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PHAL304 > Cancer > Flashcards

Cancer Flashcards

1
Q

Targeted therapy

A

Better efficacy, less side effects
Target mutations, development of tumour, highly expressed/active protein, chromosome abnormality

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2
Q

TKIs

A

Tyrosine kinase inhibitors
Target the receptor or enzyme. Block activation off signalling pathway

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3
Q

Common side effects of targeted therapies

A

diarrhoea, liver problems, blood clotting, wound healing
Less nausea and fatigue overall

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4
Q

BCR-ABL translocation

A

Both express kinases
Chromic myeloid lukemia
exchange between 9 and 22 (Philadelphia chromosome)
Uncontrolled cell growth and impaired differentiation

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5
Q

Imatinib mesylate

A

Disappearance of Philadelphia chromosome (and GI cancer)
also targets c-KIT and PDGFR (growth factor))

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6
Q

Targeting lung cancer

A

EGFR - erlotinib (successful trial - PFS), gefitinib
ALK - aletinib

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7
Q

Antibodies

A

Fab - recognition (light and variable and epitope/CDR)
Fc - binding (constant)

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8
Q

Antibody therapy

A

Can be Fab only, protein Fc or engineered Fc (chimeric, humanised, human)
Conjugation to drugs, radioisotopes or nanoparticles

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9
Q

Creating antibodies

A

Immunise mice and isolate B cells and put in cancer (myeloma) cells. Screen for antibodies that bind to the cancer cells and harvest

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10
Q

Antibodies in cancer

A

Cause apoptotic pathway
Immune response
Block angiogenesis
Delivery of toxin

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11
Q

Types of antibody mediated cytotoxicity

A

ADCC - antibody-dependant cellular cytotoxicity
CDC - complimentary-dependant cytotoxicity (bind to C1q)
Effector cell recognises antibody -> phagocytosis or lysis

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12
Q

Breast cancer targets

A

ER and PR - hormones
HER2/ErbB2 - epidermal growth factor receptor
EGFR - triple negative

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13
Q

Trastuzumab/Herceptin

A

HER2+ breast cancer
Humanised antibody causes ADCC and CDC and stops dimerisation
Can have fatal infusion reactions + cardiomyopathy and pulmonary toxicity

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14
Q

Herceptin vs antracyclines/chemo

A

increased overall survival by 5 months
Better in combo with chemo than chemo alone

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15
Q

Herceptin resistance

A

Increase in PI3K/AKT activation
Can use mTOR inhibitors to restore sensitivity

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16
Q

Cancer hallmarks

A

Sustained proliferation signalling, evade growth suppressors, replicative immortality, invasion/metastasis, induce angiogenesis, resist cell death, disregulate cellular energies, genome instability/mutation, autoimmune destruction, suppress immune responses

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17
Q

Tumour microenvironment

A

cancer, endothelial, immune cells, pericytes (line blood vessels), ECM (fibroblasts and red blood cells)

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18
Q

Hypoxic

A

no blood vessels
Tumours -> cytokines and GFs cause angiogenesis and ECM production

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19
Q

Angiogenesis

A

VEGFs activated endothelial cells, expression of cytokines cause hypersprouting of tip/stalk cells,
Chaotic vascular - blood vessels dilated, disorganised, high permeability
Prevent immune cell chemotaxis and extravasation

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20
Q

Anti-angiogenesis

A

Stop signal for blood vessels
VEGF-A inhibitors (regulates permeability and cell migration
Normalise vasculature and increase drug perfusion
(resistance possible - reversible if breaks taken)

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21
Q

Anti-angiogenesis drugs

A

Bevacizummab, aflibercept, ramucirumab
Side effects = bleeding/haemorrhage, hypertension, loss of protein/neutrophils, healing complications

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22
Q

Bevacizumab

A

Anti-angiogenesis
Combo with chemo = increase survival
No effect on OS (transient)
Reduce tumour volume, less corticosteroids needed (reduced edema)

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23
Q

Importance of VEGF-A

A

Expressed differently in tumours = measure serum/tumour levels first
More VEGF with progression of cancer

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24
Q

Extracellular matrix on angiogenesis

A

Reduce nutrient and oxygen supply, increase hypoxia, metabolic stress
Blocks angiogenesis inhibitors

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25
Q

Cytokines/GFs in TME

A

Alter myeloid cell differentiation (macrophages and dendritic cells w/o antigen presentation), suppress T cell effectors, decrease MHC I presentation, stop targeting self via immune check-points

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26
Q

Tumour macrophages

A

M2 phenotype increased immune suppression, ECM production and angiogenesis

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27
Q

Causes of MHC I down regulation

A

Mutations, methylation, ncRNA, cell signalling altered, degraded in ER, blocked binding

28
Q

Key immune check points

A

Priming
MHC=TCR and B7=CD28
B7=CTLA4 blocks immune response
Effector
PD1=PDL1 blocks immune response

29
Q

Immune checkpoint inhibitors

A

CTLA-4 inhibitors (CD28 can be activated), ipilimumab
PD-1/PD-L1 inhibition, nivolumab (PD-1), atezolizumab (PD-L1)
Showed an increased in OS and PFS, quick + prolonged response

30
Q

ICI non-responders

A

Tumour doesn’t have checkpoint, don’t display antigens to activate T cells, T cells don’t like the TME
Thus tumours with more mutations have a better response

31
Q

ICI combination therapy

A

Combination better
Chemo and antiangiogenic (T cells can access)
Have greater adverse events (autoimmune - skin rashes, colitis, endocrinopathy) - don’t give if have autoimmune disorder
CTLA-4 less tolerated

32
Q

T cell therapies

A

Use own immune cells or generic and isolate, expand, administrate
The T cells already within the body that can recognise cancer

33
Q

Tumour infiltration lymphocytes

A

Walled underneath tumour and suppressive cytokine environment (checkpoints and co-stimulation)

34
Q

Tumour infiltration lymphocyte therapy

A

Mixed population of T helper and cytotoxic cells
Administer with IL-2 after lymphodepletion to avoid immune response
Overall response 35%, sustained response, some complete responders, no relapses

35
Q

T cell culture methods

A

Young - short period for numbers, 9% complete response
Conventional - one round, exposure, expand IFN-y producing cells, 14% complete response (difficult, long time period, expensive, transportation)

36
Q

Engineered T cells

A

Genetic modification of naive lymphocytes to recognise tumour antigens
CAR - chimeric antigen receptor
Less success in solid tumours

37
Q

CARs

A

extracellular antigen binding domain, transmembrane domain, intracellular activation domain (CD3 + costimulator - not environmentally dependant)

38
Q

T cell specificity

A

CD-19 and 20, HER2, PSMA (prostate)
Hetrogenicity in the tumour limits choices
Find markers in genetic sequence (costly and slow)

39
Q

Engineered T cell adverse responses

A

Cytokine release syndrome = super activation of T cells, oedema
neurological symptoms
Can use antinflamatory drugs dexamethasone and tocilizumab

40
Q

CAR-T cell drugs

A

Axicabtagene ciloleucel
Ciltacabtagene autoleucel (patient derived)

41
Q

Allogenic

A

Universal T cells (foreign)
Frozen and readily available
Low cost, simple, good quality

42
Q

T cell therapy challenges

A

Heterogenecity of antigens
can’t access TME
When cytokines suppressing may exhaust CAR-T cells (stop being made)

43
Q

CAR-T combination therapy

A

Anti-angiogenic - increase survival
CPIs - better overall response

44
Q

Microbiome

A

Collection of microbes and genomic content - bacteria, viruses, fungi, etc.
Can sequence DNA/RNA -> microbe
Impacted by birth, genetics, diet, age, meds, toxins, stress, activity

45
Q

Microbiome in cancer

A

20% of cancers caused by microbiome (Hep B, human papilloma virus, helicobactar pylori)
May create metabolites -> blood stream

46
Q

Microbiome antitumour

A

Apoptosis activation, immune response, histone deacetylases inhibition
Inflammation and cytokine production from metabolites 0> Tregs and suppressor cells

47
Q

Microbiome and immunotherapies

A

ICIs - different bacteria have different responses
Faecalibacterium = more immune cells, lymphoid and myeloid and MHC II

48
Q

Microbiome transplant

A

Find who is a responder vs no responder based on microbiome (causative data?)
Transfer microbiome of responder into non-responder
Clinical responses observed
Some severe toxicities

49
Q

Mesenchymal stem cells

A

Daughter cells differentiate, found in all tissues, migrate around body

50
Q

MSC identification

A

Surface markers - CD73, CD90, CD105
spindle shape

51
Q

MSC wound healing

A

Express integrins, adhesion molecules, chemokines
Reduce inflammatory response, no immune reaction
Cancer = non healing wound

52
Q

MSC therapy for cancer

A

homing, immune modulation, delivery of chemotherapy or therapeutic proteins

53
Q

Autologous

A

From the patient

54
Q

MSC adverse effects

A

Autoimmune due to changes from plastic/culturing environment
Tumours might develop, blood clotting

55
Q

Prochymal (remestemcel-L)

A

Allogenic from bone marrow
Approved in NZ 2012-2016, very small difference vs placebo
Acute graft vs host disease = reaction to donor T cells (corticosteroids don’t work)

56
Q

Cartisten

A

Gel matrix structure for growth
Used for arthritis

57
Q

Nausea and vomiting

A

CINV - chemo induced
Acute - within 24 hours
Delayed - after 24 hours
Anticipatory - learned response
reduced QOL of patients by 60% - economical and clinical
Cisplatin in particular

58
Q

Emesis

A

Reflex response in the brain - vomiting centre in the medullary region of brainstem
Serotonin and dopamine receptors among others
Free radical cellular damage caused the release of serotonin from enterochromaffin cells in GI tract via 5TH3 receptors on vagal afferents

59
Q

CINV therapy

A

Dexamethasone, ondansetron or domperidone
prior, during or after chemo
Serotonin and dopamine antagonists (lorazepam, halooperidol)
Critical in the first cycle as it is more likely to occur again

60
Q

Ondansetron

A

5-HT3 antagonist
Least effective (8% vs placebo), better side effects (constipation and headache)
Before chemo, additive to opioid
IV (8.32 mg) or oral (16-32 mg), short half life 6 hours

61
Q

Domperidone

A

D2 antagonist, delayed phase CINV
Increase risk of QT prolongation, arrhythmia, cardiac death, extrapyramidal symptoms
CYP3A4 inhibitors will increase risk

62
Q

Dexamethasone

A

Corticosteroid, most effective
83% complete lack of vomiting at 20 mg
Don’t know MoA
Can use in combo with ondansetron

63
Q

Aprepitant

A

NK1 R antagonist (substance P)
block 20% of emesis
Only used in high risk regimens, fatigue adverse effect, drug interactions CYPs
Combination with other anti-emetics

64
Q

Cachexia

A

Wasting syndrome = severe loss of body weight (muscle and fat)
Inflammatory cytokines - consume aas, insulin resistance - can’t build muscles/protein
Decrease QoL, strength, increase fatigue, anorexia, hypermetabolism
Side effect of both chemo and cancer (particularly pancreatic/gastric plus colon/prostate)

65
Q

Cachexia treatment

A

Magestrol acetate and corticosteroids
Progesterol improves appetite
exercise, high calorie food, nutritional counselling

66
Q

Magesterol acetate

A

Increases appetite
Small effect on weight, no effect QoL
Clotting risks, adverse events, no change in death
low quality evidence

67
Q

Corticosteroids

A

Advanced cancer - refractory
No effect on survival
Improve appetite and strength

PHAL304 (4 decks)

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