Glycolytic Reprogramming and Metformin as Therapeutics for Radiation-Induced Salivary Gland Dysfunction - Over 53,000 new cases of head and neck cancer are projected for 2020 in the United States
with the standard of treatment involving radiation therapy. Although effective for treating cancer, radiation causes
irreversible damage to surrounding salivary glands, resulting in loss of function (i.e. chronic hyposalivation).
Treatment options for hyposalivation only provide symptom control and do not restore the production of saliva
endogenously. Therefore, the underlying mechanisms regulating salivary gland dysfunction following
radiotherapy need to be understood to achieve the long-term goal of restoring salivary gland function following
radiotherapy. It is well-established that compensatory cell proliferation is part of the radiation damage response
that is correlated with salivary gland hypofunction. Glycolysis has been identified as a metabolic pathway driving
compensatory proliferation in wound healing models and glycolytic inhibition has demonstrated success for
attenuating pathological injury, but this pathway has not been investigated in the context of radiation-induced
salivary gland dysfunction. Metformin, a common anti-diabetic drug, decreases cell proliferation in tumor cells.
Preliminary data shows metformin restores saliva production in mice following radiation treatment, yet the
mechanism in the salivary gland has not been elucidated. The goal of this proposal is to comprehensively identify
the effect of radiation on glycolysis in the salivary gland, to determine if glycolytic inhibition is a potential
therapeutic target for restoring saliva production following radiation, and to evaluate the mechanistic effect of
metformin treatment on this pathway. We hypothesize that radiation increases glycolysis in the salivary gland
and that glycolytic inhibition will increase saliva production following radiation, and that metformin decreases
glycolysis post radiotherapy. To test this, glycolysis will be comprehensively measured in salivary epithelial cells
at acute and chronic timepoints following radiation and saliva production will be measured following glycolytic
inhibition after radiation exposure in vivo, which will be compared to untreated and irradiated controls. Glycolytic
activity will also be evaluated in salivary epithelial cells following radiation and metformin treatment. The
outcomes of this project will provide an unbiased understanding of glycolytic reprogramming in salivary epithelial
cells following radiation damage and will evaluate the downstream mechanism of metformin treatment leading
to restored salivary gland function following damage. This may impact fields beyond salivary gland research, as
these results may be expandable to other types of tissue damage. This proposal will serve as part of the PI’s
doctoral dissertation as she pursues a career in academia. The PI will develop her technical, mentoring, and
collaborative skills as she works in the laboratories of Drs. Kirsten Limesand, Floyd Chilton, and Megha Padi
with other students at a Research I institution, the University of Arizona. Presenting and publishing the findings
from this proposal will build the PI’s communication skills as she pursues her career as an academic researcher.
