Understanding Apoptotic Mechanisms

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Presentation transcript:

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

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)

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;

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

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

Extrinsic Pathway http://www.hixonparvo.info/apoptosis.jpg

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

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

Targeting Apoptotic Pathways: NSCLC Mapatumumab (anti-TRAILR1) Lexatumumab (anti-TRAILR2) YM155 (Survivin inibitor) http://www.hixonparvo.info/apoptosis.jpg

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

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