Angiogenesis Inhibitors

Question 1

Angiogenesis:

Answer 1

• All tissues (including tumors) secrete substances that promote or inhibit angiogenesis (the formation of new blood vessels
• Once a group of cancer cells reaches a certain size (~1-2 mm in diameter), it must develop a blood supply in order to grow, bc. diffusion is no longer adequate to supply the cells with O2 and nutrients and to take away the wastes

Question 2

How do angiogenesis inhibitors work?

Answer 2

Interfering with the actions of substances that promote angiogenesis –> VEGF and mTOR

Question 3

What do mTOR inhibitors do?

Answer 3

Reduce cell growth and proliferation, prevent angiogenesis and increase the cytotoxicity of drugs that damage DNA

Question 4

What do primary tumors suppress everywhere?

Answer 4

Angiogenesis

Question 5

What clinical phenomenon happens after a primary tumor has been removed through surgery?

Answer 5

• Some weeks later, metastases of the tumor appear throughout the patient’s body
• Speed and appearance of 2ndary tumors indicates that they were present all along, but were too small to be detected
• –Justification for chemotherapy as an adjunct to surgery for the treatment of solid cancers

Question 6

What is rebound angiogenesis?

Answer 6

• Rapid growth of cancer when an angiogenesis inhibitor is stopped
• First described in animal models but also observed in patients with gliomas, where these is rapid, aggressive regrowth of the tumors after BEVACIXIMAB treatment is stopped

Question 7

What are the types of anti-angiogenics?

Answer 7

1. Interleukin 12 (cross out - mimicked a suppressor)
2. Interferon alpha - see cytokine lecture
3. VEGF and VEGF-R inhibitors
   - BEVACIZUMAB
   - PAZOPANIB, SORAFENIB, SUNITINIB
4. mTOR inhibitors
   - Everolimus, Temsiroliumus
5. Thalidomide

Question 8

What is mTOR?

Answer 8

-Serine/threonine kinase that plays a role in the control of cell growth and proliferation

Question 9

What does mTOR sense?

Answer 9

Changes in availability of growth factors and/or energy sources, and induces synthesis of proteins necessary for angiogenesis, cell growth/survival and nutrient uptake

Question 10

What proteins are regulated by mTOR?

Answer 10

• Cell cycle regulators (cyclin D1)
• Amino acid and glucose transporters
• Proangiogenic factors (transcriptional regulators of VEGF and PDGF)
• Enzymes required for DNA repair

Question 11

How is mTOR involved in cancer?

Answer 11

It is frequently activated in cancer cells as part of the process that leads to uncontrolled proliferation

Question 12

What is VEGF-R and what does it do?

Answer 12

-Tyrosine kinase receptor that activates mTOR in order to promote angiogenesis

Question 13

What does increased mTOR activity in cancer cells do?

Answer 13

• ->causes secretion of VEGF and PDGF –> angiogenesis due to increased mTOR activity in vascular cells
• -Therefore, dec. activity of VEGF/VEGF-R and mTOR can result in a synergistic cell kill

Question 14

What is Bevacizumab?

Answer 14

Humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF)

• Approved (in combination with 5-FU) for first-line treatment of metastatic colorectal cancer, lung cancer, breast cancer (controversial)
• –Being investigated in many other cancers, esp. GBM
• –Also approved for use in macular degeneration and diabetic neuropathy

Question 15

What is Ranibizumab?

Answer 15

Derivative of Bevacizumab
-Promoted by drug company as preferred treatment for macular degeneration bc it costs 1,500/injection while Beva costs 50/injection

Question 16

What side effects beyond those common to antibodies does Bevacizumab have?

Answer 16

• Gastrointestinal perforation, wound dehiscence and hemoptysis, which can be fatal
• There is concern that Bevacizumab can worsen coronary or peripheral artery disease by prevention the sprouting of new vessels

Question 17

What are the STIs of VEGF-R?

Answer 17

• Pazopanib
• Sorafinib
• Sunitinib

Question 18

What is the MOA for Sorafenib, Pazopanib, Sunitinib?

Answer 18

• Receptors for VEGF and PDGF are receptor tyrosine kinases
• Much less specific than IMATINIB (i.e., they block multiple kinases)
• Sorafenib = blocks Raf
• Pazopanib, Sunitinib = block c-KIT

Question 19

What are the therapeutic uses for Pazopanib, Sorafinib, Sunitinib?

Answer 19

1st line of treatment for renal cell carcinoma

• Cost controversy
• SUNITINIB is one of the most expensive drugs ever marketed, doesn’t cure cancer but only prolongs life
• Cost for Pazopanib and Sunitinib are in the 30-130,000 range
• 25% of patients with insurance said that they postponed or declined treatment because of cost

Question 20

What are the pharmacokinetics of Pazopanib, Sorafinib and sunitinib?

Answer 20

• Same PK as for STIs that block bcr-abl and HER2:
• -Oral admin; good bioavailability
• -Highly plasma protein bound
• -Metabolized in liver (CYP 3A4), and excreted in the feces (hepatobiliary excretion)

Question 21

What are toxicities for Pazopanib, Sorafinib, Sunitinib?

Answer 21

• Same as STIs that block bcr-abl and HER2:
• -relatively minor side effects (esp. compared to drugs that prevent rapid cell growth): nausea, vomiting, fatigue, myalgia, diarrhea, skin rashes, acne, drug interactions
• Congestive heart failure and decreased left ventricular ejection fraction (causing shortness of breath, palpitations, fatigue) and/or myocardial infarction
• –incidence and severity vary widely within STIs; less sever for these agents
• TERATOGENIC

Question 22

What are the specific side effects of Pazopanib?

Answer 22

Severe (fatal) hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perforation and hypertension

Question 23

What are the specific side effects for Sorafenib?

Answer 23

Increased risk of hemorrhage, hypertension

Question 24

What are the specific side effects for Sunitinib?

Answer 24

Skin discolouration, hand-foot syndrome (palmar-plantar erythrodysesthesia)