FTY720 is a sphingosine analogue drug that has been recently approved by FDA for the treatment of patients with refractory multiple sclerosis (MS). FTY720 is phosphorylated by sphingosine kinase 2 (SK2), and P- FTY720 is immune suppressive, which is required for its anti-MS activity. This proposal was designed to test a novel hypothesis that FTY720, but not its immunesuppressive form P-FTY720, suppresses NSCLC tumor growth by directly targeting I2PP2A/SET oncoprotein, leading to activation of PP2A, RIPK1-dependent programmed necrosis (necroptosis) and consequent tumor suppression. To test this hypothesis, two Specific Aims are proposed:
Aim 1 was designed to determine the roles and mechanisms by which binding I2PP2A/SET by FTY720 activates tumor suppressive PP2A.
Aim 2 was designed to determine the down- stream mechanisms by which targeting I2PP2A/SET by FTY720 induces cell death.

Public Health Relevance

The studies proposed in this application will help identify a novel molecular target, I2PP2A/SET oncoprotein, and they will provide a first-in-class treatment option using an already FDA-approved drug, FTY720, for selectively targeting I2PP2A/SET, leading to NSCLC tumor suppression via induction of programmed necrosis, providing a mechanism-based precision therapeutic strategy for the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA173687-01A1
Application #
8585322
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (01))
Program Officer
Alley, Michael C
Project Start
2013-07-01
Project End
2018-05-31
Budget Start
2013-07-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$310,213
Indirect Cost
$102,713
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Qin, Zhiqiang; Dai, Lu; Trillo-Tinoco, Jimena et al. (2014) Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol Cancer Ther 13:154-64