Abstract 5598: KX02, a novel therapeutic for glioma

Abstract

Abstract Objectives: Over 20,000 new cases of primary malignant brain tumors are diagnosed each year in the United States. Even with aggressive therapy 13,000 deaths are estimated to be attributed to these tumors. Few therapeutic agents are capable of effectively penetrating the blood-brain barrier. Fewer still are capable of selective molecular targeting. KX02 (Kinex Pharmaceuticals) is a synthetic, orally bioavailable, novel small molecule microtubule polymerization inhibitor with very high CNS penetration. In this study the efficacy of KX02 as a novel anti-cancer agent was tested directly using a mouse model of malignant glioma. Methodology & Results: The orthotopic GL261 glioma model in immune-competent, syngeneic C57BL/6 mice was used to evaluate KX02. Mice implanted intracerebrally with 1×105 GL261 cells treated with vehicle alone (saline) have a median survival time (MeST) of 21 days (range 18-28). Mice treated by oral KX02 (30 mg/kg, b.i.d.) have a MeST of 30.5 days ranging 23-32 days. In contrast, when KX02 is given orally at (30mg/kg, s.i.d.) the MeST increases to over 120 days, with more than 60% of the treatment group still alive 12 months later (p<0.0001). Specimens from these mice also showed lymphocytic infiltration of the tumor site. Further experiments were performed using immunocompromised mice (lacking functional T and B cells) on a C57BL/6 genetic background (B6.CB17-Prkdcscid/SzJ). These immunocompromised (SCID) mice bearing GL261 intracerebral tumors and treated with vehicle alone had a similar survival as the immune-competent C57BL/6 counterpart, however mice treated with KX02 now only had a MeST of 40 days (range 29-75). Interestingly, immunocompromised mice surviving longer than 45 days all progressed to develop lethal GL261 gliomas (observed by MRI) shortly after drug was discontinued. Long term survivor C57BL/6 mice from the immune-competent group also subsequently rejected a second GL261 tumor implant challenge, consistent with generation of productive immune memory. Additional molecular studies using cultured GL261 cells show that KX02 increased expression and altered the localization of intracellular survivin, a molecule that can be targeted by immunotherapy. Conclusions: The results of five independent studies indicate that KX02 slows the growth rate of intracerebral GL261 glioma relative to control groups. When given as a single dose per day (s.i.d.) KX02 led to complete tumor regression in up to 60% of treated mice without further progression. The subsequent rejection of a second tumor in these mice is indicative of immune memory. This magnitude of anti-tumor effect was not observed in the immunocompromised mice, suggesting that the once-daily dosing regimen with KX02 permits the generation of an effective immune response that contributes to long-term cures. Based on these data, further study of KX02, specifically in the treatment of brain cancer is clearly warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5598.