PROJECT SUMMARY AND RELEVANCE
Summary: A common feature of aggressively growing tumors is intratumoral hypoxia due to the
insufficient blood supply. Tumor cells adapt to hypoxia by reprogramming their metabolism to rely on
glucose fermentation as the main energetic pathway and, consequently, drastically increase their
glucose intake. This glucose dependence of hypoxic tumor cells can be exploited by limiting total
available glucose. The objective of the proposal is to test whether glucose limitation checks the
proliferation of hypoxic, glycolytic tumors. A combination of a ketogenic diet with clinically relevant
doses of metformin significantly reduced blood glucose levels in BALB/c mice without causing
morbidity. This proposal will test the efficacy of the diet/metformin combination on the growth and
metastatic outcome of orthotopically implanted, aggressively growing tumors in an established murine
model of triple-negative breast cancer (TNBC). Guided by preliminary data, we aim to 1. Establish the
efficacy of the diet/metformin combination therapy in inhibiting the progression of mammary tumors to
metastasis, and 2. Determine the efficacy of standard chemotherapy with the proposed combination
therapy to control the growth dynamics and progression to metastasis of developed mammary tumors.
This approach shifts the emphasis of cancer treatment discovery from genetic pathway or protein
targets, which tend to evolve and adapt to therapy, to a well-known and hard to escape metabolic
vulnerability of cancer by using a combination diet/pharmaceutical therapy approach. While
carbohydrate dietary restriction and metformin are well-known interventions, they have yet to be
considered in combination for cancer treatment. Significantly, low carbohydrate diets and metformin
have been shown to be compatible in humans outside of the cancer field. If effective, this treatment will
be expanded to other hypoxic and glycolytic tumors beyond TNBC, particularly those tumors that are
refractive to conventional therapies, with the ultimate goal of translating this treatment protocol into a
human cancer therapy. The combination therapy may also prove to be a significant adjuvant to existing
mainline treatments by debulking the hypoxic, typically chemo- and radio-resistant, part of a tumor. This
AREA project will provide research opportunities for undergraduate students to gain hands-on
experience in biomedical techniques and data analysis. The project is specifically designed to be
straightforward and practical for pre-med undergraduate students.
Relevance: Limited treatment options for TNBC represent a critical barrier in attempts to increase post-
diagnosis patient survival rates. This project is a rational extension of a well-known paradigm of
metabolic reprogramming of cancer cells and, if successful, can be translated into a mainline cancer
treatment or used as an adjuvant in combination with existing treatment options.