Targeted Therapies EXAM 2 Flashcards
EGFR is a protein that is often found in which type of cells?
epithelial cells
-Skin
-GI
Name an example of a unique toxicity of targeted therapy in epithelial cells
blocking EGF-receptors on epithelial cells on the skin and the GI
-rash (skin)
-diarrhea (GI)
How are EGF receptors activated in healthy epithelial cells?
by phosphorylation (PI3K)
Describe the pathways that is activated by phosphorylation in epithelial cells.
phosphorylation of EGF-R
- RAS -> Raf -> MEK -> ERK (they phosphorylate each other) -> gene activation
What is the alternative pathway that promotes cell growth in epithelial cells?
AKT phosphorylates mTOR
-> gene activation
What happens with EGFR in mutated epithelial cells that cause cancer?
- overexpression of Epidermal Growth Factor Receptor (EGFR)
-> more EGF ligands bind to EGF-R - mutation of EGFR (always ON)
Which cancer type is predominantly affected by overexpression of EGFR?
head and neck cancer
Which type of drugs block EGFR outside of the cell? Name two drugs.
Monoclonal antibodies
-Cetuximab (Erbitux)
-panitumumab (Vectibix)
MAbs that target EGF-R only work in which genotype in colon cancer treatment? Why?
K-RAS and N-RAS (wild-type)
RAS is downstream and if mutated (always ON) it is not affected by EGF-R
What are the On-target toxicities of mAbs targeting EGF-R?
!!!
-Infusion reactions: esp. cetuXimab (bc foreign proteins)
On-target: !!!!
-Acne-like rash
-Diarrhea
-Hypomagnesemia (EGF-R reabsorbs magnesium)
Which MAb that targets EGF-R is preferred to reduce infusion reaction in cancer treatment?
Panitumumab (Vectibix)
mumab = human origin
Which type of drug targets EGF-R inside the cell?
Tyrosine-Kinase inhibitors
-blocking the phosphorylation
EGF-R is always ON (phosphorylated)
Name some of the Tyrosine-Kinase inhibitors
-inib
erlotinib
gefitinib
afatinib
lapatinib (also target HER2)
lazertininb
osimertinib
Which commonly used TKI has a higher affinity to mutated EGFR (mEGFR)?
-osimertinib (newer generation)
less diarrhea and rash compared to the other ones
What is the unique toxicity of TKI (tyron kinase inhibitor)?
acne-like rash
diarrhea
we don’t see much infusion reaction (since it is PO) and hypomagnesemia
HER2 receptors often dimerize with which other receptors on epithelial cells? What makes it dangerous in cancer?
-HER2 can dimerize with itself and EGF-R
-HER2 doesn’t need a ligand to dimerize and be active
Why is HER2 a good target for cancer drugs?
because it is overexpressed and can be targeted by the drug
tissues and orgnas that have HER2 overexpression
-breast (20%)
-gastric cancer !!!
-lungs
What is the unique toxicity of HER2 mAb therapy?
-LVEF reduction (reversible if the drug is stopped)
-diarrhea
Which other anticancer drug causes cardiomyopathy?
REMINDER
Anthracyclines
Name the MAb that targets HER2.
-trastuzumab
-pertuzumab (only used with trastuzumab)
-Ado-trastuzumab
What is the difference between Ado-trastuzumab (mAb)?
Ado- contains emtansine (Adc = antibody-drug-conjugant)
3x emtansine conjugated to the mAb
Explain the MOA of Ado-trastuzumab
-it binds to HER2 receptors
-it gets into the cell
-emtansine is a microtubule inhibitor causing cell death
What side effects are seen with Ado-trastuzumab?
in addition to diarrhea and reduced LVEF it has
-myelosuppression (thrombocytopenia)
-LFT
-arthralgia (joint pain)
-myalgia
Which drug is conjugated to Fam-trastuzumab
deruxtecan
deruxtecan (8 compounds)
Deruxtecan is what type of anticancer drug?
Topoisomerase I inhibitor
What are the side effects we see with Fam-trastuzumab?
-reduced LVEF
-diarrhea
-myelosuppression (neutropenia)
-ILD (interstitial lung disease, pulmonary fibrosis)
Which other anticancer drug causes diarrhea?
REMINDER
Irinotecan (I ran to the can)
Topo I inhibitor
What has to be monitored in patients who are treated with HER2?
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
Which TKI targeting EGF-R also targets HER2?
-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
Which anticancer drugs should NOT be given together with HER2 targeting drugs and WHY?
Anthracyclines because both cause a reduction in LVEF
may give Anthracyclines after HER2 drugs (-zumabs)
Which protein stimulates blood vessel development in cancer cells?
VGEF (produced by the cancer cell)
Which mAb binds to the VGEF ligand? Does it bind intracellular or extracellular?
Bevacizumab
outside of the cell
Which TKI binds to the VGEF-R? Does it bind Intracellular or extracellular?
sunitinib
VGEF-R inhibitors are TKIs
inside the cell
What is the brand name of Bevacizumab?
!!!
Avastin
What are the On-target toxicities of VGEF-targeted agents?
!!!
-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)
Why can VEGF-R inhibitors have a variety of different side effects?
because it is a multikinase inhibitor that also targets other kinases -> causing different side effects
-hair discoloration
-Hand-Foot syndrome
-diarrhea
-LFT
What is the difference between BRAF and Raf?
BRAF is an isoform of Raf
-in the MAPKinase pathway
when BRAF is mutated it is always ON
What is the common mutation of BRAF?
activating mutation: BRAFv600E
Name the BRAF TKIs
-raf-enib
vemurafenib
dabrafenib
encorafenib
sorafenib
regorafenib
What is the On-target toxicity of BRAF TKIs?
Skin toxicities !!!
-rash
-photosensitivity
-Hand-foot syndrome
-alopecia
sometimes:
-non-melanoma skin cancer
-SJS
Why does treating skin cancer with BRAF cause other skin melanomas?
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)
Which toxicities do we see when blocking mutated BRAF?
-non-melanoma skin cancer
-hyperkeratosis
What are the advantages and disadvantages of blocking 2 different pathways in epithelial cells?
BRAF and MEK pathway
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
Which drug inhibtis the progression from G1 to S phase in cancer cells?
CDK 4/6 Inhibitors
palbociclib
ribociclib
abemaciclib
What needs to happen in a healthy cell to progress from G1 to the S-phase?
CKD needs to phosphorylate Rb
CKD inhibitor prevents that -> Cell cycle arrest
Name the CKD inhibitors.
-palbociclib
-Ribociclib
-abemaciclib
What are the side effects of CDK inhibitors?
Myelosuppression (palbociclib, Ribociclib)
-nausea
-alopecia
-diarrhea
-Qt prolongation
Which CDK inhibitor has QT prolongation as a side effect?
Ribociclib
Which of the CDK inhibitors is mostly associated with diarrhea?
abemaciclib
Why is the side effect profile of CDK inhibitors similar to “mini chemotherapy”?
Because they are sensitive to rapidly growing cells
What is the indication of CDK inhibitors?
breast cancer (men and women)
Which CDK inhibitor causes less myelosuppression and doesn’t require a rest phase during cancer therapy?
abemaciclib
palbociclib and ribociclib are given in weeks 1, 2, and 3 then we pause for 1 week
Which stimuli are part of the immune checkpoint of the immune system?
positive (needs to be there to prevent killing)
-self-antigen
-co-stimulus (CD-28)
The binding to which receptor prevents the killing of healthy cells and is used by cancer cells to hide from immune cells?
CTLA-4
PD-1/PD-L1
Which mAb blocks CTLA-4?
Ipilimumab (Yervoy)
What are the irAEs and what causes it?
Unique Toxicity of Ipilimumab
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
Explain PD-1 and PD-L1
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
What are the most commonly used PD-1 blocking agents?
-nivolumab
-pembrolizumab
What are the brand names of nivolumab and pembrolizumab?
nivolumab (Opdivo)
pembrolizumab (Keytruda)
Name PD-L1 agents
not discussed in class
-atezolizumab (Tecentriq)
-avelumab (Bavencio)
-durvalumab (Imfinzi)
-cosibelimab
Which drugs are used to manage the side effects of Immune Checkpoint inhibitors? (ICI)
high dose of corticosteroids, may add another immunosuppressant
-prednisone and infliximab
for hypothyroidism: levothyroxine
CD-20 are expressed in what type of immune cells?
B-cells
Which drug binds to CD20? What is its MOA?
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
What are the unique toxicities of Rituximab?
-infusion reactions
-reactivating of Hep B virus
check Hep serum !!!
What are the premeds for Rituximab and how do we administer the drug to check for infusion reaction?
-premeds: Tylenol and Benadryl
start at a low rate and check for reactions
Why can we start at a higher rate with 2nd cycle of Rituximab?
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
What is the single mutation that causes CML?
Translocation of chromosomes 9 and 22
fused chromosome (Philadelphia chromosome)
bcr-abl
Which drug is used for CML and what is its MOA?
Imatinib
prevents ATP binding to the pocket of the BCR-ABL fusion protein (the BCR-ABL needs ATP to work)
