Unmet Need: Greatly enhanced glucose metabolism – known as the Warburg effect – is a metabolic alteration that characterizes almost all types of cancer. Over 50 years of attempts to develop therapies that target the Warburg effect have failed, largely because of safety issues connected to interfering with central energy metabolism. There is a need for novel strategies that overcome safety issues to target this fundamental metabolic change in cancer.
Technical Details: Researchers at Johns Hopkins University have developed a strategy to ameliorate the Warburg effect in cancer using small molecule inhibitors of the hexosamine biosynthetic pathway (HBP), an oncogenic downstream pathway fed by aberrantly high levels of sugar. These small molecules consist of a hexosamine template (with thousands of potential chemical structures possible) and are designed to inhibit UDP-N-acetylgalactosamine pyrophosphorylase (UAP) to normalize metabolic flux through the hexosamine biosynthetic pathway (HBP). These inhibitors reduce the production of UDP-GlcNAc, which is a potent oncometabolite that contributes to cancer primarily through O-GlcNAcylation but also through production of tumor microenvironment components and modulation of cell surface receptor trafficking and dynamics. Importantly, complete inhibition of the HBP pathway is not required, rather, significant therapeutic benefits can accrue from even modest levels of inhibition that normalize flux to levels found in healthy cells. To date, a panel of ~10 inhibitor candidates have been designed, with lead candidate G2Bz emerging after in vitro characterization in pancreatic and glioblastoma cells, and pilot in vivo studies. Through targeting a near universal metabolic change in cancer, HBP inhibitors hold potential for widely treating all types of this disease.
Value Proposition:
· Novel approach to ameliorating the cancer driving properties of the near-universal Warburg effect
· Flexible design for additional novel inhibitors utilizing hexosamine template
· Broad treatment potential for all types of cancer
· Applicable as stand-alone treatment or alongside current standard of care therapies
Looking for Partners to: Develop & commercialize the technology as a novel treatment strategy in cancer to normalize glucose metabolism.
Stage of Development: Pre-Clinical
Data Availability: In vitro characterization, in vivo pilot studies initiated
Inventors: Kevin Yarema, Christopher Saeui, Alfredo Quinones-Hinojosa, Sagar Ramesh Shah
