Amongst the different cancer types afflicting the US population, glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. With about 8,000 new cases per year, representing only about 2% of new cancer patients, this disease benefits from an Orphan drug designation. Also, new therapies are needed to prolong patients' survival. New therapies based on novel mechanisms of action or inhibiting new biological pathways are required to improve cancer patients' survival. The Warburg effect, the higher rate of glucose metabolism of cancer cells was identified as a potential cancer target many decades ago. PFKFB3 is a key enzyme involved in the glycolytic pathway and is also required for tumor growth in animal models. Thus, inhibiting PFKFB3 may prove to be a useful strategy for the development of novel anti-neoplastic agents targeting the energy needs of cancer cells. Advanced Cancer Therapeutics (ACT), in collaboration with Jason Chesney, MD, PhD, at the Brown Cancer Center, University of Louisville, KY, who validated preclinically PFKFB3 as a potential cancer target, proposes to complete the characterization of PFK-015 in GBM preclinical models. PFK-015, is a potent inhibitor of PFKFB3, and preliminary results in a U87GM xenograft model have shown that PFK-015 has comparable activity to Temozolomide and that PFK-015 crosses the blood brain barrier. The work proposed in this application encompasses 1) completion of the in vitro characterization of PFK-015 by screening its activity in 7 glioblastoma cell lines and synergies with Temozolomide; 2) characterization of the PK profile of PFK-015 in mice including determining brain and plasma levels; and 3) tumor growth inhibition studies in several orthotopic models. Positive results in the studies described above would warrant additional preclinical studies (i.e. efficacy, toxicology) in order to determine if PFK-015 should undergo IND enabling testing to initiate a Phase I study in GBM cancer patients.
Public Health Relevance: Amongst the different cancer types afflicting the US population, glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. While it constitutes only approximately 2% of all new cancer patients, with about 8,000 new cases per year, new therapies are clearly needed for this disease that benefits from an Orphan drug designation. This application proposes to investigate the use of a novel class of anticancer agents in GBM preclinical models. PFKFB3 is a protein involved in the glycolytic pathway and commonly over expressed in many cancers (pancreatic, lung, breast, brain, ovarian...) including glioblastomas. Preliminary results obtained with PFK-015, a potent inhibitor of PFKFB3, in a glioblastoma xenograft model have shown that it has tumor growth inhibition activity comparable to that of Temozolomide, the drug currently used as first line therapy for the treatment of glioblastoma multiforme. Furthermore, PFK-015 inhibits glucose uptake by tumors as shown by PET imaging and crosses the blood brain barrier. In this application, additional PK and in vitro experiments will be done to further understand the properties of PFK-015 and determine if it has synergy with Temozolomide. Efficacy studies in several glioblastoma models will be performed, including combinations studies. A therapeutic agent based on a novel mechanism of action that would have activity as a single agent and synergies with the compound currently used as first line therapy would be extremely valuable and cancer patients would tremendously benefit from such an opportunity.
Public Health Relevance Statement: Amongst the different cancer types afflicting the US population, glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. While it constitutes only approximately 2% of all new cancer patients, with about 8,000 new cases per year, new therapies are clearly needed for this disease that benefits from an Orphan drug designation. This application proposes to investigate the use of a novel class of anticancer agents in GBM preclinical models. PFKFB3 is a protein involved in the glycolytic pathway and commonly over expressed in many cancers (pancreatic, lung, breast, brain, ovarian...) including glioblastomas. Preliminary results obtained with PFK-015, a potent inhibitor of PFKFB3, in a glioblastoma xenograft model have shown that it has tumor growth inhibition activity comparable to that of Temozolomide, the drug currently used as first line therapy for the treatment of glioblastoma multiforme. Furthermore, PFK-015 inhibits glucose uptake by tumors as shown by PET imaging and crosses the blood brain barrier. In this application, additional PK and in vitro experiments will be done to further understand the properties of PFK-015 and determine if it has synergy with Temozolomide. Efficacy studies in several glioblastoma models will be performed, including combinations studies. A therapeutic agent based on a novel mechanism of action that would have activity as a single agent and synergies with the compound currently used as first line therapy would be extremely valuable and cancer patients would tremendously benefit from such an opportunity.
NIH Spending Category: Brain Cancer; Brain Disorders; Cancer; Neurosciences; Orphan Drug; Rare Diseases
Project Terms: 6-Phosphofructokinase; Advanced Malignant Neoplasm; Animal Model; Animals; Antineoplastic Agents; Astrocytes; base; Biological; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast; cancer cell; Cancer cell line; Cancer Center; Cancer Patient; cancer type; Cell Line; Cells; chemotherapeutic agent; Clinical; Collaborations; combinatorial; Data; Development; Diagnosis; Disease; Doctor of Philosophy; Dose; Drug Kinetics; Enzymes; Female; Glioblastoma; glucose metabolism; glucose uptake; Glycolysis; Hour; Human; Human Cell Line; Hypoxia; Image; Imaging Techniques; Implant; improved; In Vitro; in vivo; inhibitor/antagonist; Inhibitory Concentration 50; Injection of therapeutic agent; Lung; Malignant neoplasm of pancreas; Malignant Neoplasms; Modeling; Mus; Names; neoplastic; novel; novel strategies; novel therapeutic intervention; Orphan Drugs; outcome forecast; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; phase 1 study; Plasma; Population; Positron-Emission Tomography; Pre-Clinical Model; preclinical study; Process; Program Development; Property; Proteins; Publishing; research study; Sampling; Screening procedure; Small Business Innovation Research Grant; small molecule; Solid; Staging; temozolomide; Testing; Therapeutic; Therapeutic Agents; therapy development; Time; Tissues; Toxic effect; Toxicology; tumor; tumor growth; tumor xenograft; U251; Universities; uptake; Warburg Effect; Work; Xenograft Model; Xenograft procedure
