A Phase 1-2, Multicenter, Open-Label Study of AEG35156 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia and Indolent B-Cell Lymphomas

Apoptotic induction in cancer cells is a sought after therapeutic goal. Most successful
anticancer agents activate apoptosis pathways in the cancers they treat. Apoptotic pathways
in cells appear to converge on a single family of enzymes, the caspases, which are proteases
that dismantle the cell in an orderly, non-inflammatory fashion, resulting in cell death.
The X-linked Inhibitor of Apoptosis (XIAP) is the only known cellular inhibitor of caspases,
its over expression thereby blocking the principal means of apoptosis. A wide range of
evidence indicates that cellular overexpression of members of the IAP family is a
fundamental means by which many cancer cells evade death, even in the presence of strong
extrinsic (death receptor-mediated) and intrinsic (mitochondria-mediated) apoptotic cues.
The inhibition of cellular XIAP activity, specifically in cancer cells under stress and
primed for apoptosis by chemotherapeutic agents, is viewed as a powerful means of tipping
the balance towards cell death. In particular, XIAP has been shown to be overexpressed in
lymphoma. AEG35156 is a second generation antisense which targets XIAP mRNA to lower XIAP
levels and the apoptotic threshold of cancer cells, enhancing their sensitivity to intrinsic
death and chemotherapy. AEG35156 has shown early evidence of activity in patients with
advanced indolent B-cell lymphomas in Phase 1 trials and merits further evaluation in this
disease.