Drugs Targeting Protein Function

Question 1

What drugs inhibit EGFR?

Answer 1

Cetuximab, Erlotinib, Gefitinib, Panitumumab

Question 2

What drugs inhibit HER2?

Answer 2

Pertuzumab, Trastuzumab

Question 3

What do tyrosine kinases do?

Answer 3

regulators of intracellular signal transduction pathways

Question 4

What role do Tyrosine kinases play in cancer?

Answer 4

TK receptors are often mutated or overexpressed in cancers

-signal transduction inhibitors and abs made to target these

Question 5

What is overexpressed in many epithelial-derived cancers?

Answer 5

EGFR

Question 6

What is the MOA for Cetuximab and Panitumumab?

Answer 6

Mabs against EGFR to prevent actions of EGFR + identify cells that express the receptor for degradation

Question 7

What are the unique toxicities associated with Cetuximab and Panitumumab?

Answer 7

skin (rash, photosensitivity, necrotizing fasciitis), lung (interstitial lung disease)

Question 8

What is the MOA for Trastuzumab?

Answer 8

interferes with Her2 signaling + identifies Her2-overexpressing cells for degradation

Question 9

What is the MOA for pertuzumab?

Answer 9

dimerization inhibitor - prevents Her2 from dimerizing with other HER receptors

Question 10

What is the MOA for Ado-Trastuzumab Emtansine?

Answer 10

internalized and degraded in lysosomes to form Trastuzumab + DM1 (inhibits microtubules by binding tubulin)

Question 11

What resistance forms to Trastuzumab/pertuzumab?

Answer 11

altering Her2 so ab cannot recognize it

Question 12

What are the toxicities of Trastuzumab?

Answer 12

infusion/hypersensitivity rxns, infections, birth defects/fetal loss

unique: ventricular dysfunction and CHF

Question 13

What is the major difference between drugs that target mutated/overexpressed proteins and drugs that target altered intracellular processes?

Answer 13

the later tends to be less specific for cancer - more AE

Question 14

What is the mechanism that L-asparaginase uses to deplete asparagine?

Answer 14

asparagine is converted to aspartate so that cancer cells cannot directly transport asparagine into the cell –> die due to lack of asparagine

Question 15

How does L-asparaginase have selective toxicity?

Answer 15

ALL cancer cells lack asparagine synthase, so they cannot transport aspartate; normal cells can transport aspartate

Question 16

Why is L-asparaginase often given with Mtx?

Answer 16

Mtx given FIRST, L-asparaginase given SECOND has synergistic cytotoxicity (more total cells killed than using either alone; timing matters)

Question 17

What drugs inhibit proteosomes?

Answer 17

Bortezomib, Carfilzomib

Question 18

What is the MOA for Bortezomib/ Carfilzomib?

Answer 18

inhibit the 26S proteosome –> triggers apoptosis

Question 19

What are the toxicities associated with Bortezomib/ Carfilzomib?

Answer 19

thrombocytopenia, neutropenia, anemia, peripheral neuropathy

Question 20

What drugs inhibit HDACs?

Answer 20

Romidepsin, Vorinostat

Question 21

What is the MOA for Romidepsin, Vorinostat?

Answer 21

inhibit HDAC –> increase transcription –> cell cycle arrest and apoptosis result

Question 22

What do HDACs do in cancer?

Answer 22

work with HAT to regulate gene expression - cancer cells can overexpress/recruit HDACs –> prevent transcription –> silence tumor suppressor genes

Question 23

What are toxicities associated with Romidepsin/ Vorinostat?

Answer 23

Hemato: PE, DVT

Drug-Drug interactions: valproic acid, Warfarin (causes warfarin to increase - bleeding)

Question 24

What are the drugs that induce differentiation?

Answer 24

Tretinoin (Atra, Retin-A), Arsenic Trioxide (ATO), Bexarotene

Question 25

MOA for differentiating agents

Answer 25

induce tumor cell differentiation to ultimately lead to apoptosis

Question 26

What differentiation block occurs in APL?

Answer 26

fusion protein PML-RAR-alpha has retinoic receptor and promyelocytic leukemia protein, t(15;17)

Question 27

What is the MOA for tretinoin?

Answer 27

activates differentiation and promotes degradation of PML-RAR fusion protein; used to treat APL

Question 28

Why is arsenic trioxide or anthracycline abx given with tretinoin?

Answer 28

tretinoin doesn’t kill cells - other drugs cause cell death

Question 29

What are the toxicities for Tretinoin?

Answer 29

• CNS toxicity
• Differentiation syndrome (fever, dyspnea, wt gain, pulmonary infiltrates) w/ or w/o pleural and pericardial effusions and leukocytosis
• birth defects

Question 30

What is the MOA for Arsenic Trioxide?

Answer 30

heavy metal toxin that promotes cell death thru apoptosis and necrosis; causes death of granulocytes when given with Tretinoin

Question 31

What are the toxicities associated with Arsenic Trioxide?

Answer 31

arrhythmia, leukocyte maturation syndrome

Question 32

What is the MOA for Bexarotene?

Answer 32

rexinoid - activates retinoid X receptors involved in differentiation

Question 33

Tx uses for Bexarotene

Answer 33

Cutaneous T-cell lymphoma

Question 34

How is Bexarotene metabolized?

Answer 34

CYP34A

Question 35

What are the toxicities associated bexarotene?

Answer 35

lipid abnormalities and pancreatitis, teratogenic