Approximately 90% of glioblastoma patients develop another tumor in two years after surgical removal and the treatment of radiation and temozolomide (TMZ), indicating that recurrent glioblastoma cells become resistant to TMZ. This resistance significantly lowers the clinical efficacy of TMZ, thereby contributing to the high incidence of tumor recurrence. One well known mechanism of TMZ resistance is related to the function of O-6- methylguanine-DNA methyltransterase (MGMT); this enzyme repairs TMZ-induced DNA damage, allowing cancer cells to replicate and spread. However, targeting MGMT has limited clinical benefits. We have recently demonstrated that a PI3K (phosphatidylinositol-4,5-biphosphate 3-kinase) catalytic subunit is a specific biomarker for the prognosis of glioblastoma recurrence. Class IA PI3K family includes PIK3CA, B, and G catalytic subunits, encoding p110?, ?, and ?, respectively. Targeting all these subunits to restore TMZ sensitivity has been widely studied; however, this treatment is often associated with non-selective killing and severe toxicity. Uncovering the selective role of PI3K subunits in TMZ resistance represents an alternative mechanism that is independent of MGMT and offers a new approach to enhancing TMZ treatment efficacy and reducing the risk of tumor recurrence. We hypothesize that (1) PIK3CB/p110? is critical for the survival of TMZ- resistant cells and (2) p110? inhibitors restore TMZ sensitivity of glioblastoma cells and recurrent tumors, while exhibiting limited toxicities to normal brain cells. We will test these hypotheses via the following specific aims: (1) To define the selective role of p110? in TMZ resistance (Year 1) and (2) To determine the efficacy of p110? inhibitors in circumventing TMZ resistance and treating tumor recurrence in mice (Years 1-2). To test the first hypothesis, we will measure the effect of four PI3K catalytic subunits (PIK3CA, B, D, and G) in the survival of p110?-high/TMZ-resistant glioblastoma cells, glioblastoma stem cells, human astrocytes, or neural stem cells. We will test whether p110? but not other PI3K subunits will induce TMZ resistance and determine whether other exogenous PI3K subunits will substitute for endogenous p110? to induce TMZ resistance. To test the second hypothesis, we will measure the therapeutic effect of PI3K isoform-selective inhibitors in TMZ- resistant GBM cells/GSCs in vitro and in vivo. Elucidating the selective role of PIK3CB/p110? in TMZ resistance and glioblastoma recurrence will explain the selective roles of PI3K genes in glioblastoma and will further foster the rational design of novel therapies tailored to glioblastoma patients with an especially high risk of tumor recurrence.

Public Health Relevance

On average, patients with the deadly glioblastoma typically live for only a year after diagnosis and another tumor inevitably occurs due to the resistance to radiation and temozolomide. We have discovered that PI3KCB/p110?, but not other PI3K subunits, plays a critical role in glioblastoma progression and temozolomide resistance. Elucidating the mode-of-action and evaluating the effect of PIK3CB/p110?-selective inhibition in restoring temozolomide sensitivity will help us design new and effective therapies for glioblastomas with an especially high risk of tumor recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA216768-01A1
Application #
9512395
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Arya, Suresh
Project Start
2018-02-02
Project End
2020-01-31
Budget Start
2018-02-02
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Miscellaneous
Type
Organized Research Units
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
Grek, Christina L; Sheng, Zhi; Naus, Christian C et al. (2018) Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics. Curr Opin Pharmacol 41:79-88