The tumor suppressor PTEN counteracts Class 1 PI3-kinase functions in membranes, leading to the massive kinase inhibitor development efforts currently attempting to counteract loss of PTEN in human tumors. However, we discovered a new PTEN signaling pathway in the nucleus that is completely decoupled from Class 1 PI3-kinases. The ?decoupling? is important for anti-cancer drug design because if a tumor is growing due to loss of nuclear PTEN, Class 1 PI3-kinase inhibitors would be ineffective against those tumors. Indeed, PI3-kinase inhibitors often fail to rescue loss of PTEN function in clinical trials, for incompletely understood reasons. Further, this new PTEN pathway has never been studied in any model of cancer, as we discovered it fortuitously while examining endocrine disorders. The kinase opposing PTEN in the nuclear pathway is a poorly characterized member of the inositol kinase superfamily called ?Inositol Polyphosphate Multikinase? (IPMK). IPMK is a nuclear PIP2-kinase with ubiquitous expression in all human tissues, structurally unrelated to Class 1 PI3-kinases. Alfred Yung showed certain glioblastoma cell lines halted growth when complemented with nuclear, not cytoplasmic PTEN2. Based on the nuclear pathway, we hypothesized IPMK knockout might mimic nuclear PTEN complementation in these cells. Indeed, preliminary data show CRSIPR knockout of IPMK phenocopies nuclear PTEN complementation in these cells. Wild type but not kinase-dead IPMK rescues the phenotype, suggesting an IPMK inhibitor could be an effective therapy. This grant develops a chemical genetic mutant of IPMK to determine if IPMK inhibitors would be effective in glioblastoma. Future projects will use physiologically relevant mouse models to establish IPMK as a validated target for full scale industrial kinase inhibitor efforts.

Public Health Relevance

- Relevance to Public Health A fundamental challenge to developing new anti-cancer therapies is the identification of tumor-specific, 'druggable' targets that scientists can pursue to kill cancer cells. This proposal validates one such new target in glioblastoma. Collectively our research will help identify candidates for drug design by providing proof of principle for further investment by pharmaceutical companies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA243036-02
Application #
10019480
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ojeifo, John O
Project Start
2019-09-17
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232