Abstract
Targeted drug approaches have been a major focus for developing new anticancer therapies. Although many such agents approved in the last 20 years have improved outcomes, almost all have underperformed expectations. The full potential of such agents may yet be obtained through novel combinations. Previously, we showed that anti-estrogen drugs combined with a dendritic cell-based anti-HER-2 vaccine known to induce strong Th1-polarized immunity dramatically improved clinical response rates in patients with HER-2pos/ERpos early breast cancer. Here, we show that the small molecule Akt antagonist MK-2206, when combined with the Th1 cytokines IFN-gamma and TNF-alpha, maximize indicators of apoptotic cell death in a panel of phenotypically-diverse human breast cancer lines. These findings were mirrored by other, structurally-unrelated Akt-targeting drugs that work through different mechanisms. Interestingly, we found that MK-2206, as well as the other Akt antagonist drugs, also had a tendency to suppress Th1 cytokine expression in stimulated human and murine lymphocytes, potentially complicating their use in conjunction with active immunotherapy. After verifying that MK-2206 plus IFN-gamma could show similar combined effects against breast cancer lines, even in the absence of TNF-alpha, we tested in a rodent HER-2pos breast cancer model either a HER-2-based DC vaccine, or recombinant IFN-gamma with or without MK-2206 administration. We found that for MK-2206, co-administration of recombinant IFN-gamma outperformed co-administration of DC vaccination for slowing tumor growth kinetics. These findings suggest a combined therapy approach for Akt-targeting drugs that incorporates recombinant Interferon-gamma and is potentially translatable to humans.
Highlights
Once existing only at the margins of cancer treatment, immunotherapy has gained a strong claim as a distinct and accepted treatment modality, taking its place among the established approaches of surgery, radiation, cytotoxic agents and targeted drugs [1]
When examining patient characteristics that predisposed toward pCR in response to dendritic cells (DC) vaccination, we observed that subjects with ERpos DCIS had only a 5% pCR rate, while their ERneg counterparts had a 30% pCR rate [3]
Because Akt sits at the nexus of such important growth and survival signaling pathways, and because we previously showed that Th1 cytokines trigger apoptosis while lowering expression of HER family oncodriver expression [6], we hypothesized that the combination of Th1 cytokines and Akt antagonists might make a effective pairing useful for immunotherapy of breast cancer
Summary
Once existing only at the margins of cancer treatment, immunotherapy has gained a strong claim as a distinct and accepted treatment modality, taking its place among the established approaches of surgery, radiation, cytotoxic agents and targeted drugs [1]. Post-vaccine recruitment of CD4pos T cells into peritumoral areas strongly predominate over CD8pos T cells, suggesting an effector mechanism dependent at least in part on Th cells Consistent with this notion, we and others have found that paired Th1 cytokines IFN-γ and TNF-α induced senescence and/or apoptosis in vitro for a variety of cancer cell lines (both human and murine) [5,6,7]. E. the drugs that blocked estrogen signaling appeared to sensitize estrogen-dependent cells to the Th1 cytokines This observation prompted a new clinical trial where a brief course of anti-estrogen therapy was supplied to ERpos DCIS subjects concurrent with vaccination. It suggested that in vitro testing of such smallmolecule targeted drugs for enhanced anti-tumor activity, when combined with Th1 cytokines, could function as an effective screen for identifying combinations with the potential to demonstrate activity in vivo
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