Additional Oncologic Agents (Wendt)

Question 1

What are the two main problems associated with targeting RAS for direct inhibition?

Answer 1

• RAS binds GTP at very low concentrations
• allosteric sites on RAS have not been identified

Question 2

Give an example of a KRAS G12C inhibitor.

Answer 2

Sotorasib (Lumakras)

Question 3

Lumakras forms an irreversible, covalent bond with the ________ residue of KRAS G12C.

Answer 3

cysteine

Question 4

What is absolutely required for indication of sotorasib?

Answer 4

identification of the G12C mutation via an FDA-approved test

Question 5

Identify the drug based on its structure.

Answer 5

Sotorasib (Lumakras)

Question 6

Beyond phosphorylation, what other posttranslational modifications (PTMs) can affect protein function?

Answer 6

acetylation and methylation

Question 7

Acetylation of histones correlates with __________ activity.

Answer 7

transcriptional

Question 8

Deacetylation of histones promotes the converesion of heterochromatin and prevents transcription of _______________.

Answer 8

tumor suppressor genes

Question 9

Give an example of an HDAC inhibitor.

Answer 9

Romidepsin (Istodax)

*also vorinostat and belinostat*

Question 10

What is romidepsin indicated for?

Answer 10

treatment of cutaneous and peripheral T-cell lymphoma in patients who have received at least one prior therapy

Question 11

What is the most prevalent warning that should be given to patients taking Istodax?

Answer 11

infections (reactivation of DNA viruses)

Question 12

True or false: romidepsin is a prodrug.

Answer 12

true

Question 13

Give an example of an EZH2 inhibitor.

Answer 13

tazemetostat

Question 14

What does EZH2 do?

Answer 14

methylates histones leading to the repression of tumor suppressor genes

Question 15

What is tazemetostat currently approved for?

Answer 15

certain sarcomas and lymphoma

Question 16

Identify the drug based on its structure.

Answer 16

tazemetostat

Question 17

Give an example of a DNMT inhibitor.

Answer 17

Azacitidine (Onureg)

Question 18

How are DNMT inhibitors and HDAC inhibitors similar?

Answer 18

they both result in the activation of tumor suppressor genes

Question 19

What is Onureg indicated for?

Answer 19

treatment of patients with myelodysplastic syndrome (MDS)

Question 20

Mechanistically, how does azacitidine inhibit DNMT?

Answer 20

it incorporates into DNA, covalent binds DNMT enzymes, and prevents their function to result in a DNA adduct

Question 21

Identify the drug based on its structure.

Answer 21

Azacitidine (Onureg)

Question 22

What do proteasomes do?

Answer 22

break down misfolded proteins

Question 23

Through what process are proteins targeted for degradation by proteasomes?

Answer 23

ubiquitination

Question 24

Why are multiple myelomas good targets for proteasome inhibition?

Answer 24

they make lots of proteins (i.e. antibodies)

Question 25

Give an example of a proteasome inhibitor.

Answer 25

Bortezomib (*Velcade*), Carfilzomib (*Kyprolis*), Ixazomib (*Ninlaro*)

Question 26

What is *Velcade* indicated for?

Answer 26

treatment of multiple myeloma

Question 27

Which proteasome inhibitor lacks the neuropathy side effects of *Velcade*?

Answer 27

Carfilzomib (*Kyprolis*)

Question 28

Which proteasome inhibitor is taken orally in a prodrug form?

Answer 28

Ixazomib (*Ninlaro*)

Question 29

Identify the drug based on its structure.

Answer 29

Bortezomib (*Velcade*)

Question 30

What protein does thalidomide bind to in order to increase protein degradation?

Answer 30

cereblon (CRBN)

Question 31

Thalidomide leads to the degradation of several proteins, including which developmental transcription factor?

Answer 31

SALL4

Question 32

Beyond being a potent teratogen, what other toxic element is important to note with thalidomide?

Answer 32

active component of proteolysis targeting chemeras (PROTACs)

Question 33

Pomalidomide is an analog of what drug?

Answer 33

thalidomide

Question 34

What indication is pomalidomide approved for?

Answer 34

multiple myeloma and Kaposi sarcoma

Question 35

How is pomalidomide regulated?

Answer 35

POMALYST risk evaluation and mitigation strategy (REMS)...must be prescribed/dispensed by certified providers

Question 36

Give an example of a BCL-2 inhibitor.

Answer 36

Venetoclax (*Venclexta*)

Question 37

What is BCL-2?

Answer 37

a protein overexpressed in many tumor cells that contributes to apoptotic resistance

Question 38

What indications has *Venclexta* been approved for?

Answer 38

* chronic lymphocytic leukemia (CLL) * acute myeloid leukemia (in combination with azacytidine)

Question 39

Identify the drug based on its structure.

Answer 39

Venetoclax (*Venclexta*)

Question 40

What is the natural binder of RANKL?

Answer 40

osteoprotegrin (OPG)

Question 41

Give an example of a RANKL inhibitor.

Answer 41

denosumab

Question 42

What is denosumab indicated for?

Answer 42

multiple myeloma and advanced breast/prostate cancer

Question 43

What characteristic makes bisphosphonates effective in treating metastatic bone disease?

Answer 43

They are analogs of pyrophosphate, a constituent of the bone matrix

Question 44

Give three examples of bisphosphonates.

Answer 44

zoledronic acid, bisphosphonic acid, pyrophosphoric acid