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HemOnc Week 4 > ICL 12.3 > Flashcards

ICL 12.3 Flashcards

1
Q

what are targeted cancer therapies?

A

drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (“molecular targets”) that are involved in the growth, progression, and spread of cancer

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2
Q

how do targeted therapies differ from standard chemotherapy?

A
  1. Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells.
  2. Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells.
  3. Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells).
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3
Q

what is epigenetic?

A

any process that alters gene activity without changing the DNA sequence and leads to modifications that can be transmitted to daughter cells

involves DNA methylation and chromatin modifications such as nucleosome positioning, histone acetylation and methylation

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4
Q

on what residue does DNA get methylated?

A

cytosine at the 5’ position

this reaction is catalyzed by DNMTs

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5
Q

what are DNMTs?

A

DNA methyl transferases

they methylate cytosine residues in DNA

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6
Q

where does DNA methylation occur in the genome?

A

CpG islands

these are regions of the genome that are enriched in GC residues

they’re close to promoters so when they’re unmethylated, RNA polymerases can bind and activate transcription

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7
Q

what does methylation of gene bodies signify?

A

increased transcription

it’s the opposite of methylation of DNA….

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8
Q

is there increased or decreased methylation in most cancers?

A

generally, there’s hypomethylation because you’re turning on oncogenes

there’s also selective hypermethylation in some places

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9
Q

what are DNA methylation inhibitors?

A

nucleoside analogues that exert their demethylating activity through the establishment of an irreversible covalent bond with DNMTs after their incorporation into DNA

they get incorporated into DNA and then DNMT binds to them irreversibly so DNMT can no longer methylate DNA

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10
Q

which drugs are DNA hypomethylating agents?

A

5-azacytidine

decitabine

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11
Q

how do you administer DNA hypomethylating agents?

A

5-azacytidine and decitabine are administered via IV

half-life is 41 minutes

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12
Q

how are azacytidine and decitabine metabolized?

A

they are metabolized and inactivated by cytidine deaminase then excreted by the kidney

some cancers have high levels of cytidine deaminase which degrades the drugs and contribute to resistance

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13
Q

how do hypomethylating drugs work?

A

in cancer they:
- decrease oncogenes

  • increase TSG
  • increase ERV and tumor antigen expression which increases sensitization to immunotherapy

in tumor microenvironment they:
- increase immune response

  • decrease angiogenesis which inhibits stem-cell niche
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14
Q

what are the targets of hypomethylating drugs?

A

DNA methyl transferases

DNMTs

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15
Q

what do hypomethylating agents do at low doses?

A

HMAs promote differentiation by inhibiting DNA methylation, activate TSGs

HMAs can also activate an immune anti-tumor response and have an effect on the tumor microenvironment

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16
Q

why do HMAs have a limited response in solid tumors?

A

likely due to lower drug penetrance and slower proliferation rate than hematological malignancies

the drug can’t get deep within the tumor

you have to have DNA replication for these drugs to be incorporated into the DNA and have an effect and solid tumors have a slower proliferation rate

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17
Q

what is an example of a next generation DNA hypomethylating drug?

A

SGI-110

decitabine linked
to a deoxyguanosine makes
it resistant to degradation

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18
Q

which is a potential therapeutic effect resulting from DNA hypomethylating agents?

A

activation of the cyclin dependent kinase inhibitor, p15

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19
Q

what are the classes of epigenetic regulators?

A
  1. writers
  2. erasers
  3. readers
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20
Q

what do drugs that target erasers do?

A

they inhibit HDACs

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21
Q

what do drugs that target readers do?

A

they target bromodomains

22
Q

what do drugs that target writers do?

A

they inhibit histone methyltransferases

23
Q

are HDAC levels increased or decreased in cancer?

A

usually over-expressed

HDACs decrease transcription by keeping DNA of TSGs in condensed form so that TSGs can’t be expressed

24
Q

what does acetylation of histones do?

A

increased transcription/gene expression

in cancer, TSGs get silenced due to over-active HDACS that condense DNA and keep TSGs from being transcribed

25
what do HDAC inhibitors do?
they inhibit HDACs so that TSGs can be expressed HDAC inhibitors block HDACs and prevents them from condensing chromatin at TSGs
26
what drug is an HDAC inhibitor?
vorinostat works for cutaneous T-cell lymphoma inhibits a bunch of different HDACs
27
what does vorinostat do?
it's an HDAC inhibitor inhibits SIRT which is an HDAC inhibits HDAC 1,2,3,6 induces cellular differentiation, increases p21 levels, promotes G1 cell cycle arrest, apoptosis
28
what is SIRT?
it's an HDAC
29
what is the AKT pathway?
it's a kinase signaling pathway AKT activates mTOR which is also a kinase mTOR activates cell proliferation
30
what drug inhibits mTOR?
rapamycin inhibits mTOR which activates cell proliferation
31
what does rapamycin do?
1. inhibits mTOR (activates cell proliferation) 2. activates SIRT (HDAC) 3. activates FOXP3 which is a transcription factor which increases T cells = increased immune system activity
32
what's the problem with vorinostat?
it inhibits HDAC 1,2,3,6 so we need HDAC inhibitors that effect more specific targets
33
how can HDACs promote acute promyelocytic leukemia (APL)?
in APL, there's a PML-RARα fusion that can recruit HDACs to promoters which silences TSGs instead of using HDAC inhibitors to treat this, you can just prevent the binding of HDACs to the PML-RARα fusion protein you can remove the HDACs by using retinoid acid which will bind to PML-RARα instead
34
a patient had AML-MS. She underwent chemo with an HDAC inhibitor. what's the mechanism by which the combination of drugs was therapeutically effective?
HDACi inactivated HDACs which caused increased acetylation of chromatin at pro-apoptotic gene promoters rendering cancer cells more susceptible to chemo
35
what are bromodomains?
readers of the histone code they recognize acetylated lysines they're epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in some cancers BRDs = bromodomains
36
what is the BET family?
it's a family of bromodomain containing proteins BRDs are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in some cancers BET proteins are often over expressed in cancer
37
which proteins are in the BET family?
BRD2 BRD3 BRD4 BRDT
38
what does BRD4 do?
it's a bromodomain protein it binds to acetylated histones and regulate transcription by recruiting activators or bringing in transcription machinery it functions in both normal cells and cancer cells inhibiting this can be a good cancer treatment
39
how do you inhibit bromodomains?
SMIs can inhibit bromodomain binding to acetylated histones if the bromodomain can't bind to the acetylated histones, it can't recruit transcription factors or activators this has therapeutic potential in cancer!
40
what is BRD4-NUT?
oncogene
41
what is NUT midline carcinoma?
driven by BRD4-NUT fusion
42
what do bromodomain inhibitors do?
they suppress oncogenes like MYC, BCL2, CDK6 they bind to promoters or enhancers of genes that would promote tumor proliferation like MYC, etc to stop the process
43
why do bromodomain inhibitors work well in cancer and not normal cells?
cancer cells may be more sensitive to drugs due to high levels of super-enhancers the super-enhancers have high levels of bromodomains! addiction to super enhancers is a feature of cancer cells that can be exploited therapeutically with BET bromodomain inhibitors
44
primary resistance to a BET-inhibitor would be most likely due to what?
activation of alternative pathways that led to MYC activation
45
what is DOT1L?
histone methyl transferase it's overactive in MLL and can be treated with penometostat
46
what does EZH2 do?
it silences TSGs in cancer by methylating histones can inhibit EZH2 with tazemetostat -- EZH2 inhibitors can promote re-expression of TSGs and decrease tumorigenicity
47
some mixed lineage leukemias are characterized by the presence of a fusion protein that promotes expression of leukemogenic genes by recruiting the histone methyltransferase DOT1. how would an inhibitor to DOT1 counteract the fusion protein and be therapeutically effective?
the inhibitor would prevent DOT1 from adding a methyl group to histone proteins at leukemogenic loci
48
what does DHMA stand for?
DNA hypomethylating agents DHMAs target DNA methyl transferases
49
what do DHMAs do?
DHMAs target DNA methyl transferases DHMAs can result in hypomethylation at promoter islands and re-expression of tumor suppressor genes, decreasing tumorigenicity, thereby having a therapeutic effect
50
why do HDAC inhibitors work in treating cancer?
in many cases, HDAC inhibitors work because they cause increased acetylation of histones at regulatory regions of tumor suppressor genes the predicted outcome would be re-expression of tumor suppressors
51
does histone methylation activate or deactivate?
histone methylation can be activating or repressive depending on the lysine residue histone methyltransferases and demethylases are specific for particular residues therefore the outcome from inhibiting these enzymes will depend on which one is being inhibited
52
what do BET bromodomain inhibitors do?
they suppress expression of oncogenes by displacing BET bromodomain proteins from gene promoters, enhancers, and superenhancers of oncogenes

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