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IHOP > Targeted Therapies EXAM 2 > Flashcards

Targeted Therapies EXAM 2 Flashcards

1
Q

EGFR is a protein that is often found in which type of cells?

A

epithelial cells
-Skin
-GI

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2
Q

Name an example of a unique toxicity of targeted therapy in epithelial cells

A

blocking EGF-receptors on epithelial cells on the skin and the GI

-rash (skin)
-diarrhea (GI)

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3
Q

How are EGF receptors activated in healthy epithelial cells?

A

by phosphorylation (PI3K)

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4
Q

Describe the pathways that is activated by phosphorylation in epithelial cells.

A

phosphorylation of EGF-R

  1. RAS -> Raf -> MEK -> ERK (they phosphorylate each other) -> gene activation
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5
Q

What is the alternative pathway that promotes cell growth in epithelial cells?

A

AKT phosphorylates mTOR
-> gene activation

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6
Q

What happens with EGFR in mutated epithelial cells that cause cancer?

A
  1. overexpression of Epidermal Growth Factor Receptor (EGFR)
    -> more EGF ligands bind to EGF-R
  2. mutation of EGFR (always ON)
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7
Q

Which cancer type is predominantly affected by overexpression of EGFR?

A

head and neck cancer

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8
Q

Which type of drugs block EGFR outside of the cell? Name two drugs.

A

Monoclonal antibodies

-Cetuximab (Erbitux)
-panitumumab (Vectibix)

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9
Q

MAbs that target EGF-R only work in which genotype in colon cancer treatment? Why?

A

K-RAS and N-RAS (wild-type)

RAS is downstream and if mutated (always ON) it is not affected by EGF-R

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10
Q

What are the On-target toxicities of mAbs targeting EGF-R?

!!!

A

-Infusion reactions: esp. cetuXimab (bc foreign proteins)

On-target: !!!!
-Acne-like rash
-Diarrhea

-Hypomagnesemia (EGF-R reabsorbs magnesium)

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11
Q

Which MAb that targets EGF-R is preferred to reduce infusion reaction in cancer treatment?

A

Panitumumab (Vectibix)

mumab = human origin

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12
Q

Which type of drug targets EGF-R inside the cell?

A

Tyrosine-Kinase inhibitors

-blocking the phosphorylation
EGF-R is always ON (phosphorylated)

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13
Q

Name some of the Tyrosine-Kinase inhibitors

A

-inib

erlotinib
gefitinib
afatinib
lapatinib (also target HER2)
lazertininb
osimertinib

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14
Q

Which commonly used drug has a higher affinity to mutated EGFR (mEGFR)?

A

-osimertinib (newer generation)

less diarrhea and rash compared to the other ones

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15
Q

What is the unique toxicity of TKI (tyron kinase inhibitor)?

A

acne-like rash
diarrhea

we don’t see much infusion reaction (since it is PO) and hypomagnesemia

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16
Q

HER2 receptors often dimerize with which other receptors on epithelial cells? What makes it dangerous in cancer?

A

-HER2 can dimerize with itself and EGF-R

-HER2 doesn’t need a ligand to dimerize and be active

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17
Q

Why is HER2 a good target for cancer drugs?

A

because it is overexpressed and can be targeted by the drug

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18
Q

tissues and orgnas that have HER2 overexpression

A

-breast (20%)
-gastric cancer !!!
-lungs

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19
Q

What is the unique toxicity of HER2 mAb therapy?

A

-LVEF reduction (reversible if the drug is stopped)
-diarrhea

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20
Q

Which other anticancer drug causes cardiomyopathy?

REMINDER

A

Anthracyclines

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21
Q

Name the MAb that targets HER2.

A

-trastuzumab
-pertuzumab (only used with trastuzumab)
-Ado-trastuzumab

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22
Q

What is the difference between Ado-trastuzumab (mAb)?

A

Ado- contains emtansine (Adc = antibody-drug-conjugant)

3x emtansine conjugated to the mAb

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23
Q

Explain the MOA of Ado-trastuzumab

A

-it binds to HER2 receptors
-it gets into the cell
-emtansine is a microtubule inhibitor causing cell death

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24
Q

What side effects are seen with Ado-trastuzumab?

A

in addition to diarrhea and reduced LVEF it has
-myelosuppression (thrombocytopenia)
-LFT
-arthralgia (joint pain)
-myalgia

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25
Q

Which drug is conjugated to Fam-trastuzumab
deruxtecan

A

deruxtecan (8 compounds)

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26
Q

Deruxtecan is what type of anticancer drug?

A

Topoisomerase I inhibitor

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27
Q

What are the side effects we see with Fam-trastuzumab?

A

-reduced LVEF
-diarrhea

-myelosuppression (neutropenia)
-ILD (interstitial lung disease, pulmonary fibrosis)

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28
Q

Which other anticancer drug causes diarrhea?
REMINDER

A

Irinotecan (I ran to the can)

Topo I inhibitor

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29
Q

What has to be monitored in patients who are treated with HER2?

A

monitor EF with ECHO every 3 months
if EF is low -> treat the EF with an HF regimen (ACEi/ARB + BB..)

when normal can use the anticancer drug again if needed

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30
Q

Which TKI targeting EGF-R also targets HER2?

A

-lapatinib
-neratinib (need diarrhea prophylaxis: loperamide)
-tucatinib

but they don’t work as well as the IV HER2 drugs (-zumabs) and they cause more diarrhea

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31
Q

Which anticancer drugs should NOT be given together with HER2 targeting drugs and WHY?

A

Anthracyclines because both cause a reduction in LVEF

may give Anthracyclines after HER2 drugs (-zumabs)

32
Q

Which protein stimulates blood vessel development in cancer cells?

A

VGEF (produced by the cancer cell)

33
Q

Which mAb binds to the VGEF ligand? Does it bind intracellular or extracellular?

A

Bevacizumab

outside of the cell

34
Q

Which TKI binds to the VGEF-R? Does it bind Intracellular or extracellular?

A

sunitinib

VGEF-R inhibitors are TKIs

inside the cell

35
Q

What is the brand name of Bevacizumab?
!!!

A

Avastin

36
Q

What are the On-target toxicities of VGEF-targeted agents?

!!!

A

-Hypertension
decreased NO

-Proteinuria (maintain fenestration in glomerulus, filtering protein)

-Impaired wound healing bc we block the mTOR pathway (blood supply in wound healing)

-Bleeding (bc we stop angiogenesis, unfinished blood vessel that leaks)

-Thromboembolic event (the body’s reaction to the bleeding)

37
Q

Why can VEGF-R inhibitors have a variety of different side effects?

A

because it is a multikinase inhibitor that also targets other kinases -> causing different side effects

-hair discoloration
-Hand-Foot syndrome
-diarrhea
-LFT

38
Q

What is the difference between BRAF and Raf?

A

BRAF is an isoform of Raf
-in the MAPKinase pathway

when BRAF is mutated it is always ON

39
Q

What is the common mutation of BRAF?

A

activating mutation: BRAFv600E

40
Q

Name the BRAF TKIs

A

-raf-enib

vemurafenib
dabrafenib
encorafenib
sorafenib
regorafenib

41
Q

What is the On-target toxicity of BRAF TKIs?

A

Skin toxicities !!!
-rash
-photosensitivity
-Hand-foot syndrome
-alopecia

sometimes:
-non-melanoma skin cancer
-SJS

42
Q

Why does treating skin cancer with BRAF cause other skin melanomas?

A

cancer cells find other ways to activate MEK

-increased activity of MEK in cancer cells and in healthy cells

-the healthy cells cause another type of cancer (need another drug -> more toxicities)

43
Q

Which toxicities do we see when blocking mutated BRAF?

A

-non-melanoma skin cancer
-hyperkeratosis

44
Q

What are the advantages and disadvantages of blocking 2 different pathways in epithelial cells?
BRAF and MREK pathway

A

advantage:
-longer disease control
-fewer non-melanoma skin cancer (since we block MEK)
-less skin toxicity

disadvantage:
more of the other toxicities since we are using 2 drugs
-cardiomyopathy, fever, hepatic, ophthalmic

45
Q

Which drug inhibtis the progression from G1 to S phase in cancer cells?

A

CDK 4/6 Inhibitors
palbociclib
ribociclib
abemaciclib

46
Q

What needs to happen in a healthy cell to progress from G1 to the S-phase?

A

CKD needs to phosphorylate Rb

CKD inhibitor prevents that -> Cell cycle arrest

47
Q

Name the CKD inhibitors.

A

-palbociclib
-Ribociclib
-abemaciclib

48
Q

What are the side effects of CDK inhibitors?

A

Myelosuppression (palbociclib, Ribociclib)
-nausea
-alopecia
-diarrhea
-Qt prolongation

49
Q

Which CDK inhibitor has QT prolongation as a side effect?

A

Ribociclib

50
Q

Which of the CDK inhibitors is mostly associated with diarrhea?

A

abemaciclib

51
Q

Why is the side effect profile of CDK inhibitors similar to “mini chemotherapy”?

A

Because they are sensitive to rapidly growing cells

52
Q

What is the indication of CDK inhibitors?

A

breast cancer (men and women)

53
Q

Which CDK inhibitor causes less myelosuppression and doesn’t require a rest phase during cancer therapy?

A

abemaciclib

palbociclib and ribociclib are given in weeks 1, 2, and 3 then we pause for 1 week

54
Q

Which stimuli are part of the immune checkpoint of the immune system? Which ones are negative stimuli?

A

positive (needs to be there to prevent killing)
-self-antigen
-co-stimulus (CD-28)

negative (if absence it stimulates T-cell killing)
-CTLA-4
-PD-1/PD-L1

55
Q

The binding to which receptor prevents the killing of healthy cells and is used by cancer cells to hide from immune cells?

A

CTLA-4
PD-1/PD-L1

56
Q

Which mAb blocks CTLA-4?

A

Ipilimumab (Yervoy)

57
Q

What are the irAEs and what causes it?

Unique Toxicity of Ipilimumab

A

because of stopping the “pedal” of the immune system -> overactivity of the immune system

-colitis (inflammation of the colon)
-hepatitis
-dermatitis
-hypothyroidism

LEGS
L: liver - hepatitis
E: endocrinopathies - thyroid
G: GI - diarrhea, colitis
S: skin - dermatitis

could also affect other organs: pneumonitis, nephritis, encephalitis

58
Q

Explain PD-1 and PD-L1

A

if PD-L1 is expressed in a cell, it stays alive even though the antigen is foreign (danger)

-cancer cells express PD-L1 to evade the immune system

59
Q

What are the most commonly used PD-1 blocking agents?

A

-nivolumab
-pembrolizumab

60
Q

What are the brand names of nivolumab and pembrolizumab?

A

nivolumab (Opdivo)
pembrolizumab (Keytruda)

61
Q

Name PD-L1 agents

not discussed in class

A

-atezolizumab (Tecentriq)
-avelumab (Bavencio)
-durvalumab (Imfinzi)
-cosibelimab

62
Q

Which drugs are used to manage the side effects of Immune Checkpoint inhibitors? (ICI)

A

high dose of corticosteroids, may add another immunosuppressant
-prednisone and infliximab

for hypothyroidism: levothyroxine

63
Q

CD-20 are expressed in what type of immune cells?

A

B-cells

64
Q

Which drug binds to CD20? What is its MOA?

A

Rituximab

CD20 is on mutated B-cells
-the antibody binds to CD20

binding to the antibody can activate cell lysis
-by T-cells
-by complement protein
-by macrophages

65
Q

What are the unique toxicities of Rituximab?

A

-infusion reactions

-reactivating of Hep B virus
check Hep serum !!!

66
Q

What are the premeds for Rituximab and how do we administer the drug to check for infusion reaction?

A

-premeds: Tylenol and Benadryl

start at a low rate and check for reactions

67
Q

Why can we start at a higher rate with 2nd cycle of Rituximab?

A

because killing of the cells causes cytokine release -> causing the infusion reaction

by the 2nd cycle, some of the cancer cells are killed, so there is less risk of reactions

68
Q

What is the single mutation that causes CML?

A

Translocation of chromosomes 9 and 22

fused chromosome (Philadelphia chromosome)
bcr-abl

69
Q

Which drug is used for CML and what is its MOA?

A

Imatinib

prevents ATP binding to the pocket of the BCR-ABL fusion protein (the BCR-ABL needs ATP to work)

70
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Q
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76
Q
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IHOP (13 decks)

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