Targeted Therapies EXAM 2 Flashcards by o e

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

epithelial cells
-Skin
-GI

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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)

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How are EGF receptors activated in healthy epithelial cells?

by phosphorylation (PI3K)

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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

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

AKT phosphorylates mTOR
-> gene activation

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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)

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Which cancer type is predominantly affected by overexpression of EGFR?

head and neck cancer

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

Monoclonal antibodies

-Cetuximab (Erbitux)
-panitumumab (Vectibix)

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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

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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)

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

Panitumumab (Vectibix)

mumab = human origin

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

Tyrosine-Kinase inhibitors

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

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Name some of the Tyrosine-Kinase inhibitors

-inib

erlotinib
gefitinib
afatinib
lapatinib (also target HER2)
lazertininb
osimertinib

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

-osimertinib (newer generation)

less diarrhea and rash compared to the other ones

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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

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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

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Why is HER2 a good target for cancer drugs?

because it is overexpressed and can be targeted by the drug

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tissues and orgnas that have HER2 overexpression

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

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What is the unique toxicity of HER2 mAb therapy?

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

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Which other anticancer drug causes cardiomyopathy?

REMINDER

Anthracyclines

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Name the MAb that targets HER2.

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

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

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

3x emtansine conjugated to the mAb

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Explain the MOA of Ado-trastuzumab

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

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What side effects are seen with Ado-trastuzumab?

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

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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)

Targeted Therapies EXAM 2 Flashcards

(69 cards)