Combinatorial Effects of CD30 Ligand Stimulation or Inhibitor of Apoptosis (IAP) Antagonist Exposure with Conventional Chemotherapy on CD30 Positive Malignancies

Abstract 4926

CD30 is a member of the tumor necrosis factor (TNF) receptor family that is normally found on the cell surface of a small subset of activated lymphocytes but is overexpressed on the surface of anaplastic large cell lymphoma (ALCL) and Hodgkins lymphoma (HL) cells. Although many drugs exist that treat lymphomas by triggering the intrinsic cell death pathway, current chemotherapeutic regimens are limited by unwanted side effects, including secondary malignancies that limit event-free survival. The tumor-restricted overexpression of CD30 makes it an attractive target for therapeutic intervention. Depending on the cellular context, CD30 stimulation has been linked to cell death, cell cycle arrest, or paradoxically, proliferation. In ALCL tumor cell lines, CD30 stimulation activates both the canonical and noncanonical NF-kB pathways while in HL tumor cell lines, CD30 stimulation only slightly enhances NF-kB activity above constitutive levels, implying a role for NF-kB in determining the sensitivity or resistance of lymphoma cells to CD30-induced apoptosis. In addition, IAP antagonists, small synthetic compounds that mimic the structure of the second mitochondrial activator of caspase (Smac) and target IAP molecules that affect the activation of the non-canonical NF-kB pathway, induce apoptosis and/or sensitize cells to death via secondary signals such as TNF. This suggests that the modulation of IAP levels, and consequently regulation of the non-canonical NF-kB pathways, may also have a role in determining tumor cell death. Using representative ALCL and HL tumor cell lines, we have found that CD30 stimulation via its physiologically ligand in combination with standard chemotherapeutic agents results in increased efficacy in tumor cell death in the majority of ALCL cell lines but not HL cell lines. Similarly, IAP antagonists in combination with standard chemotherapeutic agents also resulted in enhanced tumor cell death in most ALCL but not HL cell lines. This augmentation of tumor cell death suggests that CD30-induced apoptosis and IAP antagonist-induced killing may have important consequences in the clinical treatment of CD30 positive malignancies. Currently, we are further investigating the role of both CD30 stimulation via its physiological ligand and IAP antagonists in impacting the activation of the canonical and noncanonical NF-kB pathways alone and in combination with currently utilized chemotherapeutic agents to modulate the apoptotic threshold in CD30 positive lymphoma cells.