The Effects of Schweinfurthins and Other Potential Chemotherapies on Diffuse Intrinsic Pontine Glioma Cells
Open Access
- Author:
- Daugherty, Daniel
- Graduate Program:
- Anatomy
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- March 05, 2019
- Committee Members:
- Jeffrey D Neighbors, Thesis Advisor/Co-Advisor
Patricia Mclaughlin, Committee Member
Raymond J Hohl, Committee Member - Keywords:
- DIPG
Pediatric Glioma
schweinfurthins - Abstract:
- Diffuse intrinsic pontine glioma is a brainstem tumor representing one of the deadliest pediatric cancers with a median overall survival of 8-14 months. Currently, the two-year survival rate is <10% and has remained that for over thirty years. No therapy provides a survival benefit; however, radiation is standard of care, providing temporary symptom relief. Over 250 clinical trials have failed; therefore, many drugs have been tested against multiple cell lines. Cyclin- dependent kinase inhibitors dinaciclib and SNS-032, as well as AKT inhibitor perifosine have all shown potent effects. Similarly, the University of Rochester has synthesized a compound specifically for diffuse intrinsic pontine glioma and it has shown effects in a mouse model. Lastly, schweinfurthins were found to have potent effects against the National Cancer Institute 60-cell line screen, including glioblastoma multiforme. They have been shown to indirectly inhibit AKT, decrease cholesterol synthesis, and increase cholesterol export. This study evaluated schweinfurthins and other potential chemotherapies in a cell culture model via human diffuse intrinsic pontine glioma cell line SF8628. TTI-3066, a schweinfurthin analog, increased p-AKT and Taz, while AKT, ABCA1, and PARP protein levels all decreased. TTI-3066 was also tested for synergy with radiation as well as the other chemotherapies. The cell line tested, SF8628, is very sensitive to TTI-3066 as an IC50 of 36 nM was reported. Although TTI-3066 does not appear to synergize with radiation, it does appear to synergize with SNS-032 at higher concentrations. Perifosine and dinaciclib in combination with TTI-3066 both display synergy. Lastly, the University of Rochester compound appears to synergize with radiation. Schweinfurthins have antiproliferative effects in diffuse intrinsic pontine glioma cell line SF8628, however other cell lines should be assessed and these mechanisms should be further explored. These results are promising for the future treatment of diffuse intrinsic pontine glioma.