Program Projects

Project 1

Acid Ceramidase-S1P Metabolic Axis & Regulation of Tumor Resistance to Apoptosis

Studies proposed in this project will help determine the mechanisms by which targeting the acid ceramidase (AC) and sphingosine-1-phosphate (S1P) signaling axis provides a novel therapeutic approach to overcome therapy resistance, leading to the prevention of relapse in solid tumors, such as prostate, urinary, and liver cancers.

Aim 1: Determine the mechanisms of AC-dependent resistance to cell death following therapy stress.

Aim 2: Determine the therapeutic roles of targeting the AC/SK1/S1P/AKT axis to overcome therapy resistance for the treatment of prostate cancer.

Project Co-leader: Christina Voelkel Johnson, Ph.D.
Project Co-leader: James Norris, Ph.D.

Project 2

Regulation of Tumor Metastasis by Systemic S1P & Complement Signaling

Studies proposed in this project will help uncover how cancer cells communicate with the host via systemic sphingolipid and complement signaling to regulate tumor metastasis, leading to the development of novel therapeutic strategies for the inhibition of metastasis.

Aim 1: Define the roles and mechanisms of cancer cell-induced vascular endothelial cell complement signaling and systemic SK1/S1P in the regulation of tumor metastasis.

Aim 2: Determine the downstream mechanisms by which cancer cell-induced systemic SK1/S1P promotes tumor metastasis.

Aim 3: Determine the therapeutic efficacy of targeting systemic S1P and/or C5a signaling for the attenuation of tumor metastasis.

Project Leader: Besim Ogretmen, Ph.D.

Project 3

Targeting SK2/S1P Signaling for the Regulation of c-Myc & Tumor Suppression

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.

Aim 1: Determine the mechanisms by which inhibition of SK2/S1P mediates tumor suppression via the regulation of c-Myc expression.

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.

Project Leader: Michael Lilly, M.D.