DD-04PENAO: A POTENT MITOCHONDRIAL TARGETED INHIBITOR FOR GLIOBLASTOMA

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2014-11, Vol.16 (Suppl 5), p.v60-v61
• Main Authors: Chung, Sylvia, Decollogne, Stephanie, Luk, Peter, Shen, Han, Ha, Wendy, Day, Bryan, Stringer, Brett, Hogg, Philip, Dilda, Pierre, McDonald, Kerrie
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou246.4

PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a promising new treatment for glioblastoma patients and is currently in Phase-I clinical trial testing. PENAO selectively targets cancer-specific mitochondrial metabolism by binding to the inner-mitochondrial membrane protein adenine nucleotide translocase. This results in mitochondrial membrane pore transition and reactive oxygen species (ROS)-related cell death. PENAO, as a monotherapy, has shown potent efficacy however we have recently found significant synergism with PENAO and the blocking of glutathione. In a panel of 13 glioblastoma cell lines, including both commercial and primary patient-derived lines (from both primary and recurrent tumours), PENAO demonstrated marked anti-proliferative activity with IC 50 values ranging from 0.3-4.5 µM. This was up to 50 and 23-fold more specific than for normal MRC5 lung fibroblasts and astrocytes, respectively. Moreover, PENAO was 440-fold more potent than temozolomide, the frontline chemotherapeutic used clinically for glioblastoma. PENAO efficacy was recapitulated in-vivo in glioblastoma mice models. Administration of PENAO (3mg/kg/day) in mice bearing subcutaneous glioblastoma xenografts resulted in a significant inhibition of tumor size (7 partial and 3 complete responses), as well as Ki67 and TUNEL staining showing that PENAO significantly induced tumor growth arrest and death, respectively. Pharmacokinetic analysis demonstrated that PENAO readily crossed the blood-brain-barrier and accumulated specifically in tumor tissue. There were also no signs or symptoms of treatment toxicity. As PENAO induces cytotoxic ROS in glioblastoma cells, we hypothesized that inhibitors of the glutathione system would synergise with PENAO. Combining the glutathione inhibitor, sulfasalazine with PENAO, resulted in significant synergy (up to 93% increase in cell death) in all lines tested. Additionally, concomitant treatment with inhibitors of ABCC1/2 transporters and glutathione synthesis increased the efficacy of PENAO by up to 472-fold. Together these in-vitro and in-vivo models of glioblastoma show that PENAO is a highly promising new therapeutic for glioblastoma, alone or in combination with glutathione inhibition.