Abstract 5516: A cell penetrating c-Myc inhibitory polypeptide accumulates in brain tumors in rats and inhibits tumor growth

Abstract

Abstract Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. The current treatment strategy for patients with GBM includes surgery combined with chemotherapy and radiation therapy. However, even with aggressive treatment, survival is poor. Chemotherapy is limited by the resistance of the tumor cells to chemotherapeutic agents and by poor penetration of many drugs across the blood brain barrier (BBB). Therefore, alternative treatment strategies that can penetrate into tumor cells and kill them or slow their growth are necessary. c-Myc mRNA expression has been detected in as high as 78 % of human GBMs, and recently, c-Myc expression was found to be further elevated in glioma cancer stem cells relative to non-stem glioma cells. Wang et al. (2008) reported that knockdown of c-Myc expression in glioma stem cells induced cell cycle arrest, inhibited proliferation, and prevented tumorigenicity in mice. Our lab has generated a peptide inhibitor of c-Myc fused to a thermally responsive biopolymer, and we have previously shown that this therapeutic polypeptide is efficacious against breast cancer cells both in vitro and in vivo. This polypeptide is composed of 3 domains: a cell penetrating peptide (CPP), which enhances cellular uptake across the plasma membrane, an Elastin-like polypeptide (ELP), which is thermally responsive and can be thermally targeted to the site of a solid tumor, and a c-Myc inhibitory peptide (H1), which blocks c-Myc / Max interaction and transcriptional activation. Based on the previous results of c-Myc inhibition in GBMs and on the encouraging results obtained with CPP-ELP-H1 in breast tumor models, we hypothesized that CPP-ELP-H1 would be an effective means of targeting and inhibiting GBM proliferation. To test our hypothesis, we used the rat glioma cell line C6, which is a highly aggressive cell line that forms GBM - like tumors when implanted intracerebrally in rats. Three CPP-ELP polypeptides were constructed using the Bac, Tat, and SynB1 CPPs, and the brain tumor deposition was determined for each. Also, the potency of each CPP-ELP fused to the H1 peptide was determined in vitro. Based on these results, the lead polypeptide, Bac-ELP-H1, was assessed for the ability to reduce tumor size and / or slow tumor growth in both subcutaneous and intracranial C6 tumors in vivo. All CPP-ELP polypeptides were found to naturally accumulate in the tumor relative to normal brain, and the CPPs enhanced tumor uptake relative to ELP control. Bac-ELP-H1 was the most potent inhibitor of C6 cells in vitro. A single IV bolus dose of 65 mg/kg Bac-ELP-H1 was sufficient to induce complete regression of subcutaneous C6 tumors, and a single IV bolus of 100 mg/kg Bac-ELP-H1 slowed the progression of intracranial C6 tumors. These results support the use of the ELP-fused c-Myc inhibitory peptide, either alone or in combination with classical chemotherapeutic agents, for the therapy of GBM. 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 5516.