Additional Oncologic Agents (Wendt) Flashcards
What are the two main problems associated with targeting RAS for direct inhibition?
- RAS binds GTP at very low concentrations
- allosteric sites on RAS have not been identified
Give an example of a KRAS G12C inhibitor.
Sotorasib (Lumakras)
Lumakras forms an irreversible, covalent bond with the ________ residue of KRAS G12C.
cysteine
What is absolutely required for indication of sotorasib?
identification of the G12C mutation via an FDA-approved test
Identify the drug based on its structure.
Sotorasib (Lumakras)
Beyond phosphorylation, what other posttranslational modifications (PTMs) can affect protein function?
acetylation and methylation
Acetylation of histones correlates with __________ activity.
transcriptional
Deacetylation of histones promotes the converesion of heterochromatin and prevents transcription of _______________.
tumor suppressor genes
Give an example of an HDAC inhibitor.
Romidepsin (Istodax)
*also vorinostat and belinostat*
What is romidepsin indicated for?
treatment of cutaneous and peripheral T-cell lymphoma in patients who have received at least one prior therapy
What is the most prevalent warning that should be given to patients taking Istodax?
infections (reactivation of DNA viruses)
True or false: romidepsin is a prodrug.
true
Give an example of an EZH2 inhibitor.
tazemetostat
What does EZH2 do?
methylates histones leading to the repression of tumor suppressor genes
What is tazemetostat currently approved for?
certain sarcomas and lymphoma
Identify the drug based on its structure.
tazemetostat
Give an example of a DNMT inhibitor.
Azacitidine (Onureg)
How are DNMT inhibitors and HDAC inhibitors similar?
they both result in the activation of tumor suppressor genes
What is Onureg indicated for?
treatment of patients with myelodysplastic syndrome (MDS)
Mechanistically, how does azacitidine inhibit DNMT?
it incorporates into DNA, covalent binds DNMT enzymes, and prevents their function to result in a DNA adduct
Identify the drug based on its structure.
Azacitidine (Onureg)
What do proteasomes do?
break down misfolded proteins
Through what process are proteins targeted for degradation by proteasomes?
ubiquitination
Why are multiple myelomas good targets for proteasome inhibition?
they make lots of proteins (i.e. antibodies)
Give an example of a proteasome inhibitor.
Bortezomib (Velcade), Carfilzomib (Kyprolis), Ixazomib (Ninlaro)
What is Velcade indicated for?
treatment of multiple myeloma
Which proteasome inhibitor lacks the neuropathy side effects of Velcade?
Carfilzomib (Kyprolis)
Which proteasome inhibitor is taken orally in a prodrug form?
Ixazomib (Ninlaro)
Identify the drug based on its structure.
Bortezomib (Velcade)
What protein does thalidomide bind to in order to increase protein degradation?
cereblon (CRBN)
Thalidomide leads to the degradation of several proteins, including which developmental transcription factor?
SALL4
Beyond being a potent teratogen, what other toxic element is important to note with thalidomide?
active component of proteolysis targeting chemeras (PROTACs)
Pomalidomide is an analog of what drug?
thalidomide
What indication is pomalidomide approved for?
multiple myeloma and Kaposi sarcoma
How is pomalidomide regulated?
POMALYST risk evaluation and mitigation strategy (REMS)…must be prescribed/dispensed by certified providers
Give an example of a BCL-2 inhibitor.
Venetoclax (Venclexta)
What is BCL-2?
a protein overexpressed in many tumor cells that contributes to apoptotic resistance
What indications has Venclexta been approved for?
- chronic lymphocytic leukemia (CLL)
- acute myeloid leukemia (in combination with azacytidine)
Identify the drug based on its structure.
Venetoclax (Venclexta)
What is the natural binder of RANKL?
osteoprotegrin (OPG)
Give an example of a RANKL inhibitor.
denosumab
What is denosumab indicated for?
multiple myeloma and advanced breast/prostate cancer
What characteristic makes bisphosphonates effective in treating metastatic bone disease?
They are analogs of pyrophosphate, a constituent of the bone matrix
Give three examples of bisphosphonates.
zoledronic acid, bisphosphonic acid, pyrophosphoric acid
