Dramatic advances in cancer treatment will depend on identifying new targets for therapeutics. Here we propose as a candidate target a novel phosphoinositide signaling pathway that we have discovered. We have identified a pathway involving the phosphoinositide PtdIns(4)P and a new protein that binds to it which we have called PI4P-BP. We have shown that this pathway is required for normal Golgi architecture and function. Cancer cells often require autocrine, paracrine, or endocrine growth factor signaling for continued proliferation and survival. Since trafficking of growth factors and growth factor receptors requires intact Golgi function, interference with the Golgi is expected to interfere with cancer proliferation and survival. We have devised methods to inducibly interfere with the PtdIns(4)P/PI4P-BP pathway. We propose experiments to determine the effect of interference with the PtdIns(4)P/PI4P-BP pathway on growth factor signaling and thus whether it will be worthwhile to develop this novel therapeutic strategy further toward its clinical application.

Public Health Relevance

Dramatic advances in cancer treatment will depend on identifying new targets for therapeutics. We have identified a new signaling pathway that provides a new target for cancer therapies. The experiments that we propose will determine whether it will be worthwhile to further develop this novel therapeutic strategy for clinical application. This funding will allow creation of new jobs and purchase of supplies and equipment, helping to stimulate the economy in accordance with the American Recovery and Reinvestment Act of 2009.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA138676-01
Application #
7633803
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2009-06-04
Project End
2011-05-31
Budget Start
2009-06-04
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$248,852
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Murray, Michael J; Ng, Michelle M; Fraval, Hamilton et al. (2012) Regulation of Drosophila mesoderm migration by phosphoinositides and the PH domain of the Rho GTP exchange factor Pebble. Dev Biol 372:17-27
Schmid, Michael C; Avraamides, Christie J; Dippold, Holly C et al. (2011) Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3k?, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19:715-27
Nhek, Sokha; Ngo, Mike; Yang, Xuemei et al. (2010) Regulation of oxysterol-binding protein Golgi localization through protein kinase D-mediated phosphorylation. Mol Biol Cell 21:2327-37
Dippold, Holly C; Ng, Michelle M; Farber-Katz, Suzette E et al. (2009) GOLPH3 bridges phosphatidylinositol-4- phosphate and actomyosin to stretch and shape the Golgi to promote budding. Cell 139:337-51
Bielas, Stephanie L; Silhavy, Jennifer L; Brancati, Francesco et al. (2009) Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41:1032-6