Grant: Project Grant

The human enzyme geranylgeranyl pyrophosphate synthase (GGPPS) is responsible for the biosynthesis of the metabolite geranylgeranyl pyrophosphate (GGPP), which plays an important role in activating proteins involved in cancer progression. Recent biochemical studies have shown that GGPPS plays a leading role in the physiology of many cancers that are resistant to most of the current chemotherapeutic drugs, including acute myeloid leukemia (AML). AML is one of the most difficult-to-treat blood cancers with only approximately 23% of adult patients surviving 5 years post-treatment. Additionally, AML patients with TP53 mutations have very poor outcomes, with media overall survival of 6-9 months. The TP53 gene is a tumor suppressor gene, which is the most frequently mutated gene in many human cancers, including AML, and its mutations are generally associated with resistance to chemotherapy and much lower rates of survival. Our group has discovered novel compounds that selectively inhibit the GGPPS enzyme and as a consequence, block the proliferation of AML cells, with either a normal or a mutant TP53 gene. We are asking for funding from CIHR to further optimize our compounds and validate our findings in well-studied AML animal models. The outcome of the proposed studies can lead to the discovery of novel clinical candidates that may have a profound impact on the treatment of patients with AML, including patients with 'high-risk' TP53-mutant AML.