Fitzy 6: Targeted Therapy and biologicals

Question 1

What mutation does CML have?

Answer 1

the philadelphia chromosome t(9;22)

Question 2

What fusion ptn does the ph chromosome make?

Answer 2

the BRC-ABL fusion ptn

Question 3

What does BCR-ABL do that is bad?

Answer 3

continuous tyr kinase activity

-promotes the prliferation of CML cells

Question 4

What drug is an inhibitor of the Bcr-Abl tyr kinase?

Answer 4

imatinib

• effective tx of CML
• inhibits the prolifeation and survival of leukemic cells
• occupies the ATP cofactor binding site on the Bcr-ABL, inhibiting transfer of phosphate to tyrosine on substrates

Question 5

What drug is used for tx of primary and imatinib resistant CML?

Answer 5

Dasatinib

Question 6

What is an easy way to resist imatinib?

Answer 6

have a mutation that changes the ATP binding site, excluding imatinib
-Dasatinib can overcome this resistance

Question 7

What is the therapeutic use of imatinib?

Answer 7

CML, and GIST (because it works for c-kit and PDGFR as well…. another tyr kinase)

Question 8

What is the therapeutic use of dasatinib?

Answer 8

imatinib resistant CML, and Ph+ALL

Question 9

what do 85% of GIST tumors contain?

Answer 9

oncogenic forms of a RTK: either KIT or PDGFR

-use imatinib to stop it

Question 10

What do we use for imatinib resistant GIST?

Answer 10

sunitinib

Question 11

Adverse effects of imatinib

Answer 11

• lots of drug interactions
• CYP450 use….
• idiots taking St. John’s wort induce CYP450 and hasten clearance of imatinib

Question 12

list the membrane associated RTK inhibitors

Answer 12

Gefitinib
Erlotinib
Lapatinib
Sunitinib
Sorafenib

Question 13

Which gene is overexpressed in breast cancers?

Answer 13

HER2

Question 14

Which drugs are used for the EGFR membrane bound RTK?

Answer 14

Lapatinib
Gefitinib
Erlotinib

Question 15

Which drugs are used for the HER2 receptor?

Answer 15

LApatinib

-Her sat on his lap

Question 16

Which drugs are used for the PDGFR and VEGFR membrane bound RTKs?

Answer 16

Sunitinib

Sorafenib

Question 17

Which cancer is treated with Erlotinib and Gefitnib?

Answer 17

NSCLC

-uses EGFR

Question 18

Which cancer is treated with Lapatinib?

Answer 18

Breast Cancer

• EGFR
• HER2

Question 19

Which cancer is treated with Sunitinib?

Answer 19

GIST and RCC

• PDGR
• VEGFR
• c-kit

Question 20

Which cancer is treated with Sorafenib

Answer 20

RCC and HCC

• PDGFR
• VEGFR

Question 21

What does Vemurafenib do?

Answer 21

inhibits a different kinase in the signaling pathway that propagates oncogenic signaling
-it’s BRAF: a ser/thr kinase that can be activated by ras or by its mutation

Question 22

Which mutant form of BRAF does Vemurafinib specifically inhibit?

Answer 22

BRAF V600E

Question 23

Which antibodies get the EGFR receptor?

Answer 23

Cetuximab and panitumumab

Question 24

Which antibodies get BRC-ABL?

Answer 24

none of them!

Question 25

Which antibodies get Her2

Answer 25

Trastuzumab

Question 26

What antibodies get PDGFR and VEGFR

Answer 26

none approved

Question 27

Which antibodies get the VEGF ligand?

Answer 27

Bevacizumab

Question 28

What is Cetuximab used for

Answer 28

Colorectal and head and neck cancers

-tumors with KRAS mutation are unresponsive

Question 29

What is Panitumumab used for?

Answer 29

Colorectal cancer

-still… except for the ones with KRAS mutations

Question 30

What is trastuzumab used for?

Answer 30

HER2+ breast cancer

Question 31

What is Bevacizumab used for?

Answer 31

Renal cell carcinoma (in red and bolded)

Question 32

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

Answer 32

• mutational activation of Ras can by-pass the upstream effect on EGFR
• remember that Ras is that second step in the RTK pathway, everything else gets activated from there

Question 33

How does Tumor angiogenesis occur?

Answer 33

via overproduction of VEGF

-the receptor for it is fine, it’s just that there’s so much of it because of the tumor cell

Question 34

What blocks VEGF?

Answer 34

Bevacizumab

Question 35

What does Bevacizumab actually target?

Answer 35

ligand VEGF, not the receptor

-remember that it’s just used to suppress the tumor’s blood supply

Question 36

What are the risks of Bevacizumab?

Answer 36

severe high blood pressure, bleeding, heart attack or heart failure, damage to different parts of the body, such as the nose, stomach, and intestines

Question 37

Why does RCC respond so well to angiogensis inhibitors?

Answer 37

it’s a highly vascularized tumor strongly dependent on VEGF, PDGF, and the cognate receptor tyrosine kinases for pathogenesis

Question 38

Which drugs work on RCC again?

Answer 38

Sunitib and sorafenib

-the antibody is still Bevacizumab

Question 39

What is Rituxomab used for?

Answer 39

CD20+ B cell lymphoma

Question 40

Where does Rituxomab act?

Answer 40

at the exterior surface, not the interior of cells
-P- glycoprotein has little effect on this class of drugs

Question 41

How does Rituxomab work?

Answer 41

• antibody recruits complement proteins, which punch holes int he cell membrane, floods cell
• antibody recruits NK cells, T cells, Macs,… they attack antibody-labeled tumor cells, leading to cell lysis
• binding of antibody signals the cell to self destruct (apoptosis)

Question 42

What should we consider about the timing of treatment with chemotherapy?

Answer 42

chemotherapy-induced myelosuippression can neutralize subsequent antibody-based therapy, until the bone marrow recovers
-antibody-based therapy may sensitize tumors to concurrent chemotherapy