Under this ongoing project, several in vitro and in vivo experiments are evaluating the anti-tumor effects of progesterone and its possible mechanisms of action in GBM. We are:
determining the dose-response effect of progesterone on the growth of GBM and the survival rate of tumor-bearing mice in an orthotopic mouse model; studying the effects of progesterone treatment on behavior and quality of life of tumor-bearing mice; measuring the effects of progesterone on inflammation, proliferation, vascularization and apoptosis in tumor tissue; and determining the effects of progesterone on PI3K/Akt/mTOR signaling pathway in tumor tissue.
We are completing analyses of in vitro experiments in three GBM cell lines examining the effects of progesterone on tumor glycolytic metabolism, specifically the modulatory effect of progesterone on glucose transporters, glycolysis enzyme, and transcription factor FoxO1 and evaluating the effect of progesterone on cellular senescence in GBM cells. We have already published some of these findings in Nature Scientific Reports.
In continuing this work we plan to examine the role of the mitochondrial progesterone receptor (mPR) and metabolic reprogramming in GBM cells; determine how nuclear progesterone receptors regulate the functions of FoxO1 transcription factor in inducing premature senescence in GBM; and examine the crosstalk between nPR-FoxO1 signaling and mPR to elucidate the mechanisms of progesterone actions at the mitochondrial level. To do this we are using Seahorse technology to perform mitochondrial metabolic assays like mitochondrial stress test and cell energy phenotype test. This is the most advanced technique for studying real-time mitochondrial dysfunction.
If we continue to show tumor growth reduction and better survival, this could lead to a very significant clinical treatment that is much less expensive, has no side effects and is easy to administer, giving the GBM patient a much better quality of life during and after treatment. We were very pleased to present a plenary talk on our progesterone/mitochondrial work on stroke and GBM at a national oncology meeting sponsored by oncology faculty at the George Washington University Medical School in 2018.
Finally, in collaboration with Dr. Hui-Kuo Shu in Radiation Oncology, we have applied to the Coulter Foundation to support some of the dose-response and toxicity studies needed to plan for a Phase I clinical trial of progesterone as an adjunct therapy for fractionated radiation in GBM patients. To date, proof of efficacy was tested in only one human GBM cell line. To show clinical relevance, we need to test progesterone in both male and female animals with human tumor tissues isolated from patients during surgical removal of GBM. If Coulter support is awarded, we will test chronic progesterone treatment in combination with standard-of-care interventions for GBM like temozolomide (TMZ) and ionizing radiation. Both of these can have serious side effects and disrupt what quality of life patients may have in the face of GBM. Progesterone alone may produce better outcomes for survival than TMZ given alone. But to apply for any future clinical testing, these studies need to be confirmed and extended.