# Project 3: Targeting SK2/S1P Signaling for the Regulation of c-Myc and Tumor Suppression

> **NIH NIH P01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $476,309

## Abstract

PROJECT SUMMARY 
 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.

## Key facts

- **NIH application ID:** 9980710
- **Project number:** 5P01CA203628-05
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Carolyn D Britten
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $476,309
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980710

## Citation

> US National Institutes of Health, RePORTER application 9980710, Project 3: Targeting SK2/S1P Signaling for the Regulation of c-Myc and Tumor Suppression (5P01CA203628-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980710. Licensed CC0.

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