Additional Anti-Cancer Agents_Edit

Question 1

Problems targeting RAS

Answer 1

1. Ras binds GTP at very low concentrations

2. Allosteric sights on RAS have not been identified

Question 2

Sotorasib does what

Answer 2

forms and irreversible, covalent bond with the cysteine residue of KRAS G12C, holding the PRT in its inactive form that blocks downstream signaling

Question 3

Sotorasib indication

Answer 3

requires identification of G12C mutation by an FDA approved test

Question 4

Romidepsin (Istodax) does what

Answer 4

Inhibition of histone deacetylases (HDACs) promotes euchromatin leading to reexpression of tumor suppressor genes and tumor cell death.

Question 5

Romidepsin indication

Answer 5

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

also vorinostat and belinostat

Question 6

Tazemetostat does what

Answer 6

• Inhibits the methyltransferase activity of EZH2
• EZH2 can be mutated to become constitutively active in several cancers
• EZH2 is responsible for methylation of histones (H3K27me3) leading to the repression of tumor suppressor genes.

Question 7

Tazemetostat indication

Answer 7

Tazemetostat is approved for certain sarcomas and lymphomas

Question 8

Azacitidine does what

Answer 8

• Similar to HDAC inhibitors DNMT inhibitors result in the reactivation of tumor suppressor genes.
• Incorporates into DNA and covalently binds DNMT enzymes, preventing their function and resulting in a DNA adduct.

Question 9

Azacitidine indication

Answer 9

indicated for the treatment of patients with myelodysplastic syndrome (MDS)

Question 10

Targeting the Proteasome

Answer 10

• The proteasome breaks down misfolded proteins and proteins gets targeted for degradation by ubiquitination
• Utilized in cell signaling and in normal protein turn over.
• Multiple myeloma cells make a lot of proteins (i.e. antibodies) so they are good targets for proteasome inhibition.
• Cancer cells have to degrade more “bad” proteins than normal cells

Question 11

Bortezomib

Carfilzomib

Ixazomib

Answer 11

• Inhibitors of proteasome activity
• **26S proteasome degrades ubiquinated proteins
• **Ubiquitin-proteasome pathway critical to regulation of intracellular proteins
• **Disruption of intracellular protein homeostasis leads to cell death
• Indicated for the treatment of multiple myeloma (B-cell malignancy). These cells naturally make a lot of proteins, i.e. antibodies
• Carfilzomib lacks the neuropathy side affects of Bortezomib
• Ixazomib is taken orally in a prodrug form

Question 12

Thalidomide

Answer 12

• Interesting drug with a stormy history
• Thalidomide has anti-angiogenic activity
• Binds to a ubiquitin ligase protein called cereblon (CRBN) and increases protein degradation.
• Leads to degradation of several proteins, including the developmental transcription factor SALL4
• Toxicity
• **Potent teratogen! Extraordinary precautions taken to prevent pregnancy
• **Active component of Proteolysis targeting chemeras (PROTACs)

Question 13

Pomalidomide

Answer 13

• analog of thalidomide
• Approved for the treatment of multiple myeloma and Kaposi sarcoma
• Regulated by a POMALYST risk evaluation and mitigation strategy (REMS). Required certification to be prescribed and dispensed

Question 14

Venetoclax

Answer 14

• BCL-2 is an anti-apoptotic protein overexpressed in the several tumor cells and contributes to apoptotic resistance.
• Venetoclax a BCL-2 inhibitor that drives cell death via apoptosis
• Approved in April 2016 for the treatment of chronic lymphocytic leukemia (CLL). Approved in 2020 in combination with azacitindine for AML.
• High potential for combination therapies here.

-1st FDA approved small molecule that
inhibits a protein-protein interaction

Question 15

Bisphosphonates used for

Answer 15

bone metastasis

Question 16

Osteoprotegerin (OPG) also binds

Answer 16

RANKL

Question 17

Denosumab

Answer 17

• Antibody that binds RANKL and prevents its interaction with RANK on osteoclasts
• Interupts this “viscous cycle” of bone remodeling that is associated with bone metastasis
• Approved for multiple myeloma and advanced breast and prostate cancer
• Osteoprotegerin (OPG) is the natural binder of RANKL

Question 18

Application of Bisphosphonates for metastatic Bone Disease

Answer 18

• Bisphosphonates are analogs of pyrophosphate, a constituent of the bone matrix.
• Bisphosphonates efficiently attach to bone mineral surface.
• During bone resorption, osteoclasts release bisphosphonates embedded in the bone matrix.
• Bisphosphonates are taken up by osteoclasts and substantially inhibit bone resorption.
• This inhibits the vicious cycle of abnormal bone remodeling that occurs in metastatic cancer

Question 19

Bisphosphonate Examples

Answer 19

• Zoledronic acid
• Bisphosphonic acid
• Pyrophosphoric acid