Mucositis caused by excessive inflammation within the gastrointestinal tract is a costly and debilitating toxicity commonly experienced by patients receiving radiation and/or drugs as cancer therapy. Sphingolipids are being increasingly recognized as key mediators of inflammation, and are known to be essential for signaling by pro-inflammatory cytokines such as tumor necrosis factor-?(TNF?) and IL-4 that are of central importance in mucositis. In particular, sphingosine 1-phosphate (S1P) within gastrointestinal cells generated in response to many common anticancer drugs is critical for the recruitment and activation of neutrophils that escalate inflammatory processes in mucositis. Therefore, disruption of chemotherapy-induced S1P production is a new targeted approach to the prevention and/or treatment of mucositis. Because of the pivotal roles of sphingosine kinases (SKs) in regulating inflammation and tumor growth, Apogee Biotechnology Corporation is developing SK inhibitors to treat cancer and inflammatory diseases. We have previously shown that the SK2 inhibitor ABC294640 effectively attenuates GI damage in rodent models of inflammatory bowel diseases, as well as in radiation-induced GI toxicity. In preclinical cell and tumor models, SK inhibitors enhance the antitumor activity of several drugs, and ABC294640 is currently in single-agent phase 1/2a clinical testing in patients with advanced solid tumors. In addition to its direct antiproliferative effects on tumor cells, we hypothesize that ABC294640 will reduce GI mucositis following treatment with chemotherapy drugs, thereby providing substantial clinical benefit to patients undergoing cancer treatment. The goal of this phase 1 SBIR project is to determine the ability of a clinical drug targeting SK2 (ABC294640) to prevent chemotherapy-induced mucositis, and will consist of the following Specific Aims: 1. To determine the ability of ABC294640 to protect against GI mucositis in mice treated with anticancer drugs;and 2. To determine the effects of ABC294640 on the antitumor activity of anticancer drugs. This work will provide the first proof-of-principle efficacy studies of an SK inhibitor in models of chemotherapy-induced mucositis. We have extensive experience with animal models of GI toxicity, and believe that the use of ABC294640 for the prevention of mucositis is an innovative approach that can be rapidly translated to the clinic.
Mucositis occurs in approximately 40% of cancer patients receiving standard dose chemotherapy, and in essentially all patients receiving high-dose chemotherapy. Extensive work, including our Preliminary Studies, indicates that the drug ABC294640 may prevent this debilitating side-effect of cancer therapy. The proposed studies will provide the first test of this hypothesis, and could be rapidly translated into clinical trial with this drug.