Hepatocellular carcinoma (HCC) has an annual worldwide incidence of more than 600,000 cases and a mortality rate greater than 95%, and therefore new and more effective therapies are needed for HCC patients. Sphingolipids, particularly ceramides and sphingosine 1-phosphate (S1P), regulate critical aspects of tumor biology. The anti-apoptotic and pro-survival lipid S1P is generated by sphingosine kinases (SK1 and SK2), and there is strong evidence that SK2-generated S1P drives cancer cell proliferation. We have developed SK inhibitors, including ABC294640, that have in vivo anti-inflammatory and anticancer activities against a variety of cancer types, including HCC and prostate cancer. Mechanistically, our recently studies suggest that ABC294640 mediates tumor suppression at least in part by targeting c-Myc for proteasomal degradation. Because c-Myc is a critical driver of HCC, being overexpressed in most HCC tumors and correlating with enhanced tumor growth and poor prognosis, defining the molecular mechanism(s) for SK2-regulation of c-Myc activity is critical for optimizing the clinical activity of ABC294640 and other sphingolipid-targeted drugs. Importantly, we have successfully completed enrollment to the first-in-human Phase I clinical trial of ABC294640 at the Medical University of South Carolina in patients with advanced solid tumors, and the data demonstrate positive safety, pharmacokinetic and pharmacodynamic profiles in these patients. Of high importance, plasma levels of ABC294640 that decrease plasma S1P levels and that are predicted to have anticancer activity can be safely achieved in these patients. Based on our completed nonclinical and clinical studies, we hypothesize that inhibition of SK2/S1P by ABC294640 will mediate tumor suppression at least in part through inhibition of c-Myc expression. This novel hypothesis will be tested in the following Specific Aims:
Specific Aim 1. Determine the mechanisms by which inhibition of SK2/S1P mediates tumor suppression via the regulation of c-Myc expression. In this Aim, we will test our mechanistic hypothesis that SK2-generated S1P protects c-Myc from proteasomal degradation, thereby allowing c-Myc activity, and increased tumor proliferation. As a corollary, we also hypothesize that inhibition of SK2/S1P signaling by ABC294640 results in proteasomal degradation of c-Myc, leading to tumor suppression.
Specific Aim 2. To conduct a Phase II trial of ABC294640 in patients with advanced HCC. In this Aim, we will test our novel clinical hypothesis that ABC294640 will provide a treatment benefit to patients with advanced HCC, which will be associated with decreased c-Myc and S1P signaling in the tumor.

Public Health Relevance

Liver cancer is a common and highly deadly form of cancer, so new drugs that target critical pathways that control the growth of liver tumors are desperately needed. Sphingosine kinases play critical roles in liver cancer, and the inhibitor ABC294640 has antitumor activity in mouse models and is currently in clinical testing. The proposed laboratory and clinical studies will determine how SK inhibitors such as ABC294640 can best be used for treating liver cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA203628-02
Application #
9359480
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Timmer, William C
Project Start
Project End
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Lv, Zongyang; Rickman, Kimberly A; Yuan, Lingmin et al. (2017) S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. Mol Cell 65:699-714.e6
Scheffel, Matthew J; Helke, Kristi; Lu, Ping et al. (2017) Adoptive Transfer of Ceramide Synthase 6 Deficient Splenocytes Reduces the Development of Colitis. Sci Rep 7:15552
Dany, Mohammed; Gencer, Salih; Nganga, Rose et al. (2016) Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML. Blood 128:1944-1958
Saddoughi, Sahar A; Ogretmen, Besim (2013) Diverse functions of ceramide in cancer cell death and proliferation. Adv Cancer Res 117:37-58