Editors' ChoiceCOMBINATION THERAPY

Seeking Harmony Among Cancer Killers

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Science Translational Medicine  19 Feb 2014:
Vol. 6, Issue 224, pp. 224ec31
DOI: 10.1126/scitranslmed.3008646

“I'll tell you one thing, it's always better when we’re together” sings troubadour Jack Johnson. In the clinical development of anticancer regimens, medical oncologists often echo this refrain. Sometimes therapeutic combinations have clear synergy, but in other cases, piling on more agents adds to the toxicity burden without meaningful benefit. Rationally selecting which combinations, out of a variety of options, are most likely to benefit patients presents an important challenge to translational researchers. Now, Beug et al. present an example of a finely tuned combination regimen with potent antitumor activity in preclinical models.

The authors began with the hypothesis that smac mimetic compounds (SMCs)—anticancer agents in early clinical development that sensitize cells to apoptosis—can be favorably combined with immune-stimulating agents that trigger proapoptotic signaling. First, Beug et al. partnered the SMC LCL161 with the oncolytic virus VSVΔ51, which is known to induce a robust antiviral cytokine response. Screening a panel of human and mouse tumor cell lines, the authors demonstrated synergistic tumor-killing activity in vitro, a finding that they expanded to several additional SMC–oncolytic virus combinations.

Using small interfering RNA knockdown to probe the mechanism behind this killer activity, the authors identified an indispensable role for cytokines interferon-β and tumor necrosis factor–α in the synergy observed with the SMC–oncolytic virus therapeutic combination. Next, they tested this combination in a series of transplantable syngeneic and xenograft tumor models, observed potent antitumor activity, and confirmed the central importance of cytokine production in vivo using cytokine-depleting antibodies. Last, the authors found that alternative immune-activating agents polyinosinic:polycytidylic acid and CpG were similarly active partners for SMCs, supporting the proposed cytokine-dependent synergy.

Taking two types of anticancer agents already in clinical development, Beug et al. present a rational approach to developing combination therapies. Clinical trials will be required to test how well these agents harmonize in patients, but a robust preclinical analysis may help us pick the first two notes.

S. T. Beug et al., Smac mimetics and innate immune stimuli synergize to promote tumor death. Nat. Biotechnol. 32, 182–190 (2014). [Full Text]

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