Abstract 4715: A novel small molecule with both anti-angiogenic and anti-tubulin mechanisms of action as an oral treatment for glioma

Abstract

Abstract FLAG-003 is a novel small molecule (molecular weight of 283) that has been designed as a bi-functional compound exhibiting both anti-angiogenic and anti-tubulin effects. Binding studies have been performed to fully elucidate the mechanisms of action. The compound exhibits a selective inhibition of EGFR, VEGFR-2 and PDGFR-ß kinase activity only. The anti-tubulin activity is achieved by selective binding to the colchicine site on tubulin, thereby inhibiting tubulin proliferation. Preclinical data from the NCI 60 cell line panel showed tumor cell inhibition in the 10-50 nM range across a wide variety of cell lines. Early MTD studies suggested the possibility that this molecule could cross the blood brain barrier (BBB). Although preliminary animal studies demonstrated potent activity in triple negative breast cancer and NSCLC models, DMPK studies suggested an ability to penetrate tight junctions and showed high levels of brain penetration so a glioma model was considered. Animal studies with 3 different glioma strains demonstrated the ability to shrink established glioma tumors located in the flank or in the brain following IP injections. Brain cancers are typically unresponsive to most chemotherapeutics, with the exception of alkylating agents. This is likely due due to their small molecular weight and ability to penetrate the BBB but the utility of alkylating agents to treat gliomas are predominantly limited to those tumors with a damaged (methylated) MGMT (methyl guanidine DNA methyltransferase) gene. Tumors with inactivated MGMT genes are susceptible to treatment with temozolomide (TMZ) but this only represents approximately 30% of all glioma patients. MGMT repairs damage caused by alkylating agents and patients with an intact MGMT gene who are administered TMZ (an alkylating agent) fair no better clinically that those patients who are untreated. These 70% of glioma patients with active MGMT genes have no current approved therapy beyond surgery and radiation therapy and therefore represents a huge unmet medical need. Several new treatments have centered around ways to inactivate the MGMT gene and make TMZ therapy more effective, rather than seek new agents that are more effective in treating more glioma patients. This new class of dual-acting molecules exhibits their cytotoxic effect via tubulin inhibition rather than via alkylation and therefore may be applicable in treating all glioma patients without regard to their MGMT status. Preclinical DMPK studies have demonstrated the target selectivity and brain penetration attributes necessary to warrant further development. The molecule demonstrates oral bioavailability in three animal species and the pharmacokinetic properties lend themselves to daily dosing. Therefore, FLAG-003 is a viable candidate to progress into clinical trials and test in patients as a possible therapy for the treatment of glioma. Citation Format: Frank L. Sorgi, Aleem Gangjee. A novel small molecule with both anti-angiogenic and anti-tubulin mechanisms of action as an oral treatment for glioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4715.