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modeeling disease > cancer 3 > Flashcards

cancer 3 Flashcards

1
Q

what is melanoma?

A

A form of skin cancer

  • 5th most common in uk
  • pigment cells from moles become malignant and start growing
  • when spreads from epidermis to dermis it becomes difficult to treat
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2
Q

what are the risk factors of developing melanoma?

A
  • age (increases with age due to cumulative mutations)
  • males have higher risk
  • lighter skin tone-higher risk
  • sunburn/UV exposure
  • genetics - mutations that predispose
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3
Q

give examples of the genetic mutations which may increase the risk of developming melanoma?

A
  • TERT overexpression
  • LOF CDKN2A (produce p14,p16)
  • mutation in melanocortin receptor
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4
Q

what is the initiator mutation of melanoma?

A
  • BRAFV600E

- mapk pathway activation

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5
Q

what mutations are seen in progressing stages of melanoma?

A
  • NRAS
  • TERT
  • CDKN2A
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6
Q

what mutations are seen in late stages of melanoma?

A
  • P53
  • PTEN

usually metastatic stages

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7
Q

where are activating nevus mutations found?

A

In 60% of nevi (moles)

  • activation of the ras pathway
  • BRAF must cooperates with opther genetic lesions in melanoma formation + progression
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8
Q

give the stages involved in melanoma fomation and the genetic components involved in them

A 
Benign lesion (BRAFV600E mutation)
Intermediate lesion (NRAS, TERT) (activation)
Melanoma lesion (TERT) (overexpression)
Invasive melanoma (CDKN2A) (mutation)
Metastasis (P53, PTEN)  (mutations)
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9
Q

give some upstream controls of cell division/differentiation?

A

Mapk
Ras
EGF

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10
Q

what is a xenotransplant?

A

where human cancer cells lines are put into mice models

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11
Q

how are mouse melanoma models created?

A
  • xenotransplant of human cell lines/tumours in immunodeficient mice (nude mice - no hair)
  • BUT no AB response to cells but in tumour progression immune response/inflammation is involved
  • also cells may not be in right place at right time
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12
Q

what genetic engineered mouse model is needed to induce melanoma in mice?

A

Tyr: Cre-ERT2; Braf +/CA ; PTEN lox/lox

(activated BRAF and loss of PREN)

  • BRAF mutation alone is not enough to cause melanoma
  • Tyr promoter in melanocytes
  • cre activated via tamoxifen and when cre is activates it contitutilevly activates BRAF and excises PTEN (LOF)
  • happens in melanocytes where tyr is active
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13
Q

what was showed in the graphs after induction of melanomas in mice?

A
  • tumour size increased with time after induction

- survival rate decreases with time after induction

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14
Q

what is the major driver behind melanoma formation?

A
  • BRAF

BRAFV600E

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15
Q

what was the preclinical model (before clinical studies) developed for melanoma?

A
  • specific inhibitor of BRAFV600E developed
  • xenotransplant (3 melanoma cell lines)modelled nude mice tested inhibitor as therapy
  • Tumour size did not increase as rapidly as within mice who were not treated the drug
  • Survival rate was higher in the mice who were treated with Rg7204
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16
Q

How was treatment with RG7204 in humans?

A
  • it treated melanoma but it came back after 23 weeks

- some cancer cells were resistant to BRAFV600E inhibitor (RG7204)

17
Q

what fish are good models for melanoma?

A

Xiphophorus hydrids

  • fish develop similar tumours to humans and mice
  • found tumour gene - EGFR activate ras
  • tumour supressor gene - p16
18
Q

what was the preclinical model in xiphophorus fish for melanoma?

A
  • screen 2000 molecules which interfere with melanocyte formation/ NCC formation/crestin lineage
  • compoundto be combined wih RG7204
  • NSC2 blocked progenitor NCCs
  • NSC2 similar to leflunomide - DHODH
  • treatemtn with leflunomide/DHODH decreased melanoma formation
  • combination of leflunomide and Rg7204 - better response
19
Q

what were the transgenic fish used in the melanoma assay?

A

Mitfa:Braf(v600E)
- mitfa promoter drives expression of braf
p53-/- background

20
Q

what was found in the zebrafish to accelerate melanoma formation?

A

SETDB1 (methyl transferase) amplified in melanoma and accelerated its onset
- identified in region of chromosome 1 which promoted malignant progression of melanoma
expression plasmid encoding mitfa and different genes on chromosome 1 region
- SETDB1 enahnced cancer with mitfa

21
Q

what tg zebrafish used in mechanism of melanoma formation?

A

Tg(mitfa,braf(V600E)
(also P53-/-)

  • if remove mitfa melancytes die
  • if add expression plasmid encoding mifta gene - cancer phenotype rescued

modeeling disease (14 decks)

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