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HemOnc Week 4 > ICL 12.2 > Flashcards

ICL 12.2 Flashcards

1
Q

what is precision medicine?

A

you want to know which specific mutations are in that patient

various actionable molecular targets against cancer - like you want to target a kinase or anything that helps the tumor cells keep replicating

mode of action of drugs against such targets

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2
Q

what should a cancer target?

A

it should target both the tumor and its microenvironment!

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3
Q

what are the key targets in cancer therapy?

A
  1. receptor tyrosine kinases (RTKSs)
  2. non-receptor tyrosine kinases
  3. G-protein coupled receptors (GPCRs)
  4. hormonal axis (estrogen, progesterone, prolactin and androgens)
  5. epigenetic targets
  6. cell cycle
  7. cellular immune system
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4
Q

what are stromo cells?

A

anything other than the tumor cells

they help the tumor cells to evade the chemotherapy

so the tumor is the tumor itself plus its microenvironment! you have to treat both parts

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5
Q

what are RTKs?

A

tyrosine kinase receptors at the plasma membrane

when they are mutated they become this kinase that is just always turned on

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6
Q

what is the most common GPCR?

A

CXCR4

tumor cells highjack this receptor and use it to metastasize and involved with hematological malignancies and solid tumors

it’s a chemokine receptor involved in metastasis

it’s a coreceptor for the HIV virus

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7
Q

what are tyrosine kinase receptors?

A

these are kinases that are activated by their respective ligands

they get phosphorylated on their C-terminal end and cause a phosphorylation cascade

they use ATP to become phosphorylated

in cancer, these receptors get mutated and are just constantly on causing uncontrolled cell proliferation

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8
Q

how do you inhibit tyrosine kinase receptors?

A

TKR get phosphorylated on their C-terminal end by ATP

we can design antagonists to compete with ATP for the same site - this is how you attack a tyrosine kinase receptors

long term though, there’s usually relapse and the TKIs don’t work forever

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9
Q

what are some examples of tyrosine kinase receptors?

A

VEGF**

EGF

IGF-1

NGF

PDGF

FGF

Eph

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10
Q

how do you neutralize the VEGF receptor?

A

VEGF is a tyrosine kinase receptor

you can neutralize the ligand in VEGF by using an antibody called MAB

MAB is a competitive antagonist and competes with the ligand to bind with VEGF receptor and neutralizes it

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11
Q

which drug neutralizes the PDGF receptor?

A

imatinib

PDGF is a tyrosine kinase receptor

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12
Q

what are the main pathways that get activated with a ligand binds to a tyrosine kinase receptor?

A

PA3 kinase

MEK/ERK pathways

these 2 pathways help with invasion, survival proliferation and metastasis of cancers

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13
Q

what does TKI stand for?

A

tyrosine kinase inhibitor

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14
Q

which TKIs target EGFR receptor?

A
  1. gefitinib
  2. erlotinib

EGFR is a tyrosine kinase receptor

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15
Q

what ligands bind to EGFR receptor?

A
  1. TGFα
  2. EGF
  3. AREG
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16
Q

which monoclonal antibodies target the EGFR receptor?

A
  1. cetuximab
  2. panitumumab

mAbs are laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance or mimic the immune system’s attack on cancer cells

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17
Q

what does TNBC stand for?

A

triple negative breast cancer

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18
Q

what is TNBC?

A

tissue normally expressed estrogen, progesterone and HER2 receptors but in TNBC, none of those are there!

the tumor tissue doesn’t have any of these receptors which means you don’t have the usual targets to go after

so now you have to use targeted pathways to go after specific things

if you do have any of these receptors, then prognosis is better and survival is higher

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19
Q

what’s the prognosis for TNBC?

A

pretty lethal…

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20
Q

what does EGFR stand for?

A

epidermal growth factor receptor

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21
Q

what are the two ways you can treat an overactive EGFR?

A
  1. monoclonal antibodies
  2. small molecule inhibitors (SMI)

**TKIs are SMIs

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22
Q

how do TKIs work?

A

they competitively inhibit the binding of ATP to the kinase

so the kinase can’t get phosphorylated and cause a phosphorylation cascade

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23
Q

which cancers can be treated using erlotinib and gefitinib?

A

breast cancer, colon cancer, and head and neck cancer

erlotinib and gefitinib are TKIs for EGFR

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24
Q

what is osimertinib used for?

A

it’s an SMI used against EGFR T790M mutation in non-small cell lung cancer

the drug won’t bind to the wild type receptor, instead it’ll bind to the mutated EGFR binding pocket

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25
Q

what is afatinib used for?

A

it’s a SMI used against EGFR L858R mutation

this mutation is an EGFR exon 19 deletion or exon 21 substitution

the drug won’t bind to the wild type receptor, instead it’ll bind to the mutated EGFR binding pocket

26
Q

which monoclonal antibodies can be used to target HER2?

A
  1. trastuzumab

2. pertuzumab = inhibits dimerization of HER2 with HER3

27
Q

which SMI can be used to target HER2?

A

lapatibib

28
Q

what is HER2?

A

human EGF receptor 2 = HER2

HER2 mutations are common in luminal breast cancer

29
Q

what’s the problem with targeting IGF1R?

A

IGF1R causes resistance to P13-kinase therapy

the cancer develops resistance because the tumors express IGF1R

targeting IGF1R leads to metabolic toxicity like hyperglycemia and elevated growth hormone levels

30
Q

why would you want to target VEGFR?

A

VEGFR binds to VEGF to initiate signal cascades that stimulate angiogenesis

you’re trying to cut off the blood supply of the tumor

the endothelial cells make up the blood vessels so if you attack that you don’t have enough blood vessels being made so you can contain the tumor growth this way

targeting VEGFR targets angiogenesis!

31
Q

which drugs target VEGFR?

A
  1. bevacimumab

2. avastin

32
Q

which residue on histones gets modified?

A

lysine

can be acetylated or methylated!

tumors have lots of HDAC activity because they’re turning off TSG

33
Q

which drugs are HDAC inhibitors?

A
  1. romidepsin
  2. panobinostat
  3. belinostat

tumors have lots of HDAC activity because they’re turning off TSG so if you inhibit HDAC activity you can turn TSGs back on!

34
Q

what is PARP? BRCA?

A

an enzyme that effects the single strand DNA defects

BRCA1 fixes double strand DNA legions

PARP fixes single strand DNA legions

there’s lots of chaotic replication happening in tumors and lots of ROS that cause DNA damage

tumors need PARP and BRCA1 to fix the mutations them

35
Q

why would you want to target PARP?

A

because PARP fixes single strand DNA legions

so if you take away the tumors ability to fix DNA, mutations and ROS will pile up and kill the tumor

36
Q

how would you treat a patient if they had a BRCA1 mutation? which drugs specifically?

A

if there’s a BRCA1 mutation, they can’t do homologous recombination mediated repair in double stranded DNA

so now the tumor has to rely on PARP to fix its DNA

so this means you can target PARP and knock out both the repair mechanisms in tumors and the tumor will no longer be able to repair DNA in any way and it’ll die!

PARP inhibitors in BRCA deficiency = rucaparib, olaparib and niraparib

37
Q

what is synthetic lethality?

A

exploitation of an existing defect in tumor cells to advantage by combining with a synergistic inhibitor to achieve lethality in cancer cells

we’re taking advantage of the existing somatic mutations in the tumor

ex. using a PARP inhibitor in patients who have a BRCA1 mutation

38
Q

which drugs target CDK4 & CDK6?

A
  1. palbociclib

2. ribociclib

39
Q

what is HDM2?

A

it’s a homolog of MDM2 that’s often mutated in cancers - tumor cells have lots of HDM2

HDM2 causes ubiquitination of p53 and subsequent degradation by proteasomes

p53 is what stops cell cycle progression if there’s DNA damage

so without HDM2, p53 is unregulated and constantly being broken down so there’s no cell cycle regulation and the cell cycle is over active

40
Q

which drug is an HDM2 inhibitor?

A

nutlin-3a

you can target HDM2 where there is NO mutation for p53 - if there’s a p53 mutation, this drug won’t work

41
Q

how does AMD-3100 work?

A

it binds to a pocket away from the ligand binding site - it doesn’t bind directly to the ligand binding pocket

when it binds, there’s a conformational change which changes the ligand binding pocket structure so the ligand can’t bind anymore

it inhibits the binding of CXCL12 to CXCR4 receptor (GPCR)

42
Q

what is balixafortide used for?

A

used for stage III-IV breast cancer

it’s a GPCR inhibitor

it’s an antagonist against CXCR4 - allosterically inhibits ligand binding

43
Q

which drug is used against CXCR2 and CXCR1?

A

reparixin

CXCR2 and CXCR1 mutations are seen in breast cancer stem cells

44
Q

what does SERM stand for?

A

selective estrogen receptor modulations

45
Q

what does SERD stand for?

A

selective estrogen receptor down regulators/degraders

46
Q

how do SERMs work?

A

they form an inactive complex with estrogen receptor (ER)

they make the receptor useless by modifying its activity in such a way that it can’t bind to its ligand

SERMs prevent the ligand from binding to the ER

47
Q

which drug is a SERM?

A

tamoxifen

48
Q

how do SERDs work?

A

bind to estrogen receptor (ER) and targets it for degradation

you don’t have enough receptors so it downregulates the total protein in the tumor cell which degrades the receptor (the receptor is a protein)

even if the estrogen receptor gets into the nucleus, it won’t be able to cause a cascade because it’ll get degraded in the cytoplasm

49
Q

which drug is a SERD?

A

fulvestrant

50
Q

what are aromatase inhibitors?

A

inhibit synthesis of the hormone estradiol

estradiol is the ligand for the ER so even if you have the receptor, there’s no ligand to bind to it

aromatase converts precursor compounds into estrogen so if you inhibit it, then you’ll have less estrogen

51
Q

which drugs are aromatase inhibitors?

A
  1. exemestane
  2. anastrozole
  3. letrozole
52
Q

which three types of drugs target the estrogen receptor?

A
  1. SERMs
  2. SERDs
  3. aromatase inhibitors
53
Q

which drug targets the progesterone receptor?

A

onapristone

54
Q

which drug targets the androgen receptor?

A

enzalutamide

enzalutamide prevents testosterone from binding to androgen receptor

55
Q

which cancer is the androgen receptor involved in?

A

metastatic and non-metastatic prostate cancer

in prostate cancer, there’s excess androgen receptor activation by testosterone

enzalutamide prevents testosterone from binding to androgen receptor

56
Q

what is the AR-V7 problem?

A

there’s a truncated androgen receptor in prostate cancers

the receptor lacks an androgen-binding domain

the therapy targets testosterone from binding to the receptor but if there’s no androgen-biding domain, then it doesn’t even need a ligand to be active…

57
Q

what are the three ways that enzalutamide work?

A
  1. keeps testosterone from binding to androgen receptor
  2. prevent nucleus shuttling so there’s no transactivation of DNA
  3. prevent AR-T DNA binding
58
Q

what 4 things cause drug resistance?

A
  1. mutations of the target
  2. elevated drug transporters
  3. target up regulation
  4. activation of surrogate/alternate signaling pathways
59
Q

what do drug transporters do?

A

they pump the drug out of the tumor cell…

ex. P-glycoprotein, ABCG2, ABCC1

one drug transporter can create resistance to multiple drugs…

you can’t go after these things because they’re in the blood-brain barrier so if you target them, then you’d kill the brain

60
Q

what is tumor heterogeneity?

A

when tumors are made of different types of cells

this makes tons of different targets and mutations so even if you kill of one line of cells, there’s still others left over

can cause drug resistance

61
Q

what is activation of surrogate pathways?

A

if you disarm one pathway with a drug, another pathway can turn on

alternative pathways are turned on which causes drug resistance

ex. you inhibit BRAF but then the RAS and MEK pathways are turned on which bypass the BRAF pathway
ex. you activate a different tyrosine kinase receptor

62
Q

how do cancer stem cells play a role in chemotherapy and targeted therapy?

A

therapy will clear up the bulk tumor cells and leave behind cancer stem cells

they survive and repopulate the whole tumor again….this is a big problem that leads to relapse and causes more aggressive and metastatic cancers = minimal residual disease

cancer stem cells have lots of ABC drug transporters in them and they’re immune-invasive which is how they survive

HemOnc Week 4 (10 decks)

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