Flashcards in Angiogenesis Inhibitors Deck (24)
-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
How do angiogenesis inhibitors work?
Interfering with the actions of substances that promote angiogenesis --> VEGF and mTOR
What do mTOR inhibitors do?
Reduce cell growth and proliferation, prevent angiogenesis and increase the cytotoxicity of drugs that damage DNA
What do primary tumors suppress everywhere?
What clinical phenomenon happens after a primary tumor has been removed through surgery?
-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
What is rebound angiogenesis?
-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
What are the types of anti-angiogenics?
1. Interleukin 12 (cross out - mimicked a suppressor)
2. Interferon alpha - see cytokine lecture
3. VEGF and VEGF-R inhibitors
-PAZOPANIB, SORAFENIB, SUNITINIB
4. mTOR inhibitors
What is mTOR?
-Serine/threonine kinase that plays a role in the control of cell growth and proliferation
What does mTOR sense?
Changes in availability of growth factors and/or energy sources, and induces synthesis of proteins necessary for angiogenesis, cell growth/survival and nutrient uptake
What proteins are regulated by mTOR?
-Cell cycle regulators (cyclin D1)
-Amino acid and glucose transporters
-Proangiogenic factors (transcriptional regulators of VEGF and PDGF)
-Enzymes required for DNA repair
How is mTOR involved in cancer?
It is frequently activated in cancer cells as part of the process that leads to uncontrolled proliferation
What is VEGF-R and what does it do?
-Tyrosine kinase receptor that activates mTOR in order to promote angiogenesis
What does increased mTOR activity in cancer cells do?
-->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
What is Bevacizumab?
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
What is Ranibizumab?
Derivative of Bevacizumab
-Promoted by drug company as preferred treatment for macular degeneration bc it costs 1,500/injection while Beva costs 50/injection
What side effects beyond those common to antibodies does Bevacizumab have?
-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
What are the STIs of VEGF-R?
What is the MOA for Sorafenib, Pazopanib, Sunitinib?
-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
What are the therapeutic uses for Pazopanib, Sorafinib, Sunitinib?
1st line of treatment for renal cell carcinoma
-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
What are the pharmacokinetics of Pazopanib, Sorafinib and sunitinib?
-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)
What are toxicities for Pazopanib, Sorafinib, Sunitinib?
-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
What are the specific side effects of Pazopanib?
Severe (fatal) hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perforation and hypertension
What are the specific side effects for Sorafenib?
Increased risk of hemorrhage, hypertension