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Cancer Week > Targeted Therapies > Flashcards

Targeted Therapies Flashcards

1
Q

What are the basic subclasses of antineoplastic drugs?

A
  • alkylating agents
  • antimetabolites
  • plant alkaloids
  • hormones and antagonists
  • targeted therapy
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2
Q

What do antimetabolites do?

A

Attach groups to DNA

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3
Q

What do plant alkaloids do?

A

Stabilise or destabilise microtubules

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4
Q

What are examples of alkylating agents?

A
  • cyclophosphamide
  • melphalan
  • chlorambucil
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5
Q

What are examples of antimetabolites?

A

methotrexate

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6
Q

What are examples of plant alkaloids?

A
  • taxanes

- vinca alkaloids

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7
Q

What are examples of hormones and antagonists?

A
  • anti-oestrogens

- anti-androgens

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8
Q

What are examples of targeted therapy?

A
  • monoclonal antibodies

- small tyrosine kinase inhibitors

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9
Q

What are the cancer targets?

A
  • BEST = found in cancer cells but not normal cells
  • NEXT BEST = more targets in cancer cells than normal
  • targets in both, normal cell regenerates
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10
Q

Why is genomic profiling important?

A
  • can identify prognostic markers
  • identify if drugs will be effective
  • whether patients develop resistance
  • patients develop adverse effects
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11
Q

Why are targeted therapies necessary?

A
  • more precise treatment
  • interfere with specific molecules stopping growth and progression
  • oral therapies used in combination with adjuvant therapies
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12
Q

How does tyrosine kinase receptor signalling work?

A
  • ligand binds to EC domain
  • dimerization of tyrosine kinases causing conformational change in the IC domain (phosphorylation)
  • tyrosine phosphorylated = recruit adaptor proteins
  • triggers cascade of signalling pathways
  • MAPK/PI3 kinase pathway activated
  • increase in growth survival and motility of cells
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13
Q

What does antibody therapy consist of?

A
  • antibody inhibitors of growth receptors preventing growth signal
  • antibody drug conjugates targeting drug to tumour cells
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14
Q

What are the 3 mechanisms of monoclonal antibodies?

A
  • kill tumour cells directly
  • kill tumour cells via an immune-mediated mechanism
  • vascular or stromal ablation
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15
Q

How do monoclonal antibodies directly kill tumour cells?

A
  • block signals
  • induce apoptosis
  • deliver toxic payload
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16
Q

How do monoclonal antibodies kill tumour cells via an immune mediated mechanism?

A
  • induce phagocytosis
  • complement dependent cytotoxicity
  • antibody dependent cell cytotoxicity
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17
Q

How do monoclonal antibodies allow vascular or stromal ablation?

A
  • possible delivery of toxic payload

- VEGF antagonism

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18
Q

What does cetuximab do?

A
  • cetuximab

Binds to extracellular part of RTK and prevents dimerization preventing signalling

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19
Q

Which monoclonal antibodies target EGFR?

A

Cetuximab

Panitumumab

20
Q

Which monoclonal antibodies target HER2/ERB2?

A

Trastuzumab

21
Q

Which monoclonal antibodies target HER3?

A

Pertuzumab

22
Q

Which monoclonal antibodies target VEGFR?

A

Bevacizumab

23
Q

How does trastuzumab Herceptin prevent cleavage?

A

prevents cleavage of HER2 receptor

  • if HER2 overexpressed = mutations
  • allows EC parts to be cleaved off
  • therefore continuously activated
24
Q

What are the 4 actions of trastuzumab Herceptin?

A

1) Prevents cleavage
2) Inhibits dimerization
3) antibody dependent cell-mediated cytotoxicity
4) activate endocytosis of the HER2 receptors

25
Q

What is the role of VEGF?

A
  • formation of new blood vessels
  • upregulated antigen in cancer
  • protects endothelial cells from death by activating PKC pathways/upregulating Bcl2
  • activity mediated by VEGFR1 and 2
  • indirectly functions as survival for tumour cells
26
Q

What is the mechanism of action of bevacizumab?

A
  • blocks receptor

- inhibits tumour growth and metastasis

27
Q

What is the significance of the last syllable of monoclonal antibodies?

A
  • U and ZU humanised (panitumumab and trastuzumab)

- XI chimeric (rituximab)

28
Q

What is the significance of the previous syllable of the monoclonal antibodies?

A 
tu(m) = general tumour
ma(r) = breast
pro(o) = prostate
co(l) = colon
ci(r) = circulatory
29
Q

How do antibodies access normal tissue?

A

Blood vessels have intact endothelial layer

30
Q

How do antibodies access tumour tissue?

A
  • leak blood vessels so all sized molecules access malignant tissue
  • no lymphatic drainage system so macromolecules retained
  • enhanced vascular permeability of circulating antibodies = accumulation in solid tumours
31
Q

What are conjugated antibodies?

A
  • cytotoxic drug attached via Fc part link

- antibody binds to cancer cell and cytotoxic load is adjacent

32
Q

What is an example of a conjugated antibody?

A

trastuzumab emtansine (kadcycla)

  • for HER2+ women but inoperable breast cancer
  • effective but expensive
33
Q

How do naked antibodies work?

A
  • activate immune system
  • target immune system checkpoints
  • inhibit activity of antigen and prevent growth
34
Q

What are the 2 types of tyrosine kinase inhibitors?

A

TKIs of growth factors

Inhibition of other kinases

35
Q

What is the kinase domain?

A
  • binding pocket for ATP to cause phosphorylation

- if pocket blocked = phosphorylation blocked

36
Q

What is an example of a TKI?

A

Tarceva

- non-small cell lung cancer

37
Q

What are small molecule TKIs?

A
  • target oncogene product (EGFR)
  • inhibit signalling at key steps
  • safer than chemo
  • specific side effects
  • specificity
38
Q

What do TKIs end in?

A

tinib

39
Q

What are examples of mutation cancers?

A

Adenocarcinoma
PIK3CA mutations
KRAS

40
Q

What is the significance of drug resistance in tyrosine kinase domain of EGFR in lung cancer?

A
  • exon 20 mutations

- to gefitinib or erlotinib

41
Q

What are examples of first generation EGFR TKIs?

A

(reversible)

  • erlotinib
  • geitinib
42
Q

What are examples of second generation EGFR TKIs?

A

(irreversible)

- afatinib

43
Q

What are examples of third generation TKIs?

A

(mutant-selective)

- osimertinib

44
Q

What are some side effects of targeted therapy?

A
  • skin changes
  • hypertension (VEGF)
  • slow wound healing and blood clotting (EGFR)
  • congestive heart failure (HER2)
45
Q

What skin changes are cause by targeted therapy>

A
  • skin rashes (EGFR)
  • dry skin
  • itchy skin
  • hand foot syndrome (VEGF)
  • changes in hair (alopecia/brittle)
  • dry/red eyes/red or tender eyelids
46
Q

How does trastuzumab cause cardiotoxicity?

A

HER2 survival pathways in the heart are inhibited = increase in NO = endothelial cell dysfunction

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