Transcript Combination of Pim kinase inhibitor with Bcl

Bethany LaVergne and Curt Phifer, Ph.D. at Northwestern State University
Fabiola Gomez, Ph.D. and Varsha Gandhi, Ph.D.; MD Anderson Cancer Center




“A disease in which abnormal cells divide
without control and can invade nearby
tissues” (NCI dictionary)
Enhanced survival mechanisms  difficult to
kill cancer cells
Physical, emotional, and financial impact
Prevention and treatment protocols for many
cancers are available







Leukemia = cancer of the blood
Lymphocytic = B-lymphocytes
Chronic = slow, gradual development
Patients are 60-80 years old; rarely under 40
Complications with immune system
Family history is good predictor of risk
Elevated levels of Bcl-2 and Pim kinase

ABT-737 (Abbot Labs) binds to and
sequesters Bcl-2

AZD-1208 (Astra Zeneca) inhibits Pim kinase
function





Blood samples were obtained from 7 CLL
patients and 1 healthy blood donor
Mononuclear cells (including B-lymphocytes)
were isolated from blood
Each sample was treated 24 hours total
Cell death determined by Annexin
V/Propidium iodide staining
Additive, Antagonistic, and Synergistic

1nm was used in
combination
treatments

3μM and 10μM
AZD-1208 were
determined
sufficient by a
similar
experiment
1nM ABT-737
3μM AZD-1208
10μM AZD-1208
1nM ABT-737 +
3μM AZD-1208
1nM ABT-737 +
10μM AZD-1208
1nM ABT-737
3μM AZD-1208
10μM AZD-1208
1nM ABT-737 +
3μM AZD-1208
1nM ABT-737 +
10μM AZD-1208
No treatment
DMSO



Variation between samples
Additive results at best
Highest % cell death induced: 40% from 1nM
ABT-737 + 10μM AZD-1208
Kang, M, Reynolds, C. “Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways
in Cancer Therapy.” Clinical Cancer Research 2009, 15: 1126-1132.
Martinou, J, Youle, R. “Mitochondria in Apoptosis: Bcl-2 Family Members and
Mitochondrial Dynamics.” Developmental Cell 2011, 21: 92-101.
Nawijn, M, Alendar, A. Berns, A. For better or for worse: the role of Pim oncogenes
in tumorigenesis. Nature Reviews 2011, 72: 23-34.
Perez, K, Winer, E. “Chronic Lymphocytic Leukemia: Something Old, Something
New and Something Borrowed…” Rhode Island Medicine and Health 2011, 94: 1518.
Reed, J, Pellecchia, M. Apoptosis-based therapies for hematologic malignancies.
Blood 2005, 106: 408-416.
Song, J, Kraft, A. Pim kinase inhibitors sensitize prostate cancer cells to apoptosis
triggered by Bcl-2 family inhibitor ABT-737. Cancer Research 2012, 72: 294-303.