
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13
Q

When do cells enter G1, and how is this reg?

A
  • if get signal to divide

- checkpoint to check clear signal received, if there is then rep DNA

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14
Q

Why is p53 commonly mutated in cancers?

A
  • involved in checkpoint to ensure DNA rep
  • if not rep, then p53 stops cell cycle for repair, if can’t then p53 triggers apoptosis
  • so mutation common in order to get past this checkpoint
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15
Q

Why is Rb often absent or switched off in cancers?

A
  • involved in checkpoint for whether cell should survive

- usually stops cell cycle and inactivated by phos to allow division

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16
Q

How does normal cell behaviour turn signals into effects?

A
  • DIAG*

- signals sensor mols transducer mold effector mols effects

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17
Q

What are eg.s of how mol pathways link certain states/events to cellular responses?

A
  • eg. contact w/ other cells induces in culture to stop dividing
  • eg. presence of insulin induces tissues to take up glucose
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18
Q

What else modulates balance between cell quiescence and cell div?

A
  • prolif and anti-prolif signals
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19
Q

What are proto-oncogenes?

A
  • normal genes whose prot product promotes growth
  • ie. GFs and receptors, signal transduction prots, nuclear transcrip prots, prots that control cell cycle progression eg. cyclins and CDKs
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20
Q

What has opp effects to oncogenes?

A
  • tumour suppressor genes
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21
Q

Are oncogenes switched on or off in cancer?

A
  • on
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22
Q

How does a proto-oncogene become an oncogene?

A
  • consequence of mutations, chromosomal rearrangement or gene amp
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23
Q

How are oncogenes mutated?

A
  • inapprop exp, alt by eg. chrom rearrangements

- point mutations, so prot can no longer be reg

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24
Q

What is an oncogene?

A
  • mutated version of normal genes
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25
Q

What genomic changes can take place to lead to cancer?

A
  • mutations or changes in nucleotide seq of gDNA
  • -> gain of portion of chrom
  • -> genomic amp = many copies of small chromosomal region
  • -> translocation = 2 sep chromosomal regions become abnormally fused
  • -> point mutations, deletions and insertions
  • gain or loss of 1 or more chroms through errors in mitosis
  • many result in prots not being expressed, but other effects can occur
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26
Q

What is the consequence of genomic changes?

A
  • amp and gene overexp = elevated cellular concs of normal gene product
  • chrom translocation = can cause exp of chimeric prots created by fusion of coding seqs from sep genes
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27
Q

What is an eg. of how amp and gene overexp can lead to cancer?

A
  • myc, a TF essential for cell prolif amp approx 1000x in many cancers
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28
Q

What are eg.s of how chrom translocation can lead to cancer?

A
  • BCR-ABL, chimeric prot that is driving force for leukemia dev
  • ABL1, tyr kinase w/ increased activity in chimeric form, powerful prolif signal
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29
Q

What is an eg. of a common point mutation in cancer, and how does this have effects?

A
  • Ras
  • normally relays signals from cell surface receptors into cell
  • activated by GTP binding –> conformational change allowing binding to RAF
  • Raf now active
  • once signal conferred Ras cat breakdown of GTP to GDP, GDP removed by SOS and back to inactive form of Ras
  • if point mutation in prot resulting in changing Gly12 to any other AA, locks Ras in hyperactive, permanently on state, so GTP not converted back to GDP
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30
Q

What are tumour suppressor genes?

A
  • genes that encode prots that discourage cell growth
  • -> cell surface receptors
  • -> signal transduction
  • -> cell cycle control, eg. p53 inhibits cell cycle and often inactivated in tumours
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31
Q

How are key prots of tumour suppressor genes disabled in cancer?

A
  • loss of entire gene or complete chrom

- point mutations, eg. Rb inhibits cell cycle and point mutation in promoter will block its transcrip

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32
Q

How are both oncogenes and tumour suppressor genes involved in cancer dev?

A
  • combo of activation of oncogenes and inactivation of tumour suppressor genes important
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33
Q

Why is colon cancer a good model?

A
  • can track a lot of changes
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34
Q

What changes can be tracked t/o colon cancer dev?

A
  • loss of tumour suppressor gene, get small bump on side of colon
  • activation of Ras oncogene
  • loss of another tumour suppressor gene
  • loss of p53 tumour suppressor gene
  • other changes –> some genes switched on, some off, some alt
  • in order to spread must grow through basement mem surrounding it, if can migrate into bloodstream can metastasise
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35
Q

How might genes involved in apoptosis be affected in cancer dev?

A
  • genes coding for prots involved in apoptosis may be damaged
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36
Q

How might genes involved in DNA damage repair be affected in cancer dev?

A
  • genes coding for prots involved in DNA damage repair may be damaged, eg. BRCA2
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37
Q

What are the 2 diff pathways of apoptosis?

A
  • intrinsic

- extrinsic

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38
Q

What is the intrinsic pathway of apoptosis?

A
  • p53 activated after DNA damage, ER stress etc.
  • BAX activated (normally inhibited by Bcl-2)
  • causes release of cytochrome c from mt
  • forms complex w/ caspase 9 at centre, activates caspase 9, which cleaves caspases 3, 6, 7
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39
Q

How do cancer cells influence intrinsic apoptosis pathway?

A
  • upreg BCL2 (an anti apoptotic prot)
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40
Q

What is the extrinsic pathway of apoptosis?

A
  • extrinsic as takes in signals from outside
  • ligand binds to death receptor (fas ligand receptor)
  • activates caspase 8, which cleaves and activates caspases 3, 6, 7
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41
Q

How do cancer cells influence extrinsic apoptosis pathway?

A
  • tend to mutate receptor so no longer active
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42
Q

What are the triggers for apoptosis?

A
  • DNA damage, hypoxia, loss of adhesion, death receptors
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43
Q

What are the modulators of apoptosis?

A
  • FADD, TRADD, Bcl-2, C-myc, p53
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44
Q

What are the effectors of apoptosis?

A
  • caspases
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45
Q

What are the substrates of apoptosis?

A
  • many cellular prots, DNA
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46
Q

How are apoptosis reg prots exp changes in cancer?

A
  • p53 and Bax normally stim apoptosis, so downreg/mutated
  • Bcl-2 normally inhib apoptosis, so upreg
  • exp of death receptors/ligands alt (FAS/FASL)
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47
Q

What role do BRCA1/2 play in cancer dev?

A
  • tumour suppressor genes that play role in cellular DNA repair
  • switched off in some types of familial breast cancer
  • increases breast cancer risk 6-14 fold
  • genetic testing available for women w/ approp fam history
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48
Q

What is the Knudson ‘2 hit’ hypothesis?

A
  • proposed that carcinogenesis req 2 hits:
  • -> 1st event = initiation
  • -> 2nd event = promotion
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49
Q

When is the Knudson ‘2 hit’ hypothesis true?

A
  • in retinoblastoma dev

- Rb1 is tumour suppressor gene acting as brake on cell cycle, brake failure permits uncontrolled proli

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50
Q

What is an alt theory to the Knudson ‘2 hit’ hypothesis?

A
  • need multiple hits to occur (5+)
  • each hit prod change in genome which is transmitted to its progeny
  • this gen true → need 5-15 genes EXCEPT in case of retinoblastoma
  • normal healthy indiv may randomly inactivate 1 gene (this wouldn’t lead to cancer)
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51
Q

What is the lag period in cancer dev?

A
  • time before exposure (1st hit) and dev of clinically apparent cancer
  • alt cell shows no abnormality during lag period
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52
Q

Why is it hard to identify carcinogens?

A
  • exposed to so many diff things, imposs to know which is causative
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53
Q

What are the hallmarks of cancer?

A
  • growth signal autonomy
  • resistance to inhib growth signals
  • resistance to apoptosis
  • unlimited rep capacity
  • induction of angiogenesis
  • metastatic pot
54
Q

How is growth signal autonomy a hallmark of cancer?

A
  • prolif of normal cells reg by GFs and nutrient availability, cancer cells gen have reduced req for GFs
55
Q

How is unlimited rep capacity a hallmark of cancer?

A
  • cancer cells maintain length of telomeres to escape finite number of divisions, 90% cancers express telomerase
56
Q

How is induction of angiogenesis a hallmark of cancer?

A
  • cancer cells induce formation of new blood vessels, essential for tumour dev
57
Q

How is metastatic pot a hallmark of cancer?

A
  • cancer cells can spread via the lymphatic or blood circulation systems from 1° site to other locations
58
Q

What are the emerging hallmarks of cancer?

A
  • dereg cellular energetics –> changing ways cancer cells metabolise things (Wallberg effect), use glycolysis in presence of oxygen instead of OP, by upreg exp of GLUT1 so can pull lots of glucose into cell (not done in iso, lots of other changes)
  • avoiding immune destruction –> immune cells have pot to recognise and eliminate cancer cells, need to avoid this as they are more susceptible to IS than originally thought, as IS targets abnormal prots
59
Q

What are the enabling characteristics for cancer dev?

A
  • genome instability and mutation –> increased tendency of genome to acquire mutations when various processes involved in maintaining and rep genome are dysfunctional
  • tumour providing inflam –> tumour cells manip infiltrating inflam cells to provide GFs to sustain hallmarks
60
Q

How much of cancer risk is genetic/env?

A
  • 15% inherited risk and 85% env factors
61
Q

What is angiogenesis?

A
  • dev of new blood vessels from existing vasculature (in adults)
62
Q

How is angiogenesis important in health?

A
  • reproductive health, wound healing (supplies oxygen to wound)
63
Q

Is angiogenesis involved in disease?

A
  • found in over 50 diff disease states

- inc chronic inflam diseases, vascular malformations, cancer

64
Q

What blood vessels are most likely to respond to angiogenesis signals, why?

A
  • capillaries

- as less lining, thinner, smaller

65
Q

What state are endothelial cells held in, and how is this reg?

A
  • naturally quiescent, but poised for action

- held in balance by pro-angiogenic promoters (eg. VEGF, PDGF, FGF) and anti-angiogenic inhibitors (eg. THBS1)

66
Q

Why do tumours need angiogenesis, and how is it stim?

A
  • tumours cannot grow beyond 1-2mm2 w/o blood supply
  • lack of nutrients and oxygen (have diffusion limits) causes release of factors that stim angiogenesis
  • unlike normal vasculature up to 10% of tumour endothelial cells are dividing at any 1 time
  • tumours may also vascularise by vessel incorp
67
Q

How are tumour cells able to alt their microenv as they grow?

A
  • decrease pH, as not enough O, so prod lactic acid
  • decrease conc of nutrients
  • increase in interstitial pressure, as not adequate drainage
  • decrease in O tension (hypoxia)
68
Q

What does the angiogenic switch involve?

A
  • as tumours grow they alt their microenv:
  • cells sense these changes and respond by gen angiogenic mols, eg. VEGF
  • an extended blood vasculature resulting from angiogenesis relieves pressure from these stress factors
69
Q

How do nuclei differ in actively dividing cells?

A
  • larger and more dense
70
Q

What governs tumour cell viability?

A
  • range of O diffusion
71
Q

Why is tumour angiogenesis such a problem?

A
  • supports growth of tumour by providing nutrients and gas exchange
  • allows tumours to invade their surroundings
  • promotes metastasis
72
Q

In what patients is disease free survival enhanced?

A
  • those w/ low vessel density

- if remove 1° tumour w/ low microvessel density, much less likely to metastasise than if high microvessel density

73
Q

What are the steps in tumour induced sprouting angiogenesis?

A

1) release of angiogenic factors
2) activation of endothelial cells
3) matrix degrad
4) release of cell matrix interactions
5) invasion and migration of endothelial cells through basement mem
6) prolif of endothelial cells
7) lumen formation and morphogenesis
8) capillary formation in tumour
9) recruitment of pericytes/blood vessel stab/maturation

74
Q

What occurs during release of angiogenic factors (1)?

A
  • particular conditions cause upreg and release of cytokines and GFs –> eg. high interstitial pressure, hypoxia, hormones
  • hypoxia
  • -> low O tension happens as tumours grow faster than their surroundings
  • -> results in translocation of HIF1α and HIF1β to nucleus where act as TF for genes containing HRE (hypoxia response element) in their promoters
  • -> HIF normally degrad if O present
  • -> VEGF req HRE
75
Q

What is VEGF and where is it found?

A
  • most abundantly exp angiogenic factor –> exp in many tissue/cell types
  • found in most angiogenic states –> physiological and pathological
76
Q

What are some diff isoforms of VEGF, and how does their diffusion differ?

A
  • VEGF189: heparin binding region so doesn’t diffuse far from tumour
  • VEGF165: most commonly discussed, intermed binding to heparin so can diffuse further (most important to remember)
  • VEGF121: much shorter and doesn’t bind heparin, so diffuses furthest
77
Q

What is the clinical importance of VEGF?

A
  • prod by majority of tumour and high levels correl w/ tumour burden, survival and angiogenesis
78
Q

What occurs during activation of endothelial cells (2)?

A
  • VEGF acts as ligand binding to receptor tyr kinase (VEGFR2) on surface of endothelial cells
  • receptor then phos and triggers signalling pathway in Grb2
  • Grb2 then binds SOS, activates Ras and MAPK signalling pathway
  • this endothelial cell activation results in:
  • -> matrix breakdown, by release of proteases
  • -> prolif
  • -> migration
  • -> permeability and tube formation
79
Q

What occur during matrix degrad (3)?

A
  • in order for endothelial cells to migrate, need to dissolve cell-cell and cell-matrix contacts
  • under normal circumstances matrix remodelling tightly reg, balanced by signals promoting and inhibiting proteolysis → MMPs and TIMPs
  • in repair endothelial cells secrete the proteases along w/ their inhibitors
  • in disease reg is lost leading to uncontrolled proteolysis
80
Q

What are MMPs, what is their role and how are they alt in tumours?

A
  • matrix metalloproteases
  • Zinc dep endopeptidases (eg. collagenases, stromelysins, gelatinases) that cleave ECM components
  • shown to reg EC attachment, migration and prolif –> prolif directly or through release of GFs sequestered in ECM
  • majority are upreg
81
Q

What are TIMPs and what is their role?

A
  • tissue inhibitors of MMPS
  • inhibit binding to active site on each MMP
  • block angiogenic response –> inhib EC invasion through collagen and inhib angiogenesis in CAM assay
82
Q

Why is a balance between MMPs and TIMPs req for angiogenesis?

A
  • as when level of proteolysis is too high angiogenesis is inhibited
83
Q

What occurs during release of cell-matrix contacts (4), ie. what are integrins and how are they important?

A
  • tm glycoprot heterodimers
  • ligand specificity determined by particular αβ combo (16 diff α chains and 8 diff β chains): eg. α5β1 binds fibronectin/fibrinogen and α2β1 binds laminin/collagen
  • mediate cell migration and cell adhesion to range of matrix prots
  • multiple exp on endothelial cells
84
Q

What do GFs binding to endothelial cells cause (in relation to release of cell-matrix contacts)?

A
  • down reg of integrins for basement membrane

- upreg of integrins for ec matrix

85
Q

What occurs during endothelial cell migration and invasion (5)?

A
  • MMPs degrade basement mem allowing cells to invade through it
  • endothelial cells migrate along conc grad of chemoattractants inc VEGF
  • migrate into the area that req new vessels, ie. hypoxic area of tumour cells
86
Q

What occurs during endothelial cell prolif (6)?

A
  • endothelial cells enter cell cycle to rep and provide enough new cells for new vessels to grow (stim by VEGF)
87
Q

What happens during lumen formation (7)?

A
  • need lumen to allow blood flow
  • how formed dep on whether single or double strand of cells
  • DIAG*
  • if single (= cell hollowing): pinocytosis (pinching from outside to inside of mem), vesicles form and fuse, line up along central line and get vacuolar fusion, exocytosis, then luminal expansion –> results in cell w/ single nuclei and lumen
  • if double (= cord hollowing): pinocytosis, repolarisation of cells so all vesicles line up and fuse, vacuolar fusion, then luminal expansion
88
Q

What occurs during capillary formation (8)?

A
  • need 2 tip cells to join, in order to form functional network
  • endothelial cells differentiate
  • vacuoles join to form lumen
  • anastomosis = joining of many capillaries
89
Q

What occurs during vascular stab (9)?

A
  • -n physiological angiogenesis endothelial cells lay down basement membrane, followed by recruitment of pericytes and smooth muscle cells –> help vessels function
90
Q

How do tumour cells differ from normal vessels?

A
  • increased vessel no.
  • more prolif endothelial cells
  • decreased endothelial cell-cell adhesion –> bad for tumour as O/nutrients harder to transport and bad for patient as easier route for metastasis
  • leaky vessels –> lots of fibrinogen where shouldn’t be, can get clotting in tumour
  • decreased vessel stability –> decreased assoc of mural cells w/ endothelial cells
  • loss of close assoc of basement membrane w/ endothelial cells
91
Q

How do normal and tumour vessel hierarchy differ?

A
  • in normal tissue gaps between vessels and can see diffs between diff types of vessels, good diffusion of O/nutrients as functioning well
  • in tumour cells, vasculature chaotic –> some vessels too small for any blood flow, blunt ends, shunting, backwards blood flow
92
Q

What is the result of the fact that tumours have a loss of EC intercellular adhesion?

A
  • gaps so blood flow not smooth and easy for cells to escape into/out of blood
93
Q

Why is tumour angiogenesis so important?

A
  • results in increased O/nutrients for tumour cells
  • can therefore grow bigger –> outgrow blood supply and cycle starts again
  • due to leakiness of vessels it’s easier for cancer cells to escape into circulation
  • by increasing no. vessels in tumour more cancer cells can escape
94
Q

Is angiogenesis well reg?

A
  • no, basically always active
95
Q

What are the problems w/ conventional therapies in targeting tumour angiogenesis?

A
  • delivery of blood borne agents to tumour cell targets in solid tumour difficult due to:
    –> abnormal blood flow (doesn’t carry chemo as effectively)
    –> lack of lymph drainage (increases pressure)
    –> high interstitial pressure (hard to move in against pressure grad)
    » results in poor access to majority of tumour mass
  • tumour cells inherently unstable and quickly become resistant to therapy
    –> eg. metastasised cells no longer growing so can escape chemo
96
Q

Why are rounds of chemo often given?

A
  • to try and avoid resistance
97
Q

Why could tumour blood vessels potentially be good therapeutic targets?

A
  • occlusion of single vessel has pot for killing many tumour cells –> as blocks O/nutrient supply to many cells, doesn’t req treatment to be effective in all cells
  • only prolif endothelium in otherwise healthy adult
  • delivery relatively simple through bloodstream
  • endothelial cells non-malignant, so drug resistance less likely to dev
  • effects less likely to complement those of conventional agents
  • tumour blood vessels diff from normal
  • tumour endothelial cells express specific mol signatures (diff to normal), may be poss to target for treatment
98
Q

What are the only prolif endothelium in healthy adults?

A
  • female reproductive system, wound healing
99
Q

What makes a good drug target?

A
  • specific against 1 key target and doesn’t bind other targets (ie. no side effects)
  • able to get to target –> pref oral admin (most antiangiogenics not), ie. small, and hydrophilic
  • good pharmacokinetics –> good bioavailability, low metabolism, low excretion rate
  • not toxic –> balance between toxicity to tumour and to patient
100
Q

What model is often used for in vitro studies of a drug, and why?

A
  • often animal flank used as easy to measure
101
Q

What is the best dosage for antiangiogenics?

A
  • max non-toxic amount may not be most effective
102
Q

What are the diff pot endpoints for phase III clinical trials?

A
  • response rate: measured w/ response evaluation criteria in solid tumours (RECIST)
    –> complete response (CR) = disappearance of all target and non-target lesions
    » this is main aim, but rarely seen
    –> partial response (PR) = >30% decrease in all target lesions
    –> stable disease (SD) = no progression
    –> progressive disease (PD) = >20% increase in target lesions or appearance of new lesions
  • progression free survival (PFS) = time from randomisation to disease progression or death
    –> or TTP = time to disease progression (rarely used)
  • overall survival (OS) = time from randomisation to death, any cause
    –> or disease specific survival = time from randomisation to death due to disease (rarely used, as harder to look at and smaller no.s)
  • QoL –> symptom burden, toxicity (side effects)
  • cost effectiveness
103
Q

What is RECIST?

A
  • set of published rules that define tumour response
104
Q

What are the advs and disadvs of response rate as endpoint?

A
  • +ve = early primary endpoint

- -ve = poor correl w/ overall survival and subjective measurement

105
Q

What are the advs and disadvs of progression free survival as endpoint?

A
  • +ve = early primary endpoint

- -ve = poor correl w/ overall survival and subjective measurement

106
Q

What are the advs and disadvs of overall survival as endpoint?

A
  • +ve = direct measurement of QoL and objective so easy to measure
  • -ve = late primary endpoint and pot effects of other therapies which may be given if start to progress
107
Q

What is the main target for anti-angiogenic therapy, why?

A
  • VEGF
  • involved in lots of aspects of tumour growth –> both pro and anti-angiogenic, but pro outweighs anti, so KO is a good strategy
108
Q

What diff agents can target VEGF?

A
  • anti VEGF Abs
  • soluble receptors that bind and stop binding to receptors on cell surface, eg. VEGF-Trap
  • anti-VEGFR Abs
  • small mol inhibitors of RTKs
109
Q

How would anti VEGF Abs work?

A
  • binds VEGF and prevents its binding to receptors

- eg. bevacizumab

110
Q

How would anti-VEGFR Abs work?

A
  • stop VEGF binding to receptor
111
Q

What is the adv/disadv of small mol inhibitors over the other agents targeting VEGF?

A
  • all others are large (can’t be taken orally), complex mols
  • but don’t have to cross endothelial mem and can be injected directly into bloodstream –> small mol inhibitors have problems w/ off target effects
112
Q

How would small mol inhibitors of RTKs work?

A
  • stop phos and therefore signalling pathway

- eg. sunitinib

113
Q

What is bevacizumab and how does it work?

A
  • humanised monoclonal Ab to VEGF

- blocks binding of VEGF to its main receptors (VEGF-R1/2), thus neutralising it

114
Q

What evidence is there for the efficacy of bevacizumab?

A
  • inhibition of:
  • -> endothelial cell prolif, migration and tubule formation in vitro
  • -> tumour growth in vivo and regression in some models
  • in vivo: colorectal tumour xenografts showed decrease in vascular density 48hrs post treatment
115
Q

How do animal results differ from humans for angiogenesis inhibitors?

A
  • animal results show inhibition of tumour growth initially, often w/ regression after repeated dosing and reduction in no. metastases
  • clinical trials do not have same expected efficacy –> although some stabilisation of disease reported
116
Q

Why do animal trials results differ from humans for angiogenesis inhibitors?

A
  • established, slow growing tumours have diff angiogenic requirements to fast growing tumours (model doesn’t represent this)
  • dose choice, trials often use upper limiting dose, may not be most effective, only true of poisons, likely a bell shaped curve DIAG
  • admin protocol, ie. can inject animals everyday, but not patients, so need to use clinically relevant protocol in animals
  • drugs have varied effects on diff tumours, as not all solid tumours need angiogenesis, more angiogenic tumours respond best
  • assessed by effect on tumour shrinkage, not reduction in blood supply etc.
  • tumours ‘out-smart’ anti-angiogenic therapy, as mol crosstalk and cross reg, so can’t just target VEGF, other factors may be able to compensate
117
Q

What is the mech of bevacizumab?

A
  • pruning of abnormal tumour vasculature
  • functional normalisation through:
  • -> reduced tumour interstitial pressure
  • -> decreased tumour hypoxia
  • -> improves delivery of concurrent chemo
  • -> increases efficacy of concurrent radiotherapy
118
Q

How could better results be achieved from future angiogenesis inhibitor trials?

A
  • antiangiogenics only target endothelium and/or specific aspects of angiogenesis, so combining w/ drugs that target tumour cells likely to yield better results
119
Q

What have the results been of bevacizumab in combo trials?

A
  • for prev untreated metastatic colorectal cancer
  • given w/ chemo
  • results
  • -> signif increase survival
  • -> signif slowed progression
  • -> shrank tumour at least ½ in 45% patients, comp to 35% in placebo + chemo group
  • but toxicity problems = hypertension, bleeding problems, wound healing complications, arterial thromboembolic complication
120
Q

What were the results from use of bevacizumab in metastatic breast cancer?

A
  • in 1st trial, on patients prev treated w/ chemo
  • -> signif increase in ORR
  • -> no improvement in PFS or OS (poss as already had chemo)
  • -> toxicity = hypertension, cardiac
  • in 2nd trial, on prev untreated MBC
  • -> increased ORR
  • -> prolonged PFS
  • -> no diff in OS
  • -> toxicity = grade 3/4 hypertension
121
Q

What is bevacizumab approved for?

A
  • use in metastatic colorectal cancer and lung cancer in combo w/ chemo
  • approval for breast cancer withdrawn
122
Q

What are the issues w/ bevacizuman?

A
  • expensive, as large complex prot to gen
  • increased toxicities (more than anticipated)
  • tumours eventually escape treatment control (short improvements in PFS and OS) –> so faster, more aggressive disease at end (worse for patient as worse end of life?)
123
Q

What pot side effects can antiangiogenics have?

A
  • hypertension
  • proteinuria
  • delayed wound healing
  • haemorrhage
  • thrombosis
124
Q

Why do treatments that increase PFS fail to improve OS?

A
  • insufficient stat power to detect signif diff
  • measurement of progression (and thus PFS) imprecise, but date of death exact
  • biological effects –> things happening in tumour
  • effect of post-progression therapy
125
Q

Does resistance to antiangiogenics dev?

A
  • predicted to be slow as tumour endothelial is genetically stable
  • but dev rapidly
126
Q

How does tumour escape from antiangiogenic treatment control?

A
  • initially when add antiangiogenic get increase in hypoxia, so increased prod of pro-angiogenic factors –> but only VEGF inhibited
  • vascular normalisation –> get rid of abnormal vessels, so get better blood flow
  • vascular mimicry –> endothelial cells killed, but still channels where were, lined by tumour cells not affected by antiangiogenic, and blood can still flow (even if only poorly)
  • exp of multiple angiogenic factors (indep of hypoxia) –> targeting 1 doesn’t stop angiogenesis
  • recruitment of BDMC (bone marrow derived cells) –> endothelial progenitor cells, can form new vessels, not dep on VEGF
  • selection of metastatic cancer cells –> as gets more stressed
  • vessel co-option –> grow around vessels already estab, so not angiogenic and won’t be affected by this treatment
127
Q

What might reduced tumour blood flow lead to?

A
  • more hostile tumour env –> so promotes tumour invasion and metastasis
128
Q

Why is there resistance to treatments?

A
  • tumour growth, gaining vessels
  • antiangiogenic kills some vessels
  • stops growth, no increase in size –> increased PFS
  • but increases hypoxia, so tumour looks like being inhibited, but causes upreg of alt factors, tumour cells become dormant, adapt to hypoxia, get metastatic switch and recruit vascular progenitor and modulator cells
  • get more and more vessels formed and get tumour regrowth and dissemination - growth faster than if didn’t treat –> so OS often not changed
129
Q

What are the consequences of the resistance to antiangiogenic therapies?

A
  • benefit of VEGF inhibitors transient
  • rapid regrowth of vessels/tumour on discontinuation of therapy
  • not all tumour types/patients respond
  • -> renal cell carcinoma highly angiogenic and responds v well
  • -> breast doesn’t respond v well
  • upreg of other pro-angiogenic molecules (can differ between patients)
  • recruitment of pro-angiogenic inflam cells from bone marrow (eg. macrophages)
  • utilisation of other routes for vascularisation
130
Q

What is the future for antiangiogenic therapy?

A
  • biological agents and small mol inhibitors starting to show clinical efficacy
  • use combo –> need to consider toxicity
  • scheduling –> use alongside chemo? before? after?
  • identify biomarkers, to see which patients will respond –> working towards patient specific treatment
  • prevention rather than cure –> as angiogenesis occurs in v early stages of tumour dev

MBB334 - Biochemical Basis of Human Disease (7 decks)

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