ABSTRACT
Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death in the United States, and
despite the advances made in EOC therapy, the five-year survival rate has been stagnant at approximately 45%
for decades. The current standard therapeutic approach is accompanied by toxic side effects, and the high cost
of chemotherapy places an enormous financial burden on patients, reducing their quality of life. Thus, there is a
critical need to identify low-cost approaches that can both enhance responses to current therapies and improve
survival by inhibiting tumor progression. Calorie Restriction has a strong capacity to alter the responses of cancer
cells and host cells in the tumor microenvironment, yet the mechanisms of such cross-talk are elusive. Our long-
term goal is to identify dietary mechanisms that can be modulated to impede EOC progression and thus be
translated into the development of more effective therapies and lifestyle changes for EOC patients. Our studies
show that 30% calorie restriction (CR), without malnutrition, in a mouse model of EOC decreases tumor burden,
ascites, and metastases. Additionally, our preliminary data strongly suggest that CR inhibits EOC due to a
decrease in alternatively-activated pro-tumorigenic (M2-like) macrophages and a corresponding increase in
classically-activated anti-tumor macrophages (M1-like), resulting in an increased M1/M2 ratio. This is important
as 50% of cells in EOC ascites are pro-tumorigenic macrophages (M2-like) and an increased M1/M2 ratio is an
indicator of better prognosis in EOC patients. Macrophage polarization is regulated, in part, through metabolic
reprogramming, with M1-like macrophages mainly relying on glycolysis and M2-like macrophages primarily
utilizing aerobic respiration. AMPK, a well-known regulator of energy metabolism, controls the balance between
glycolysis and mitochondrial respiration and our studies demonstrate that mice fed a CR diet have increased
AMPK activity. The overall objective of the proposed research is to determine the mechanism by which a CR
diet regulates macrophage polarization in EOC. Our central hypothesis is that the increased activity of AMPK
due to a CR diet remodels the glycolysis-tricarboxylic acid (TCA) pathway to promote an M1 (anti-tumor)
phenotype, thus leading to a robust anti-tumor immune response and reduction of the tumor. This hypothesis
will be tested in two aims: Aim 1 will identify the effects of increased AMPKa1 activity due to CR on the EOC
progression, and Aim 2 will determine the mechanisms underlying CR-mediated macrophage polarization in
EOC. The proposed study is expected to have a translational impact by elucidating how the simple approach of
dietary intervention can cause metabolic regulatory changes responsible for macrophage plasticity during EOC.
Ultimately, this process could be exploited to tailor novel complementary therapeutic strategies and life-style
modifications to curb progression of EOC and other types of cancer.
