1. Understanding Apoptotic Mechanisms
Christine L. Hann, MD, PhD
Assistant Professor of Oncology
Johns Hopkins University School of Medicine
18th Annual Perspectives in Thoracic Oncology
November 16, 2013

2. Apoptosis
A process of programmed cell death by which cells undergo an ordered sequence of events which lead to death of the cell
Involves high coordinated cellular events that lead to the activation of a family of cysteine proteases (caspases)
Intrinsic (mitochrondrial)
Extrinsic (death receptor)

3. Apoptosis: morphologic changes
First morphological description in 1885
Apoptosis in 1972
Annexin V staining to detect PS
DNA Laddering
Ueda et al., JCB 2007; Cotter TG. Nat Rev Cancer 2009;

4. Intrinsic and Extrinsic Pathways
Favaloro et al., Role of Apoptosis in Disease, Aging 2012

5. Intrinsic Apoptotic Pathway
Tahir et al., Can Res 2007; Chen et al., Can Res 2007; van Delft et al., Cancer Cell 2006

6. Extrinsic Pathway

7. Cancer: Many ways to evade apoptosis
Overexpression of antiapoptotic proteins
Inactivation of proapoptotic proteins
Inhibition of APAF1
Suppression of Caspase activity
Cell survival and therapy resistance
Favaloro et al., Aging 2012; Fernald and Kurokawa, Trends in Cell Biol 2013

8. Apoptotic Pathways in Lung Cancer
SCLC
NSCLC
IAPs
Favaloro et al., Role of Apoptosis in Disease, Aging 2012

9. Targeting Apoptotic Pathways: NSCLC
Mapatumumab
(anti-TRAILR1)
Lexatumumab
(anti-TRAILR2)
YM155
(Survivin inibitor)

10. Targeting Apoptotic Pathways: SCLC
Bcl-2 is over-expressed in the majority of SCLC and is associated with therapeutic resistance
Agents
Antisense
Oblimersen
Did not hit target
Small molecule inhibitors
Obatoclax with PE
Safe, trend toward improved PFS
ABT-263
DL thrombocytopenia
Could not be combined with chemotherapy

11. Targeting Apoptosis in Lung Cancer
Studies are ongoing for extrinsic pathway -directed therapies
Recombinant TRAIL (ligand)
Anti-TRAIL receptor antibodies
IAP targeted therapies
Biomarker….
Targeting Bcl-2 family members continues to be a clinical challenge
Bcl-2 specific SMI (ABT-199) is very effective in lymphoma
Unclear whether it will be efficacious in solid tumors
ABT-263 (Bcl-2/xL)
Cannot be combined with chemotherapy
What about other targeted therapies
Data in KRAS-mutant NSCLC in combination with MEK inhibitors