Antiangiogenesis & Combination Chemotherapy -Fitz

Question 1

Rebound Angiogenesis

Answer 1

Rapid growth of cancer when an angiogenesis inhibitor is stopped

Question 2

Drug that blocks VEGF

Answer 2

Bevacizumab

Question 3

Function of mTOR?

Answer 3

• serine/threonine kinase that plays a role in the control of cell growth and proliferation
• senses changes in availability of growth factors/energy sources

Question 4

VEGF-R function?

Answer 4

tyrosine kinase receptor that activates mTOR in order to promote angiogenesis

Question 5

Bevacizumab:

MOA?

Answer 5

antibody against VEGF
-first line tx for some cancers when in combo with 5-FU

-Ranibizumab is derivative but a lot more expensive

Question 6

Bevacizumab specific side effects?

Answer 6

• gastrointestinal perforation
• wound dehiscence and hemoptysis
• worsen coronary/peripheral artery disease by preventing the sprouting of new vessels

Question 7

STIs of VEGF-R?

Answer 7

Pazopanib, Sorafinib, Sunitinib

-less specific than Imatinib
Sorafenib –>Raf
Pazopanib and Sunitinib –> c-Kit

Question 8

What are the STIs of VEGF-R used for?

Pazopanib, Sorafinib, Sunitinib

Answer 8

1st line treatment for renal cell carcinoma

Question 9

What is the PKs of all STIs?

Answer 9

• oral, good bioavailability
• high plasma protein bound
• metabolized in the liver (CYP 3A4)

Question 10

What are the general toxicities for STIs?

Answer 10

• relatively minor side effects
• congestive heart failure
• myocardial infarction
• teratogenic

Question 11

Specific side effects of:
Pazopanib?
Sorafenib?
Sunitinib?

Answer 11

Pazopanib–> severe hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perforation, hypertension

Sorafenib–> increased risk of hemorrhage, hypertension

Sunitinib–> skin discoloration, hand-foot syndrome

Question 12

mTOR inhibitors MOA?

Answer 12

Everolimus, Temsirolimus

1. Reducing cell growth and proliferation
   
   • mTOR regulates protein synthesis of cyclin D1 (control for G1/S checkpoint)
   • mTOR increases expression of amino acid and glucose transporters –>mTOR inhibition decreases access to nutrient and metabolic fuel
2. Prevention of angiogenesis (VEGF and PDGF)
3. Synergy with drugs that damage DNA
   - Damaged DNA–> activates p53 –> p53 controls transcription of gene encoding p21 (cell cycle inhibitor that allows DNA repair)
   - mTOR regulates transcription of p21 –>mTOR inhibition prevents p21 mediated cell cycle arrest :)))

Question 13

mTOR inhibitors pharmacokinetics?

Answer 13

metabolized by CYP 34A

substrate for P-glycoprotein (MDR :( )

Question 14

mTOR inhibitors side effects?

Answer 14

• hypersensitivity
• immunosuppressants –> increased risk of lymphomas and infection
• angioedema
• kidney arterial and venous thrombosis

Question 15

Immunomodulatory Drugs (IMiDs)?

Answer 15

Lenalidomide
Pomalidomide
Thalidomide

Question 16

What diseases do we use Thalidomide for?

Answer 16

Hansen’s disease complication: Erythema nodosum leprosum (ENL)

Multiple myeloma

Question 17

Mechanism of Thalidomide?

Answer 17

• Unknown
• suppressing immune and inflammatory reactions
• alter the ratios of various types of immune cells and changes expression of molecular markers on their surfaces
• Antiangiogenic
• most effective anti-TNF agent (Th2 response over Th1)
• sedating and improves well being (restores appetite and decreases wasting)

Question 18

Toxicity of Thalidomide?

Answer 18

• peripheral neuropathy
• risk of deep vein thrombosis (esp in multiple myeloma pts on Warfarin and Thalidomide)

-severe TERATOGENIC EFFECTS

Question 19

Phocomelia?

Answer 19

hands and feet are attached to abbreviated arms and legs

-toxicity of Thalidomide in pregnant pts (effects children and grandchildren!)

Question 20

Benefits of giving antineoplastic drugs in combination?

Answer 20

• decreases development of resistance
• synergistic effects
• decreases toxic effects
• broader cell kill in cancers that consist of heterogeneous tumor cell population

Question 21

Pusle therapy:

Answer 21

intermittent treatment with very HIGH doses of drug, followed by drug-free periods

• allows hematologic and immunologic recovery
  ex: Methotrexate for tx of choriocarcinoma

Question 22

Rescue Therapy:

Answer 22

following administration of toxic doses of chemo agent, normal cells can be rescued by giving “antidotes” that only they can use

Ex: Leucovorin following high dose MTX tx

Question 23

Principles of drug selection for combo therapy?

Answer 23

• active when used alone
• different MOA or different chemical class
• CCNS vs CCS or active in different stages of cell cycle
• different toxicities

Question 24

Recruitment:

Answer 24

Use a CCNS drug to achieve a significant log kill

• cause cancer cells in G0 to be recruited back into cell cycle
• then administer CCS drug to kill dividing cells

Ex: CMF (cyclophos, MTX, 5-FU)
Daunorubicin + Cytarabine

Question 25

Synchrony:

Answer 25

Using CCS drugs to synchronize cells into simultaneous cell division so they are more sensitive to other drugs or radiation ``` Ex: Hydroxyurea then radiation Vinca alkaloids (M phase) then CCS drug like etoposide (S phase) ``` MTX then L-asparaginase for ALL