mTOR Inhibitors

Question 1

What are the two mTOR inhibitors?

Answer 1

• Everolimus

- Temsirolimus

Question 2

What are there 3 MOA?

Answer 2

1. Reducing cell growth and proliferation
2. Prevention of angiogenesis
3. Synergy with drugs that damage DNA

Question 3

What does reducing cell growth and proliferation do to the cancer cell?

Answer 3

1. Decreased cell cycle progression
   - mTOR regulates protein synthesis of cyclin D1, which controls progression through the G1/S checkpoint
   - –Important when cyclin D1 is overexpressed (e.g. mantle cell lymphoma)
2. Reduced bioenergetics
   - Cancer cells rely on glycolysis to provide ATP
   - mTOR increases expression of amino acid and glucose transporters, which are unregulated in several cancers
   - –> mTOR inhibition decreases access to nutrient and metabolic fuel

Question 4

What does preventing angiogenesis do to the cancer cell?

Answer 4

• Decreasing synthesis and release of angiogenic growth factors (esp. VEGF and PDGF) from the cancer cells
• Blocking growth and proliferation of vascular cells

Question 5

What does synergy with drugs that damage DNA do to cancer cells?

Answer 5

• DNA damage activates p53, which either triggers DNA repair or initiates cell death (if the DNA cannot be repaired)
• –p53 controls transcription of the gene encoding p21, a cell cycle inhibitor that allows DNA repair to occur
• mTOR regulates translation of p21 –> mTOR inhibition prevents p21-mediated cell cycle arrest
• –Increases the likelihood that the DNA-damaged cell will progress through the cell cycle, and die (remember the discussion of alkylating agents and p53)

Question 6

What are the pharmacokinetics of mTOR inhibitors?

Answer 6

• Oral admin; must be taken consistently (either with or without food) in order to minimize variability in drug concentration
• Metabolized by CYP 3A4 (drug interactions)
• Substrate for P-glycoprotein

Question 7

What are the side effects of mTOR inhibitors?

Answer 7

• Hypersensitivity
• Increased risk of lymphomas (like other immunosuppressants), particularly of the skin and infection
• Angioedema
• Kidney arterial and venous thrombosis
• Delays in wound healing
• Hyperlipidemia
• Nephrotoxicity and proteinuria
• Male infertility