Chemo Lecture 6: Targeted Therapy and biologicals

Question 1

MOA and therapeutic use of imatinib

Answer 1

• Imatinib occupies the ATP cofactor binding sites on Bcr, Abl fusion gene of CML, inhibiting transfer of phosphate to tyrosine on substrates.
• GIST ( imatinib inhibits c-kit and PDGFR)

Question 2

Therapeutic use of Dasatinib

Answer 2

• primary and imatinib resistant CML (inhibits bcr-abl)

- GIST (dasatinib inhibits Src family)

Question 3

Mechanism of imatinib resistance

Answer 3

• mutation of ATP binding pocket to exlcude imatinib

- Dasatinib can overcome imatinib resistance

Question 4

Main adverse effects of imatinib

Answer 4

many drug interactions due to hepatic CYP450. Agents that induce CYP450 (e.g. st johns wort, rifampin) hasten clearance of imatinib

Question 5

List drugs that are membrane associated receptor tyrosine kinase inhibitors

Answer 5

• Gefitnib
• Erlotinib
• Lapatinib
• Sunitinib
• Sorafenib

Question 6

Erlotinib and gefitinib target which receptor and thus is useful for what cancer?

Answer 6

Blocks EGFR, useful for NSCLC

Question 7

Lapatinib blocks what receptors and thus is useful for what cancer?

Answer 7

EGFR and HER2, useful for breast cancer

Question 8

Sunitinib blocks what receptors and thus are useful for what cancers

Answer 8

Blocks C-kit, PDGFR, VEGFR, useful for GIST and RCC

Question 9

Sorafenib blocks what receptor and thus used for what cancer?

Answer 9

blocks PDGFR and VEGFR, useful for RCC and HCC

Question 10

What drug blocks mutated form of BRAF kinase (V600E), and used for what cancer?

Answer 10

Vemurafenib, used for melanoma

Question 11

which antibodies target EGFR

Answer 11

Cetuximab and panitumumab

Question 12

Which antibody target HER2

Answer 12

Transtuzumab

Question 13

Which antibody targets VEGF?

Answer 13

Bevacizumab

Question 14

What is cetuximab used for?

Answer 14

Colorectal; head and neck cancers

Question 15

What is panitumumab used for?

Answer 15

Colorectal cancer (w/o KRAS mutation)

Question 16

What is trastuzumab used for?

Answer 16

HER2+ breast cancer

Question 17

What is bevacizumab used for?

Answer 17

RCC

Question 18

Why is mutational status of KRAS a determinant of response to antibodies that inhibit EGFR activation?

Answer 18

Mutational activation of Ras can by-pass the upstream effect on EGFR tyrosine kinase

Question 19

what drugs are used as angiogenesis inhibitors?

Answer 19

• Bevacizumab (antibody): targets VEGF and stop angiogenesis and tumor progression
• Sunitinib and sorafenib (RTK inhibitors)

Question 20

Side effect of Bevacizumab

Answer 20

• Severe high BP
• Bleeding
• Heart attack or HF
• damage to body parts

Question 21

Why does RCC respond well to angiogenesis inhibitors?

Answer 21

RCC with VHL mutation governs degradation and clearance of hypoxia inducible factor (HIFa) transcription factory family which allows HIF proteins to accumulate and activate VEGF and PDGF. Angiogenesis inhibitors blocks VEGF

Question 22

antibody drug used to treat B cell lymphoma

Answer 22

Rituxomab (anti-CD20).

Question 23

MOA of rituxomab

Answer 23

1. recruits complemnt proteins
2. recruits NK cells, T cells, macrophages
3. Binding of antibody signals apoptosis