slide set 22 Flashcards

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1
Q

driver mutations: 2 broad types of cancer-critical mutations

A

oncogenes: gain of function mutations

tumor suppressor genes: loss of function mutation

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2
Q

oncogenes

A

gain of function

cause cell/protein to be overactive

promotes cancer progression!

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3
Q

tumor suppresor genes

A

loss of funtion mutations

causes protein to not function

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4
Q

Pathway 1: Rb (control cell growth and division)

A

active Rb is bound to inactive E2F

inactive Rb = phosphorylated

loss of function mutation (tumor suppressor gene)

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5
Q

Pathway 2: Ras (control cell growth and division)

A

gain of function mutation would cause cancer

over active Ras = activating this pathway more, even when it shouldn’t be

cells would go through the cell cycle that shouldn’t be

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6
Q

PI3K/Akt/mTOR pathway

A

stimulates growth

  1. growth factor binds to and activates receptor tyrosine kinases (PI 3-kinase)
  2. leads to activation of Akt
  3. leads to mTOR activation
  4. mTOR increases transport of glucose into cells
    1. increased glycolysis
    2. makes more energy, more lipids for cell to grow and divide

gain of function mutations would cause cancer

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7
Q

PI3K/Akt/mTOR pathway also…

A

inhibits apoptosis

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8
Q

Pathway 3: p53

A

p53 (control responses to cell stress and DNA damage)

don’t memorize these, just know p53 senses a lot of different

at least 50% of all human cancers have a p53 mutation

(this occurs through loss of function mutation, bc it can’t sense DNA damage, can’t activate transcription of genes that inhibit cell cycle)

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9
Q

Pathway 3: p53

A

p53 (control responses to cell stress and DNA damage

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10
Q

general pathway overview

A
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11
Q

oncogene collaboration

A

we know cells need more than one mutation to override cell safety mechanisms

as mutations accumulate, cancerous phenotypes and cancer occurance can increase

cancer is rare in mice expressing either oncogenic Myc or Ras: need more mutations

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12
Q

cancer cells evolve

A

driver mutations are aquired and lead to cancer cells

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13
Q

colorectal cancer

A

shows us steps in tumor progression

identified genes that are highly mutated in colorectal cancer

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14
Q

although the route to full blown cancer progression is not the same for any two cancers,

A

colorectal cancers often fall into this pattern

don’t memorize image!

just know: cell progresses towards cancerous state before getting there

cells begin to proliferate more, but need more mutations to progress into a carcinoma

ADDITIVE MUTATIONS!

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15
Q

hyperplasia

A

increase in cell numbers, not cancer yet

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16
Q

mutations needed for metastasis

A

mutations needed for mestastasis are poorly understood

metastasis is hard to make happen

17
Q

therapeutics main goal:

A

kill cancer cells without harming normal, healthy cells

chemo is affective, but harms normal cells and normal tissues

18
Q

target something novel: in this case a novel enzyme

A

Abl normally functions in signal transduction in hematopoiesis:

promotes cell proliferation, inhibits apoptosis

Philadelphia chromosome!

forms a novel protein

19
Q

Gleevec targets Bcr-Abl fusion (oncogenic kinase)

A

great results!

but having a new protein to target is rare

20
Q

kinases are good targets for small molecule inhibitors

A

kinases must bind a nucleotide (ATP) before they can phosphorylate other proteins

21
Q

new direction: use passenger mutations to trigger T-cell killing

A
  • almost all of our cells constantly present small peptides of proteins they are expressing on their surface
  • normal presentation on cell surface means that cancer cells can be detected by the immune system (cancerous mutations can be detected)
    • BUT some cancers can block immune response
  • if we could unblock the tumor’s ability to mask surface antigens, tumors could be killed with high specificity
22
Q

T-cells are restrained by cancer cells

A

use antibodies to block that interaction

cancer cell turns of T-cell response

treat with antibodies to inhibit interaction so T-cell can properly recognize cancer cell and turn on the appropriate response

23
Q

engineer a patient’s T-cells to attack their specific cancer

A

CAR T-cell therapy