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Bridging Interventional Development Gaps

Inhibitors of Glutaminase 2 as Therapeutic Agents for Neuro-Oncological Diseases and Celiac Sprue

Neuro-oncological diseases, such as glioblastoma multiforme (brain cancer), sometimes called meningioma, can start from brain cells, the membranes around the brain (meninges), nerves or glands. Tumors can directly destroy brain cells. They also can damage cells by producing inflammation, placing pressure on other parts of the brain and increasing pressure within the skull. It is estimated that more than 14,000 people will die from brain and other nervous system cancers in 2014. This new experimental drug blocks the action of an enzyme called transglutaminase 2, which is believed to play an important role in neuro-oncological diseases.

Scientific Synopsis

Transglutaminase 2 (TG2), an extracellular enzyme found in many organs, catalyzes the formation of protein-protein crosslinks in the extracellular matrix. It is believed to play an important role in the pathogenesis of diverse human disorders, including certain neuro-oncological diseases and celiac sprue. The medicinal attractiveness of this protein target is underscored by the observation that TG2 knockout mice lack developmental, physiological or reproductive defects. A lead compound, KCC009, has been evaluated as an inhibitor of human TG2 and shows considerable promise as a chemo-sensitizing and radio-sensitizing agent for the treatment of glioblastomas, meningiomas and melanomas.

Preliminary data also suggest that orally administered KCC009 may have suitable pharmacokinetic and pharmacodynamic features for treating celiac sprue. This proposal seeks support from the program to evaluate the therapeutic utility of KCC009. Specifically, we propose to test whether TG2 inhibition selectively sensitizes glioblastomas, meningiomas and melanomas to chemotherapy with an alkylating agent and/or radiation therapy.

Lead Collaborators

Stanford University, California
Chaitan Khosla, Ph.D.

Washington University School of Medicine, St. Louis
Keith M. Rich, M.D.

Public Health Impact

Given the large and growing body of data that implicates TG2 in the pathogenesis of several unmet medical needs, including neuro-oncological diseases, such as glioblastoma multiforme, meningioma and metastatic melanoma, and inflammatory diseases of the small intestine, such as celiac sprue, the availability of an experimental therapeutic agent has enormous potential for impact at an exceptionally broad level. Moreover, based on available data from TG2 knockout mice as well as multiple dosing studies with KCC009 in rodents, this mode of therapy appears to have attractive safety considerations.

Outcomes

Work on this project is complete.

Project Details

  • Synthesis of Good Manufacturing Practice (GMP) material
  • Development of an IV and oral formulation
  • Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
  • Investigational New Drug (IND)-directed toxicology
Last updated: 07-25-2017
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