Lecture 8

Question 1

CML (Chronic Myelogenous Leukemia)

Answer 1

Characteristics: increased number of granulocytes and their precursors in the peripheral blood

Question 2

Philadelphia Chromosome

Answer 2

Comes from a chromosomal translocation between chromosomes 9 & 22 (responsible for CML)

Question 3

Bcr-Abl

Answer 3

Oncogene produced by the chromosomal translocation in CML
- non receptor tyrosine kinase

Question 4

Gleevec pt. I

Answer 4

Primary drug used for targeted therapy of CML
Tyrosine kinase inhibitor

Question 5

Gleevec pt. II

Answer 5

Success: almost all CML patients have a complete response to Gleevec
For most patients responses last for years but drug resistance develops in ~10-15% of patients

Question 6

Gleevec Resistance

Answer 6

Bcr-Abl gene amplification & mutation of Bcr-Abl decreases Gleevec binding affinity
Treated using Dasatinib

Question 7

Metastatic Melanoma

Answer 7

Generated by mutated melanocytes

Question 8

B-raf (V600E)

Answer 8

Primary driver oncogene for metastatic melanomas
Serine/threonine kinase

Question 9

PLX 4032 (Zelboraf)

Answer 9

Treated metastatic melanomas and targeted B-raf (V600E)
Also inhibits regular B-raf but at a 10-fold higher drug concentration

Question 10

PLX 4032 pt. II

Answer 10

High % of patients achieved large success responses, but resistance developed

Question 11

Resistance to PLX 4032

Answer 11

Up-regulation of PDGF receptors which activated a new survival pathway
Also mutation of N-ras which stimulated c-RAF to reactivate MAPK survival pathways