Ninety years ago Otto Heinrich Warburg observed that cancer cells have much higher rates of glycolysis than normal cells. In the following decades, this response - dubbed the Warburg Effect - has become recognized as a universal feature of cancer. A less recognized, although firmly scientifically established, aspect of the Warburg Effect is glucose metabolite-driven activation of anabolic networks such as the hexosamine biosynthetic pathway (HBP), which is a branch of glycolysis devoted to protein glycosylation. Abnormally high flux through the HBP can exacerbate cancer progression through the overproduction of certain cell surface N-glycan structures as well as through perturbation of intracellular O-GlcNAc protein modifications. Accordingly, an enticing approach towards the development of broad-based cancer treatments is to attack the bridge that links these forms of protein glycosylation with the Warburg Effect. To accomplish this goal, we propose to inhibit uridine diphosphate-N-acetylglucosamine pyrophosphorylase 1 and 2 (UAP1/2), which comprises a non-circumventable enzymatic link between carbohydrate metabolism and protein glycosylation, by using newly-designed small molecule drug candidates. We hypothesize that inhibition of UAP1/2, which has not previously been proposed as a disease modifying strategy in cancer, will normalize flux though the HBP and O-GlcNAc cycling while simultaneously blocking the production of glycans that contribute to oncogenic progression and metastasis. We predict that successful pharmacological modulation of UAP1/2 will have profound implications beyond cancer because abnormal metabolic flux through the HBP is increasingly being associated with diseased states such as diabetes and Alzheimer's that are rapidly becoming more prevalent in society but remain largely incurable.
Abnormal glucose metabolism is a universal feature of cancer and has also been implicated in increasingly widespread diseases such as diabetes and Alzheimer's. Although sugar consumption is most strongly associated with energy production, carbohydrate metabolism also modulates many anabolic biochemical pathways and signaling events vitally important to cancer cell proliferation and oncogenic progression. In this proposal we focus on UAP1/2, a previously un-targeted bridge between carbohydrate consumption and the production of cancer-promoting carbohydrates to both gain new insights into this disease and design of a new class of cancer drug candidates.
